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When we bought Te Ana Lodge in 2004, the house had been a rental property for 10 years. It had been moved to the Coromandel at least 20 years earlier by someone called Miller and had been partially renovated by previous owners.
One day in 2005 our tenant broke the news that she was moving out and we decided to start renovating. It was no easy task. First we had to clear all of the old furniture and junk left by the last ten years of tenants.
There was some building work to be done in each room. Two rooms had creaky wooden wardrobes fixed into the wall studs, with gib board fitted around them. The end of the house had a sunroom and its floor sloped three inches over a distance of ten feet.
As we were pulling it up we noticed newspapers had been laid underneath - not just pages but entire newspapers. The date on the first one was 16 October 1924. There was a name scribbled on the front cover by the paper boy: Miss Wishart. Who could she be? And how many more papers were under there?
There were 26 in all, counting the supplements. There was no more renovating that day. We sat and read them all and marvelled at how much the world had changed since those days.
The black-and-white photographs hadn't lost any of their clarity in their time hidden under the floor. There were New Zealand Heralds (some with photo supplements) and Daily Stars, the newspapers themselves all columns of text apart from enormous adverts in the middle sections.
There was one article about a man who was arrested by police in Auckland after throwing a block of wood over a hedge in a city park - it landed on the ground in front of a gentleman and his wife who were sitting on a park bench. They called the police and the culprit was fined one pound after admitting to the crime.
There were photographs of the All Blacks' 1924 tour of the UK, the royal family, Zeppelins - the new mode of transport - a tram crash in Queen Street, Auckland.
There was a story about a mounted police sports event at Ilford in England, the policemen riding their horses with balloons on their heads, trying to clobber their opponent's balloon! Wouldn't Monty Python have loved this?
There were sections of land for sale on Waiheke Island from 35 pounds, payable at no interest for one pound per month.
I called the Herald and asked if these newspapers were worth anything. They explained that they weren't, because a copy is kept in the archives of every edition ever printed and anyone can go in and read them.
They did tell me however that memorabilia collectors might offer something for the papers containing photos of the All Blacks, royal family etc.
I prefer to hang on to them and we are considering allowing guests to read them if they ask - as long as they don't trash them.
My question to all other bach owners is, 'Have you had a look under your lino recently?' I think it might have been a common thing to insulate floors from draughts in the days before heat pumps.
We would love to know who Miss Wishart was/is and where the house was from originally but we may never find out.
By Kingsley Burn


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We Still Have room for Sellers at our Annual Artist's Yard Sale!
Calling all artists! Here's an opportunity for you to clean out your art studios and sell all your excess art supplies and artwork. On Saturday June 15, 2019 from 9 am to 2 pm the Falmouth Art Center is holding its annual Artists' Yard Sale. Sign up to sell your excess art supplies such as paints, canvases, craft supplies, artwork, brushes, books, frames, easels, crafts and so forth. To participate in the yard sale, you may rent a table from the Art Center or bring your own and pay a lower fee. You keep ALL the profits from your sale-it's that easy!
$30.00 to rent a table
$20.00 to bring your own table
To sign up, call the office at 508-540-3304. Reserve your space early! Space is limited and table locations will be determined by the Art Center on a first come, first serve basis. We ask participants to plan on being at the Art Center for the full length of the yard sale (9-2).

subset: commoncrawl


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This rice pudding takes significantly less time than its baked counterpart, although still longer than most of my other recipes. Next time I'll make a triple batch then portion it out and store it in the fridge for later use. You also have to be careful not to let it boil over, so it requires constant supervision. I got distracted and mine boiled over twice
Ingredients – serves 2 generously
100g long grain rice, not easy cook
800ml soy milk
1 tsp organic vanilla powder
2-4 tsp brown sugar or sweetener of choice, optional
Splash of soy milk to serve, optional
1. Put the rice and a little over half the soy milk into a heavy bottomed saucepan. Bring to the boil then simmer for 15 min, ensuring it doesn't boil over. The rice will cook and swell and the liquid will thicken somewhat.
2. Add in all of the rest of the ingredients and bring to a rapid boil, stirring all the time. Stirring breaks up the rice grains and thickens the mixture more, 7 minutes later you should be done. If u want it smoother you could use a stick blender, or add a bit more liquid and cook until everything dissolves.
Serve immediately


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Property for sale in Geresdlak - Hungary
- $ 520 000 ( $ 2 736 / sq m )
- Single-Family Home For Sale
- Bedrooms 4
- Bathrooms 2
- Rooms 5
- Floor area 190 sq m
- Lot size 1 165 sq m
- Total square 270 sq m
- Year of build 1981
- Facing South
We offer for sale this two-storey, 190m2 sized, brick-built family house in a 1165 m2 plot. Wonderful, big bright places are in the upper and the lower levels.
Coming into the second floor, there is a corridor, from where you can enter into a 15,6m2 and a 13,6m2 sized bedrooms. The corridor leads to the kitchen with a dining-room, and a living-room with a balcony, with a beautiful view. From the living-room opens a 11,23 m2 sized room, and from the dining-room you can reach the bathroom with a toilet, the staircase and a back entrance as well.
The bedrooms have fitted carpet, the living room has parquet and the other rooms have tiled floor.
You can built the loft in, there is also a balcony.
In the ground floor there is a 26,6 m2 sized garage with an inspection pit. In the garage there is a gas heating boiler, which heats the entire house. Going further, you get to a 20,8 m2 sized room, which is now used as a workshop and a mixed heating boiler is located also here.
Going forward you can find a 18,3m2 sized kitchen, from where open a bath-, and laundry-room, a chamber and a 17,6m2 sized, very bright room. You can also find here the staircase, which leads to the second floor.
The doors and windows are made of double wood, equipped with shutters. The warm of the house is provided by the unique mixed and gas heating furnace. The house is connected to the industrial power.
The building is ideal for two generation, because the separate entrance is resolved.
To the house belongs to an outhouse and a railed off space where you can keep poultry.
In the yard you can find a cellar, where you can store vegetables, fruits, and vine and there is a nice garden, filled with beautiful flowers, and fruit trees, which is an entertainment for all ages.
- View: Mountain
- Listing status: Active
- Available from: Aug 17, 2016
- Listing #: 12916
- Construction type: Masonry
- Parking: 2 Cars
- Parking type: Garage attached
- Heating System: Other
- Fireplace: Gas
- Broadband Internet
- Electricity
- Gas
- Hot water
- Telephone
- Trash
- TV Cable
- Water
General facilities
- Attic
- Balcony
- Basement
- Disabled access
- On the ground floor
- Porch
- Satellite
Indoor facilities
- Bathroom with shower
- Bathroom with tub
- Bathroom with window
- Fitted kitchen
- Freezer
- Furnished
- Washing machine
- Wood flooring
Outdoor facilities
- Barbecue area
- Courtyard
- Garden
Latitude / Longitude: 46.105267 / 18.529280
|Nearest airport
|200 km
|Nearest beach
|20 km
|Nearest childcare
|200 Meters
|Nearest restaurant
|300 Meters
|Nearest school
|500 Meters
|Nearest train station
|30 km
Geresdi dombság, and the Mecsek has a unique beauty, and the town is a favorite tourist destination.
If you would like more information or pictures, please contact me to this email address:


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Log In needed $15,493 · 2013 Harley-Davidson® V-Rod® V-Rod Muscle®Report Ad
MakeHarley Davidson
Price: $15,493
Stock Number: U13-805528
Doc Fee: $495
*Easy financing available
*Zero Down Available
All Prices Do Not Include Taxes. Financing Available And Trade In's Are Always Welcome. Freight / PDI & Doc Fee Included.
For Your Convenience, Take Delivery Of This Motorcycle At Any Of Our Barnes Harley Davidson Langley, Victoria or Kamloops Locations. Ask Today.
We Are Now Open 7 Days A Week!
Stock Number: U13-805528
Motor Dealer License Number: 8594
2013 Harley-Davidson® V-Rod® Muscle®
The 2013 Harley-Davidson® V-Rod® Muscle® VRSCF motorcycle is full of power cruiser style, performance and ride enhancement features including a 'slipper' Harley® clutch. The 'slipper' motorcycle clutch ('slip and assist') is a unique Harley® clutch that provides smooth, high-power handling in turns or whenever you downshift. By reducing clutch friction, the V-Rod® Muscle® models' slipper clutch helps your rear wheel at a controlled clip. The Harley® slipper clutch also comes on the V-Rod® Night Rod Special H-D® power motorbike. In addition to the slipper clutch, the V-Rod® Muscle® model features satin chrome, dual side exhaust with turnout mufflers. Jetting out past the rear axle, these dominating motorcycle pipes add to the fierce, beefy look of the bike. This Harley® V-Rod® Muscle® motorcycle exhaust system proves that a performance exhaust can still be a beautiful set of pipes. The 240 mm wide tire in back also enhances the fat custom look of this power motorbike. Check out another Harley® V-Rod® motorbike, the Night Rod® Special model, which is also a power motorcycle cruiser.
Drag-style Handle Bars with Instrument ClusterTake to the streets in an aggressive power cruising position. With its aluminum shell cast over steel 1-inch tubing and internally-routed wiring, this angular drag-inspired bar comes on with a clean, mean and meaty attitude. The attached triple gauge cluster-bold, sleek and easy-to-read mph, rpm and fuel gauges-is our distinct take on custom performance.
Revolution® Engine HeritageFrom the Strip to the Street. Harley-Davidson® has a passion for performance that is rooted in decades of racing and winning championships. So when The Motor Company set out to produce a high-powered,
Ad #32431296
PostedOctober 07, 2018
ExpiryJanuary 05, 2019
DetailsCommercial Seller
CategoryAutos › Motorcycles
EditMy ad
SellerBarnes Harley-Davidson Victoria
PhoneNot available
|Last hour
|Last 24 hours


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|Helen Hunt and John Hawkes
Written and directed by: Ben Lewin
Starring John Hawkes, Helen Hunt and William H. Macy
Based on a true story. That sentence, so often found flashing across movie trailers and posters, usually signifies an inspiring tearjerker that will tug at your heartstrings as it works its way up the red carpet to the Academy Awards.
However, while The Sessions does have moments that will leave you reaching for the tissues, it's also a gentle comedy that touchingly delves into the most basic of human desires.
Mark O'Brien (John Hawkes) was diagnosed with polio at the age of six and, as a result, must spend the majority of his days enclosed in an iron lung. For those few blissful hours where he is allowed to leave his prison, he's wheeled around town by a string of caretakers. However, Mark, who went on to become a successful essayist and poet, desired a sort of physical contact that many often take for granted.
The film, based on a 1990 article Mark wrote titled "On Seeing a Sex Surrogate", focuses on his quest to lose his virginity at the age of 38. A devout Christian, Mark grapples with his religious conscience and his desire for a physical act that is deemed a mortal sin. In an attempt to come to terms with his inner turmoil, Mark regularly visits a local priest (William H. Macy) to unburden himself. After several meetings, Mark admits his desire for sexual fulfillment and his priest, in one of the standout moments in The Sessions, gives his blessing to Mark with a simple, "In my heart, I feel He will give you a free pass on this one. Go for it."
And go for it he does. He hires Cheryl (Helen Hunt), a sex surrogate who is assigned to six sessions with Mark. Her goal: To not only help him in his quest to lose his virginity but to help him find comfort with his own body and sexuality. Quick to brush off any association with prostitution, Cheryl is a sex therapist who also happens to take off her clothes in order to help heal her clients. The restriction to six sessions is to prevent therapist and client from becoming too involved with one another. It's a quick and effective way to cut the strings.
Hawkes is a likely Best Actor nominee shoo-in at the Oscars this year. Speaking in a higher voice and contorting his body, Hawkes is only able to use his face to convey his emotions. A versatile actor who has really come into his own in the last five years, the Oscar nominee gives arguably his finest performance to date. Hawkes doesn't make Mark a character to be pitied -- he's to be admired for his strength of character, minus the cliched trappings of many films that revolve around a person living with a disability.
Hunt returns to the silver screen after a self-imposed hiatus and she's back in full force -- just as likable and charming as ever. One of the flaws of The Sessions is the manner in which it glosses over Cheryl's life. It stands back from her rocky marriage and forces the audience to watch from a distance. How does her career choice affect her marriage? And why does she fall so hard for Mark? What is it that is missing from her life? All of these questions, and more, are left unanswered yet, thanks to Hunt's quietly commanding performance, you're still drawn into Cheryl's story.
The screenplay, written by director Ben Lewin, is a little all over the map -- changing narrative point-of-views that leave the film feeling like detached fragments and vignettes. However, The Sessions is ultimately buoyed by the two standout lead performances. You only wish you had more sessions in which to spend with them.


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Alabama CD, Southern Drawl. Release date September 18, 2015!
*Track listing:
1. ) Southern Drawl
2.) Wasn't Through Lovin' You Yet
3.) This Ain't Just a Song
4.) As Long As There's Love
5.) Back to the Country
6.) Hillbilly Makes a Lotto Money
7.) Come Find Me
8.) No Bad Days
9.) One On One
10.) American Farmer
11.) It's About Time
12.) Footstompin' Music
13.) I Wanne Be There


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Hart Health Strategies provides a comprehensive policy briefing on a weekly basis. This in-depth health policy briefing is sent out at the beginning of each week. The health policy briefing recaps the previous week and previews the week ahead. It alerts clients to upcoming congressional hearings, newly introduced bills, regulatory announcements, and implementation activity related to the Patient Protection and Affordable Care Act (PPACA) and other health laws.
- Senate Reauthorizes FDA User Fee Programs
- Where Health Care Reform Stands
- VA Choice Bill Sent to the President's Desk
- Durbin Comments on Opioid Quotas
- Upcoming Congressional Meetings and Hearings
- Recently Introduced Health Legislation
- Recently Introduced Health Legislation Cont.
Senate Reauthorizes FDA User Fee Programs
The Senate also successfully passed the Food and Drug Administration Reauthorization Act (FDARA) last week. H.R. 2430 extends for five years the FDA's authority to collect $400 million in user fees from drug and medical device companies to fund the new product approval process. The bill passed by a vote of 94-1, with Sen. Bernie Sanders (I-Vt.) being the only lawmaker to vote against the bill. As a part of a deal to secure passage of FDARA, the Senate also passed the Trickett Wendler Right to Try Act (S. 204) by unanimous consent. The Right to Try Act would increase access to experimental drugs for terminally ill patients. The bill's sponsor, Ron Johnson (R-Wis.), had previously said that he would oppose FDARA if the Right to Try language was not included. The policy is strongly supported by Vice President Pence. FDA user fee programs faced a September 30 deadline for reauthorization. The House previously passed FDARA on July 12. FDARA now heads to the President to be signed into law.
Where Health Care Reform Stands
Leadership on both the Senate Finance Committee and Senate Health, Education, Labor, and Pensions (HELP) Committee announced that they would hold hearings on health care reform following August recess. HELP Committee hearings will begin the week of September 4, and will focus on stabilizing the insurance market. Witnesses will include state insurance commissioners, patients, governors, health care experts, and insurance companies. Chairman Lamar Alexander (R-Tenn.) stated that he has discussed a bipartisan market stabilization bill with his panel. He also supports the continuation of cost-sharing reduction payments by the President through September, followed by a yearlong appropriation by Congress.
The President and Secretary of the U.S. Department of Health and Human Services (HHS) met with Sen. Bill Cassidy (R-La.) last week to discuss his proposal to give block grants to states in an amount equal to what the federal government currently spends on the Affordable Care Act (ACA). In the House, a bipartisan group of lawmakers are discussing a health care reform plan that would pay for cost-sharing reduction payments, alter the law's employer mandate, and eliminate the impending tax on medical devices. Members on both sides of the aisle, along with stakeholders and experts, agree that cost-sharing reduction payments are necessary to ensure stability in the individual marketplace. The talks are led by Rep. Josh Gottheimer (D-N.J.) and Rep. Tom Reed (R-N.Y.).
Senate leadership continues to stress that it will not bring up health care legislation again until they can guarantee 50 votes, but state that health care reform proposals continue to be scored at the Congressional Budget Office (CBO).
VA Choice Bill Sent to the President's Desk
The Senate cleared legislation to fund the Veterans Choice Program last week. S. 114 will provide $2.1 billion to continue funding the program, which was projected to run out of money in mid-August. The bill passed the House of Representatives last month. The Department of Veterans Affairs also announced the creation of three programs aimed at modernizing health care for veterans. Veterans will have access to a new a new scheduling system via mobile phones, as well as additional care for the homebound. The $1 billion budget for telehealth will remain the same.
Durbin Comments on Opioid Quotas
Sen. Dick Durbin (D-Ill.) has asked the Acting Administrator of the Drug Enforcement Administration (DEA) to lower the quota for the number of opioids allowed to be produced and sold in the U.S. in 2018. He hopes reducing the quota will reduce the number of people who are addicted to and overdose from prescription painkillers.
December 31, 1969: | Page 1 Page 2 Page 3
- Strategy & Planning
- Information & Counsel
- Washington Presence & Influence
- Materials Development
- Grassroots Advocacy
- Partnership & Coalition Building
- Communications
- 2019
- - May 2019
- + April 2019
- + March 2019
- + February 2019
- + January 2019


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Home | News & Events | Events | 2009 Events | NISO Webinar: SSO Authentication | Questions and Answers
SSO Authentication Webinar Q&A
Below are listed questions that were submitted during the NISO Single Sign-On Authentication
Webinar. Answers from the presenters will be added shortly. Not all the
questions could be responded to during the live webinar, so those that could
not be addressed at the time are also included below.
Feel free to contact us if you have any additional questions about library, publishing, and technical services standards, standards development, or if you have have suggestions for new standards, recommended practices, or areas where NISO should be engaged.
Single Sign-On Authentication: Understanding the Pieces of the Puzzle
Webinar Questions & Answers
February 11, 2009
- Question: Hi Adam, On the first slide you mentioned the proxy server solution and only mentioned EZProzy. We are a reseller for H+H a German software company who have build Hidden Automatic Navigator (HAN). Its does the same as EZProxy but even more. Are you aware of any US libraries using this HAN?
Adam Chandler: No, I am not. I have not heard of any US libraries using it. If it is licensed, perhaps H+H has a list of US libraries?
- Question: For Adam: How about III ILS system? WE use one of the URLs as the proxy gateway and it works fine for IP authentication. It acts as an SSO by default. Is that acceptable?
Adam Chandler: Same problem. The remote user must first go to the catalog in order to be authenticated. I am interested in a model in which the patron can start from the open web and find their way into the library's licensed content.
- Question: I am curious about what Adam's thoughts are about LibX?
Adam Chandler: I remain frustrated by the way LibX has beeb implemented. It appears nobody has built in a redirect counter to find out if patrons even use it! Installing another widget is a high threshold for most users. I doubt if they are using it much, but like I said, nobody knows.
- Question: Steve had on his slides a mention of work with federated access groups, but this received no mention. Please can all speakers talk about how these technologies work with federated search services?
- Question: How does Shibboleth work together with a local authentication system and/or with EZproxy? Could you give examples? How much work is involved in implementing and maintaining Shibboleth?
- Question: Could you explain a bit about personalization in Athens, which is not available in Proxy?
Keith Dixon: Where institutions are using the Athens service to maintain user identities, an opaque, persistent identifier is provided to publishers. Publishers can then use as the basis for providing personalization. It also provides the basis for tracking down misuse and aggregate authorization statistics, which are available to both institutions and service providers.
- Question: Where are the other campus technology providers in this discussion? Campus portals and CMS's, etc?
- Question: Hi, Karen, can you review again next steps that NISO is taking to form a Working Group? thanks
Karen Wetzel (NISO): I'm glad to help. Probably the best overview of NISO's standards process is found on NISO's Documents page: Standards Development Process: An Overview. This PowerPoint file provides a quick look at the procedural requirements surrounding ANS standards development at NISO. In brief, though: no comments were received to the draft new work item proposal on SSO Authentication that was made available as part of this webinar. The draft was distributed to the Discovery to Delivery Topic Committee at the same time; it was then reviewed March 16, 2008 and approved in Topic Committee (with a small clarification on the interest groups section). With that edit, the proposal will go to the NISO membership for their approval, which requires that a minimum of 10% of NISO's members agree to join the voting pool for the item. With that, we can then begin the work of forming a working group, finalizing timelines, and moving ahead on the proposed work. Please contact me at email@example.com if you are interested in joining the working group or interest group, if you have additional questions, or if you would like to propose new work to take place within NISO.
- Question: Concerning the federated search answers. Unfortunately, even though the techniques discussed work (we use them in some instances) it is not *allowed* by many of the authentication providers to do this.
- Question: The general tenor of the presentations and discussion is too high-level as it rather has to be. Will [further discussion] be available?
Karen Wetzel (NISO): We would be thrilled to continue this discussion; please contact me if you have any suggestions for what format you think would be best to do that in. We hope to also see a new working group on SSO Authentication be approved shortly; with that will be an opportunity to engage through that group or more informally via an interest group list. The working group will also be involved with making sure there is more opportunity within the community to discuss this topic, and your input is very welcome. In the meantime, I encourage additional resources to be sent in so we can build on this event, and if there are lists or other venues where this topic is being discussed that we can point to, I'd be happy to add those to the resources page, as well. Feel free to send me a note at firstname.lastname@example.com.


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Believe it or not, electrical wiring can be required for your swimming pool, spa or sauna for a number of purposes (including filtration and heating). The Smillie team installs wiring prior to any water being added to ensure that the process is completed as safely as possible.
It is important to note that a certain rating is required when it comes to pool wiring, spa wiring and sauna wiring – when standard wiring gets wet it shorts out, so it's not at all suitable. There are also certain restrictions in place for when and where power outlets can be installed in the vicinity of water.
This is why it is important that only qualified pool electricians handle the installation, maintenance and repair of such wiring.


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The Note on my Door
In the old days professors might tape brief notes on their office doors. Welcome to the future.
Friday, May 11, 2012
Social Media for Journalists presentation
Today I'll be presenting a talk at the Madison SPJ "Social Media for Journalists" training session.
Here's a PDF copy of the slides I'll be talking through
Posted by
Greg Downey
Friday, May 11, 2012
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text: I have zero experience with whizzer cones, other than old stereo systems I've owned that had coaxial speakers. But I know I'm pretty disenchanted with tweeters, and I'm wondering if whizzers would be an option to look into. I'm probably not concerned with anything past 12K since that's where a cable typically shelves the highs anyway, so would a whizzer make the highs less intense? So what are your opinions of bass cabs loaded with whizzers? I know EA is probably the leading maker that uses them, but I have no experience with them. I have a Markbass Mini CMD121P combo, and everything about it is perfect except the tweeter. If you've heard that amp, how would a whizzer cab compare to the tweeter and 12" in it?


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Josh Lenartowicz, 3rd place finisher at the 2016 Arnold Classic (4th at the Arnold Australia) reveals to RXMuscle.com why he has withdrawn from this year's competition. Find out why the 2016 Olympia 9th place finisher decided to take this year's competition off after drawing universal praise during his 2016 Arnold appearance. Also, Blackstone Labs gets raided by the feds, Dave fills you in on the latest. Finally, the passing of Nicole Bass, a former WWE wrestler, member of Howard
Stern's "Wack Pack," and a friend to Dave Palumbo. It's Muscle News on RXMuscle.com.
Subscribe to RxMuscle on Youtube


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12-26-14 Denver Area Winter Storm
Heavy snow fell across much of the Denver metro area last evening and caused some problems on area roadways. Drivers of small vehicles seemed to have the most trouble with traction on the snow. I-25 and 225 had seemed to have the most issues as accumulations of 3 inches plus piled up pretty quickly. Shots filmed by Max Olson of Live Storms Media.


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Somehow I *just* noticed this post--thanks so much for the write-up!
Completely agree with your points. Part of the reason I established early on that Santa is a real guy in this universe is so people would realize the whole thing was silly, and wouldn't make a serious effort to solve the "mystery".
I do hope to add in music/sound at some point, and am working on a sequel as well!


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Aye, Aye Captain!
By Morgane East
A Beginning Reading Lesson
Rationale: This lesson teaches children about the long vowel correspondence i_e = /I/. In order to be able to read, children must learn to recognize the spellings that map word pronunciations. In this lesson children will learn to recognize, spell, and read words containing the spelling i_e. They will learn a meaningful representation (a sailor saying "Aye, aye Captain") to help them remember the pronunciation, they will spell and read words containing this spelling in a Letterbox lesson, and read a decodable book that mainly contains the correspondence i_e = /I/.
-Image of a sailor saluting the captain
-Whiteboard and markers
-Elkonin boxes for modeling
-Elkonin boxes for each student
-Letter manipulatives for each student: I, i, k, e, m, t, l, p, r, s, n, d
-List of spelling words on poster board or whiteboard: Ike, time, lime, pile, rim, spine, stride
-Decodable text: Kite Day at Pine Lake
-Fun Fonix Long I assessment worksheet
Step 1: In order to become expert readers we need to learn the code that tells us how to pronounce words. We have already learned to read short vowel words with i, like bib, and today we are going to learn about long I and the silent e signal that is used to make I say its name, /I/. When I say /I/ I think of a sailor saying "Aye, aye Captain!" (show image representation). Now let's look at the spelling of /I/ that we'll learn today. One way to spell /I/ is with the letter i and a signal e at the end of the word to tell me to say I's name. (Write i_e on the board.) This blank line here means there is a consonant after i, and at the end of the word there is a little silent e signal.
Step 2: Before we learn about the spelling of /I/, we need to listen for it in some words. When I listen for /I/ in words, I hear i say its name /I/. When I say /I/ my jaw drops and comes back up, and the sides of my tongue touch the inside of my top teeth as I say /I/. (Make vocal gesture for /I/.) I'll show you first: bike. I heard i say its name and I felt my jaw drop and come back up with the sides of my tongue touching the inside of my top teeth [exaggerate motion pointing out how my jaw drops and comes back up]. There is a long I in bike. Now I'm going to see if it's in pit. Hmm, I didn't hear i say its name and my jaw didn't drop to make the /I/ sound. Now you try. If you hear /I/ in one of the words I say I want you to say, "Aye, aye Captain!" If you don't hear /I/ say, "That's not it." Is it in ripe, pain, cat, like, pin, pipe?
Step 3: What if I want to spell the word stride? "I have a small stride because my legs are short." Stride is the distance between my feet when I take a step. To spell stride in letterboxes, first I need to know how many phonemes I have in the word so I stretch it out and count: /s//t//r//I//d/. I need 5 boxes. I heard that /I/ just before the /d/ so I'm going to put an i in the 4th box and the silent e signal outside the last box. The word starts with /s/, so I need an s. Now it gets a little tricky so I'm going to say it slowly, /s//t//r//I//d/. I think I heard /t/ so I'm going to put a t right after the s. There's one more phoneme before the /I/, hmm . . . /s//t//r//I//d/, I think I heard growling /r/. I have one empty box now. (Point to letters in boxes when stretching out the word: /s//t//r//I//d/.) The missing one is /d/. Now I'll show you how I would read a tough word. (Draw attention to the list of words on the board with spine on the top and model reading the word.) I'm going to start with the i_e; that part says /I/. Now I'm going to put the beginning letters with it: s-p-i_e, /spI/. Now I'll put that chunk together with the last sound, /spI-n/. Oh, spine, like "My grandfather broke his spine."
Step 4: Now I'm going to get you to spell some words in letterboxes. We'll start out easy with two boxes for Ike. Ike is a boy name: "Ike went to the store for his mother." What should go in the first box? (Respond to children's answers). What goes in the second box? What about silent e, did you remember to put it outside the boxes? I'll check your spelling while I walk around the room. (Observe progress.) You'll need three letterboxes for the next word. Listen for the beginning sound to spell in the first box. Then listen for /I/ and remember to put the signal silent e at the end, outside the boxes. Here's the word: time, "I don't have time to go shopping today"; time. (Allow children to spell remaining words: lime, pile, rim, spine, and stride.)
Step 5: Now I am going to let you read the words you've spelled. (Have children read words in unison. Afterwards, call on individuals to read one word on the list until everyone has had a turn.)
Step 6: You've done a great job at reading words with our new spelling for /I/: i_e. Now we are going to read a book called Kite Day at Pine Lake. This is a story about a bunch of kids that go to the lake to fly their kites, but Bob is sad because he does not have a kite. Let's pair up and read the story to find out if Bob cheers up. (Children pair up and take turns reading alternate pages while teacher walks around the room monitoring progress. After individual paired reading, the class rereads Kite Day at Pine Lake aloud together, and stops between page turns to discuss the plot.)
Step 7: Before we finish our lesson about one way to spell /I/ = i_e, I want to see how you can solve a reading problem. On this worksheet, we have some words missing. Your job is to read the short passage on the left of the paper and circle the picture of words that are in the passage. First try reading all the sentences, then pictures that represent long i words from the sentences. Check your answers to make sure you only circled pictures in the story. (Collect worksheets to evaluate individual child progress.)
Assessment Worksheet:
Noie Yancey, Oh, Oh, My Knee Hurts: http://www.auburn.edu/academic/education/reading_genie/invitations/yanceybr.htm.
Unknown. Kite Day at Pine Lake. Carson, CA. Educational Insights, 1990. 8pgs.
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SlyDoggie Productions is a full service independent music production company that provides in-house management, development, and a variety of music services. Our overall goal is to help prepare artists that want to make the transition from performing as a hobby to performing professionally, and eventually go from local to national recording artists. We help coordinate the business side of being an independent artist so that our clients are free to focus on the creative side.
In today's market, labels are looking for "the complete package." We work with artists of all musical styles at every level of their career helping them grow to their fullest potential. The team of professionals at SlyDoggie Productions can help with producing a radio ready recording, music video production, professional photo shoots and more. We also develop the artist as a whole including: social media presence, gaining the attention of a record labels, image consultation, booking and prepping for shows, and most any other industry-related direction.
As a performer, you only get a few chances to make a good impression in the Industry. If the quality of work and image being displayed on your social media and at shows does not compete with national acts there is no incentive for a label to pursue you. A good development team will help shape YOUR brand and properly showcase your work to potential fans and music industry professionals. WE help our artists get the sound and image that can compete in the major market.
One conversation with Sly Doggie Productions' Christian "Davis" Stalnecker and you are instantly taken on a journey – subtle at times, boastful at others, funny, truthful, authentic, and always full of color and realism. As a songwriter and producer, Christian's unique skill sets are nothing less than an extension of his daily conversation. Lyrically, he paints metaphoric pictures that translate the emotional tug of wars experienced in life and love. The music itself is the canvas that these pictures are painted on.
As an artist Christian began his career as a baby touring the country with his family as Christian revival singers. His talent for singing continued to grow through out his youth which lead to him signing a Pop record deal with Babylon Records in the 90's. While signed Christian toured and performed with Destiny's Child, Christina Aguilera, and Backstreet Boys to name a few. After moving to Los Angeles to work on new material, Christian's writing and producing began to evolve into his strength. Artists and record labels began to request his product. This demand lead him to open his production company "Sly Doggie Productions."
Once Christian's primary focus was writing and producing the sky was the limit. Signing as a writer to Grammy award winning producer Rodney "Dark Child" Jerkins and Sony Publishing in 2008. Earning himself a Grammy nomination in 2012 for R&B Album of the Year for El Debarge's "Second Time Around." Christian has had collaborations with multiple artists and producers all over the world through his production company and independently. Currently he is enjoying being bicoastal and developing multiple new acts and sounds for 2016.
Writing is a natural gift for Christian. He often co-writes with his artists and is a master at crafting commercial hits.
Writing is a natural gift for Christian. He often co-writes with his artists and is a master at crafting commercial hits.
Christian Davis began producing records for other artists early in his career. He was born into a musical family and carries that legacy on.
Christian Davis began producing records for other artists early in his career. He was born into a musical family and carries that legacy on.
Christian Davis is a prolific artist with an extensive resume and discography.
Christian Davis is a prolific artist with an extensive resume and discography.


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Borrowell's Eva Wong: There is no better time to build tech in Toronto
Eva Wong is a first-time founder on a mission to build Borrowell into a global FinTech company. She is passionate about building businesses customer-first, and brings that passion into everything she does at Borrowell. Read on to see her global idea for tech and innovation.
How did you get involved in tech?
Looking back at my career, I had many informal touch points with tech before officially "getting into tech."
I studied Business at Queen's University, joining CIBC during my time as a student, working in their tech process engineering division. I also worked as a Microsoft Access database developer for the university during my studies.
After that, I became a Management Consultant. I worked for a few different consulting firms and eventually got my Master's of Public Administration degree. After graduating, had a couple jobs before returning to management consulting, where I worked closely with the tech industry and with many tech CEOs.
I formally got involved in the tech scene when Andrew Graham, the CEO of Borrowell, approached me to join his founding team.
This was early days for the company, prior to office spaces or even the name "Borrowell." It was just an idea. I joined in an operations role, and I've been here since July 2014.
You have 3 hours to make someone fall in love with Toronto – where do you take them and what do you show them?
I live in Leslieville and love the area, so I'd want to start there. We'd walk around so I could show them the independent shops, retailers, and cafes in the area.
I'm a huge fan of Centre Island as well, so we'd take the ferry over. I think the Toronto Islands are one of the real treasures of the city, and you get a beautiful skyline view. In particular, I'd take them on the Skyride Gondola where you can ride in the sky and look back at Toronto.
Elevate Toronto is founded on three principles (#DiversityIsOurStrength, #DisruptTogether, #ItsOurTime). Which one resonates most with you?
I love all three, but the one that personally resonates is #DiversityIsOurStrength.
Diversity is a core principle upon which we founded Borrowell, and it's a very real belief for our whole team. I don't think we're perfect in tech or in society as a whole, and we have a long way to go. However, what I love about diversity is its potential. We can accomplish so much and Toronto can take a global leading role in leveraging the potential of diversity.
What is your "global idea" for tech and innovation?
My global idea is to remind every business person and entrepreneur to be customer-first in your thinking about new ideas, businesses, or ways of doing things.
The more we focus on what the customer needs and building a fantastic customer experience, the more we will see silos breaking down between industries. Instead, we will focus on how we can learn from one another to build better companies.
In the tech world alone, we see this. We all borrow great design cues from Apple or great customer insights structures from Netflix or Amazon.
A lot of times in non-tech industries, we used to see things like banks only taking cues from other banks or other financial services companies on how they can better themselves. Now, we need to look way outside our own industry in order to be truly innovative.
What should the world know about the Toronto tech community?
The world needs to know that there is no better time to be in Toronto tech. Our ecosystem is large enough to be successful but still small enough that it is a tight-knit community.
Given where the community is right now, there's so much opportunity to break into tech and even become an "insider." At the pace we're growing, the tech community is set to be massive in the next ten years.
If you get into tech in Toronto now, you'll be able to ride the crest of the wave into the future when Toronto is much, much larger.


text: Cat mom Ginger sent us a lovely adoption update on her cat Raven. She has also given her the nickname "Rav-a-licious". Now that is just precious! Her note reads, Raven is a true "cuddle bunny." Talks a lot, too. Loves to play with her banana catnip and her pink ribbon (made out of heavy material). Since she is so active, I made sure my house is totally "kitty-proofed." We are so glad that Raven has adjusted so beautifully to your home Ginger! We wish you a lifetime of cuddles together 🙂


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- Research
- Open Access
Serotonin receptors are involved in the spinal mediation of descending facilitation of surgical incision-induced increase of Fos-like immunoreactivity in rats
- João Walter S Silveira1,
- Quintino M Dias1,
- Elaine A Del Bel2 and
- Wiliam A Prado1Email author
© Silveira et al; licensee BioMed Central Ltd. 2010
- Received: 14 January 2010
- Accepted: 23 March 2010
- Published: 23 March 2010
Descending pronociceptive pathways may be implicated in states of persistent pain. Paw skin incision is a well-established postoperative pain model that causes behavioral nociceptive responses and enhanced excitability of spinal dorsal horn neurons. The number of spinal c-Fos positive neurons of rats treated intrathecally with serotonin, noradrenaline or acetylcholine antagonists where evaluated to study the descending pathways activated by a surgical paw incision.
The number of c-Fos positive neurons in laminae I/II ipsilateral, lamina V bilateral to the incised paw, and in lamina X significantly increased after the incision. These changes: remained unchanged in phenoxybenzamine-treated rats; were increased in the contralateral lamina V of atropine-treated rats; were inhibited in the ipsilateral lamina I/II by 5-HT1/2B/2C (methysergide), 5-HT2A (ketanserin) or 5-HT1/2A/2C/5/6/7 (methiothepin) receptors antagonists, in the ipsilateral lamina V by methysergide or methiothepin, in the contralateral lamina V by all the serotonergic antagonists and in the lamina X by LY 278,584, ketanserin or methiothepin.
We conclude: (1) muscarinic cholinergic mechanisms reduce incision-induced response of spinal neurons inputs from the contralateral paw; (2) 5-HT1/2A/2C/3 receptors-mediate mechanisms increase the activity of descending pathways that facilitates the response of spinal neurons to noxious inputs from the contralateral paw; (3) 5-HT1/2A/2C and 5-HT1/2C receptors increases the descending facilitation mechanisms induced by incision in the ipsilateral paw; (4) 5-HT2A/3 receptors contribute to descending pronociceptive pathways conveyed by lamina X spinal neurons; (5) α-adrenergic receptors are unlikely to participate in the incision-induced facilitation of the spinal neurons.
- Ketanserin
- Spinal Dorsal Horn
- Spinal Neuron
- Methysergide
- Rostral Ventromedial Medulla
Bulbospinal pathways descend to the spinal cord to either inhibit (antinociceptive) or facilitate (pronociceptive) the transmission of nociceptive inputs (for review see [1, 2]). The contribution of supraspinal areas in the control of descending pronociceptive pathways was confirmed by several studies. As examples, the lesion or neural block of rostral ventromedial medulla (RVM) or periaqueductal gray (PAG) reduces the hyperalgesia induced by spinal nerve ligature [3, 4], or intraplantar injection of formalin [5, 6] or mustard oil [7]. Furthermore, low intensity electrical stimulation of, or low dose of glutamate into the RVM facilitates the response of spinal nociceptive neurons to noxious inputs, whereas high intensity electrical stimulation or high dose of glutamate produces the opposite effect [8].
Descending pronociceptive pathways may be implicated in states of persistent pain [9, 10] and elucidation of their spinal mediation may be useful for discovery of new antihyperalgesic drugs. Spinal serotonin produces antinociception but may be pronociceptive as well (for review see [11]). Also, spinal activation of α2-adrenergic receptors is antinociceptive whereas activation of α1-adrenergic receptors is pronociceptive [12, 13]. A spinal muscarinic cholinergic mechanism activated by descending noradrenergic inputs has also been proposed and it seems to be linked only with antinociception (for review see [14]).
Surgical incision of a rat paw causes primary and secondary punctate hyperalgesia [15] and increases the number of c-Fos positive neurons in the spinal cord [16], an immunohistochemical method that allows the identification of neurons activated by peripheral noxious stimulation [17]. Although being a poorly understood problem, very little effort has been dedicated toward research on the spinal mediation of descending mechanisms of post-incision pain, a model that may allow us to understand mechanisms of sensitization caused by surgery and investigate new therapies for postoperative pain.
The present study was therefore undertaken to examine the changes in the number of c-Fos positive neurons in the spinal cord of rats treated intrathecally with antagonists of serotonin, noradrenaline or acetylcholine, to evaluate whether they contribute in the spinal mediation of descending pronociceptive pathways activated by a surgical incision. The laminae I/II, V and X were systematically examined, since they are predominantly implicated in the reception, processing and rostral transmission of nociceptive information [11].
Effects of intrathecal muscarinic cholinergic, α-adrenergic and serotonergic receptor antagonists on the number of Fos-immunoreactive neurons in the laminae I/II, and V of the rat spinal cord
The incision-induced increase in the number of Fos-LI neurons in the ipsilateral laminae I/II of rats from the group ASI was significantly less intense following methysergide (30 μg/5 μl), and was not changed significantly by atropine (30 μg/5 μl) or phenoxybenzamine (20 μg/5 μl) (ANOVA: F5,26 = 24.64; P < 0.0001) (Figure 1a). Similar results were found in the contralateral laminae I/II, but the differences were not significant (ANOVA: F5,26 = 1.74; P > 0.05) (Figure 1b).
The incision-induced increase in the number of Fos-LI neurons in the ipsilateral lamina V of rats from the group ASI was less intense after methysergide (30 μg/5 μl), and was not changed by phenoxybenzamine (20 μg/5 μl) or atropine (30 μg/5 μl) (ANOVA: F5,26 = 9.94; P < 0.0001) (Figure 2a). Similar, but less intense effect occurred in the contralateral lamina V of rats treated with methysergide (30 μg/5 μl) or phenoxybenzamine (20 μg/5 μl) as compared with rats from the group ASI, but it was significantly more intense in the contralateral lamina V of rats treated with atropine (30 μg/5 μl) (ANOVA: F5,26 = 9.68; P < 0.0001) (Figure 2b).
Effects of intrathecal muscarinic cholinergic, α-adrenergic and serotonergic receptor antagonists on the number of Fos-immunoreactive neurons in the lamina X of the rat spinal cord
Effects of intrathecal antagonists of 5-HT receptor subtypes on the number of Fos-immunoreactive neurons in the laminae I, II, and V of the rat spinal cord
The incision-induced increase in the number of Fos-LI neurons in the ipsilateral laminae I/II was significantly reduced by methiothepin (1,5 μg/5 μl) or ketanserin (30 μg/5 μl), but was not changed by LY 278,584 (100 μg/5 μl) (ANOVA: F5,30 = 24.77; P < 0.0001) (Figure 5a). However, no significant difference was demonstrated in the contralateral laminae I and II among the experimental groups (ANOVA: F5,30 = 2.02; P > 0.05) (Figure 5b).
The incision-induced increase in the number of Fos-LI neurons in the ipsilateral lamina V was also reduced by methiothepin (1,5 μg/5 μl), ketanserin (30 μg/5 μl) or LY 278,584 (100 μg/5 μl), but only the effect of methiothepin was significant (ANOVA: F5,26 = 9.94; P < 0.0001) (Figure 6a). In contrast, ketanserin, LY 278,584 and mainly methiothepin all reduced significantly the incision-induced increase in the number of positive cells in the contralateral lamina V (ANOVA: F5,30 = 7.27; P = 0.0001) (Figure 6b).
Representative photomicrographs taken from sections of the spinal cords of control and test rats are given in Figure 3a and 3b for superficial and deep laminae, respectively.
Effects of intrathecal antagonists of 5-HT receptor subtypes on the number of Fos-immunoreactive neurons in the lamina X of the rat spinal cord
Fos protein is a product of the proto-oncogene c-Fos, which is expressed in the neuronal nuclei few hours after an appropriate stimulus [18]. The increase in the expression of Fos-LI neurons in spinal cord has been used as a marker of the neuronal activity induced by noxious stimuli in various pain models [17]; for review see [19, 20]. Although being a poorly understood problem, very little effort has been dedicated toward research on the spinal mediation of descending mechanisms of post-incision pain, a model that may allow us to understand mechanisms of sensitization caused by surgery and investigate new therapies for postoperative pain.
The present study confirmed that a surgical incision in a rat hind paw increased significantly the number of Fos-LI neurons in the spinal dorsal horn laminae I/II ipsilateral, and lamina V bilateral to the incised paw as shown elsewhere [16, 21, 22].
Also, a significant increase in the number of Fos-LI neurons were also found in the lamina X of the spinal gray matter following the incision, as described elsewhere subsequent to peripheral or visceral nociceptive inputs [23].
Incision of a hind paw increases both the response of spinal wide dynamic range cells to mechanical stimulation [15] and the spontaneous activity of nociceptive primary afferents [24]. The model of incision pain differs from inflammatory pain models [25, 26], but the tissue reactions to incision are likely to involve some inflammatory responses to local injury [27].
Evidence that descending influences can affect spinal phenomena induced by a paw incision includes the demonstration that incision pain is further increased in rats with lesion of dorsolateral funiculus [28], that conveys descending pain inhibitory pathways [11], or electrolytic lesion of the anterior pretectal nucleus [29], that participates in the activation of descending mechanisms of pain control [30]; in the ipsilateral spinal cord, the incision-induced increase in the number of Fos-LI neurons was significantly reduced in the superficial lamina and significantly increased in the deep lamina of animals previously treated with bupivacaine in the contralateral anterior pretectal nucleus [16]; finally, descending pathways are known as the only sources of serotonin in the spinal cord [2, 11, 31].
Acetylcholine, noradrenaline and serotonin modulate noxious inputs processing in the spinal cord (for review see [11]. Atropine, a non selective muscarinic receptor antagonist was used here at 30 μg/rat, 3 fold superior to the dose known to be effective against the neostigmine-induced antinociception in rats [32].
Phenoxybenzamine, a non selective α-adrenergic receptor antagonist was used here at 20 μg/rat, 2.5 fold superior to the dose early shown to be effective against glutamate-induced analgesia from the RVM of rats [33]. Nonetheless, neither the atropine nor the phenoxybenzamine changed the incision-induced increase in the number of Fos-LI neurons in the laminae I/II, bilaterally, ipsilateral lamina V, or in lamina X. Consequently, muscarinic and α-adrenergic receptors are unlikely to participate in mechanisms that facilitate the response of spinal neurons to noxious inputs evoked by the incision. On the contrary, the increase in the number of Fos-LI neurons in the lamina V contralateral to the incised paw was significantly greater in atropine- than in saline-treated rats. In agreement to earlier studies [34–36], we interpret the result as indirect evidence that a muscarinic cholinergic mechanism responds to a surgical incision reducing the response of spinal neurons to noxious inputs from the contralateral paw. A possibility remains that the depression of c-Fos labeling is due to toxic effects of the antagonists used in the study. However, as far as we know, there is no report showing that at the doses used in the study, the intrathecal antagonists induces toxic effects against spinal dorsal horn cells in rats.
Among the seven classes of serotonin receptors (5-HT1-7) currently known (for review see [37]), at least three (5-HT1/2/3/) were found in the spinal cord [38, 39] and are implicated in spinal pain processing [40–43]. The antinociceptive effect of 5-HT may also occur via interaction with spinal 5-HT4 receptors [44, 45], but experiments involving pharmacological blockade of these receptors were not conducted in this study.
The increase in the number of Fos-LI neurons in the lamina I/II ipsilateral to the incised paw was significantly inhibited by antagonists for 5-HT1/2B/2C (methysergide), 5-HT2A (ketanserin) or 5-HT1/2A/2C/5/6/7 (methiothepin) receptors, but was not changed by a 5-HT3 antagonist (LY 278,584). The same effect was also significantly inhibited in the lamina V ipsilateral to the incised paw by methysergide or methiothepin, but remained unchanged following ketanserin or LY 278,584. Therefore, 5-HT1/2A/2C receptors in laminae I/II and 5-HT1/2Creceptors in lamina V, but not 5-HT3 receptors in either laminae I/II or V, are involved in the activity of a descending pathway that facilitates the response of spinal neurons to noxious inputs induced by a surgical incision in the ipsilateral paw.
The significant increase in the number of Fos-LI neurons in the contralateral lamina V was inhibited by all the serotonergic antagonists used in the study. Thus, 5-HT1/2A/2C/3 receptors contribute to the effect of serotonin in the activity of a descending pathway that facilitates the response of spinal neurons to noxious inputs induced by a surgical incision in the contralateral paw. Finally, the increase in the number of Fos-LI neurons in lamina X was significantly inhibited by LY 278,584, ketanserin or methiothepin, but not by methysergide. We then conclude that 5-HT2A/3 receptors contribute to the effects of serotonin in a descending pronociceptive pathway conveyed by lamina X spinal neurons.
Altogether, these results support the involvement of serotonin in descending mechanisms that facilitate the response of spinal neurons to nociceptive inputs in the spinal cord. Serotonergic nerve terminals found in the spinal cord originate from supraspinal sources [2, 11, 31] and, therefore, descending pathways utilizing serotonin somehow excite nociceptive cells in the spinal cord while a postoperative pain is in course. Bulbospinal influences from the RVM contribute to facilitation of noxious inputs and development of secondary hyperalgesia in persistent inflammatory, neuropathic, and visceral pain models[46]. Primary and secondary hyperalgesia observed after a surgical incision do not appear to be modulated by descending influences from the RVM, thus supporting the view that incision pain involves different mechanisms compared with inflammatory and neuropathic pain[47]. However, in this study Pogatzki et al., utilized rats 5 days after RVM lesion and, therefore, it is possible that a structure located more rostrally assumes the control of the primary and secondary hyperalgesia observed after a surgical incision. In fact, several other studies have shown the involvement of descending pain pathways in this model [29, 30, 48–51].
The spinal actions of serotonin has long been associated to suppression of the responses to nociceptive inputs [52–54], but evidence has accumulated questioning whether descending serotonergic pathways play an exclusive spinal suppressive effect against nociceptive inputs [53, 55]. The activation of spinal serotonin receptors has been associated with both pronociceptive and antinociceptive effects depending on algesimetric test, drug dosage, duration of the treatment and pathophysiological condition [56–58].
The spinal dorsal horn contains high concentrations of 5-HT1A, and 5-HT1B receptors [39, 59], but the occurrence of 5-HT1D receptors is possible [60, 61]. The activation of spinal 5-HT1A may result analgesia [62, 63] (see also [64]), or hyperalgesia [65, 66], while the activation of spinal 5-HT1B receptors produces antinociception [67, 68].
The presence of spinal 5-HT2A [69, 70], and 5-HT2C receptors [71, 72] has already been demonstrated. Stimulation of spinal 5-HT2A receptors is pronociceptive [53, 73], but the presence of 5-HT2A receptors on spinal inhibitory interneurons supports an antinociceptive role for 5-HT [74, 75]. The activation of spinal 5-HT2C receptors excites neurons [55, 76, 77], and its distribution in the spinal cord is compatible with a pronociceptive role of 5-HT in the dorsal horn [12, 78]. Conversely, 5-HT2C sites on spinal inhibitory interneurons allow a potential antinociceptive role for serotonin [79].
Studies have demonstrated that 5-HT3 receptors are concentrated in superficial layers of the dorsal horn [59, 80] and a significant proportion is located on the terminals of C fibres [12, 81]. The activation of the 5-HT3 receptors depolarizes neurons in dorsal root ganglions and, therefore, is expected to increase the transmitter release from the primary afferent terminals into the spinal cord (see [64]). In line with the present results, the activation of spinal 5-HT3 receptors increases nociception [62, 82, 83], and blockade of spinal 5-HT3 receptor reduces the hypersensitivity of spinal dorsal horn neurons of nerve-ligated rats [84]. A pronociceptive role for 5-HT3 receptors in the spinal cord following activation of descending pronociceptive pathways has already been proposed [84, 85].
It is also noteworthy, that a direct facilitation by serotonin of glutamatergic synapses has been demonstrated in the spinal cord [86, 87] and, therefore, this mechanism may account for some of the excitatory effects of serotonin found here.
There is evidence that a peripheral damage simultaneously triggers both descending inhibition and facilitation onto both primary and secondary spinal hyperalgesic mechanisms, but the balance for primary hyperalgesia is different from the balance for secondary hyperalgesia (for review see [48]).
Behavioral nociceptive responses of our animals were not evaluated during this study but it may be assumed that the increased number of Fos-LI neurons in the dorsal horn ipsilateral to the incised paw essentially reflects primary hyperalgesia. By extension, a secondary hyperalgesia evoked by central sensitization may be assumed to occur when the effect was observed in the contralateral dorsal horn (see [88]). Therefore, our results show that incision-induced primary and secondary hyperalgesias seem to be spinally mediated by 5-HT1/2A/2C and 5-HT1/2A/2C/3 receptors, respectively.
Few studies have accessed which neurotransmitters are involved in the spinal processing of hyperalgesia in the mode of post-incision pain. They have shown that noradrenergic receptors are involved in the spinal mediation of descending inhibitory pathways in the primary hyperalgesia of postoperative pain [29, 49, 51]. Few reports are also available regarding secondary hyperalgesia after post-incision pain [47, 89–94] but, as far we know, none of them have studied spinal neurotransmitters involved in descending mechanisms.
Effects of antagonists in the incision-induced increase of Fos-like immunoreactivity in the rat spinal cord
Atropine (muscarinic)
Phenoxybenzamine (α-adrenergic)
Methysergide (5-HT1/2B/2C)
Ketanserin (5-HT2A)
Methiothepin (5-HT1/2A/2C/5/6/7)
Male Wistar rats (200-250 g) were used in this study. Animals were housed two to a cage under controlled temperature (22 ± 1°C) and on a 12-h light-dark cycle, with the dark cycle beginning at 07:00 h, and had free access to food and water. The experiments were approved by the Commission of Ethics in Animal Research, Faculty of Medicine of Ribeirão Preto, University of São Paulo (Number 009/2004). The guidelines of the Committee for Research and Ethical Issues of IASP [95] were followed throughout the experiments.
Each rat was anesthetized with halothane via a loose-fitting, cone-shaped mask, and catheterization of the spinal subarachnoid space was performed as described elsewhere [96]. Briefly, a 20-gauge Weiss needle was introduced through the skin into the L5-L6 intervertebral space. The correct positioning of the needle was assured by a typical flick of the tail or hind paw. A 12-mm length of polyethylene tubing (PE tubing, o.d. = 0.4 mm, dead space = 10 μl) was then introduced through the needle to protrude 2.0 cm into the subarachnoid space in a cranial direction. The needle was then carefully removed and the tubing anchored to the back skin with a cotton thread suture. Drug or saline was injected intrathecally soon after the catheterization in a volume of 5 μl over a period of 60 s, followed by 5 μl of sterile saline at the same rate to flush the catheter. The plantar side of the right hind paw was prepared with a 10% povidone-iodine solution 15-min later. A 1-cm longitudinal incision was made with a surgical blade, through the skin and fascia of the plantar region, starting 0.5 cm from the proximal edge of the heel, as described elsewhere [97]. The plantaris muscle was elevated, but its origin and insertion were left intact. After hemostasia, the skin was apposed with one single suture of 5-0 nylon, and the animal was allowed to recover in the home cage for a period of 2 h. The positioning of the intrathecal catheter was verified when the spinal cord was removed for Fos immunohistochemistry.
Fos immunohistochemistry
The animals were sacrificed with an intraperitoneal overdose of sodium thiopental performed 2 h after the plantar incision, and perfused transcardially with saline followed by 4% paraformaldehyde in 0.1 M PBS, pH 7.4. The spinal cord was removed, fixed for 2 h in paraformaldehyde and stored for at least 48 h in 30% sucrose. The side ipsilateral to the incised paw was marked with a little knife cut. The samples were then frozen in Tissue Teck (Sakura®). Fos immunohistochemistry was processed, as described elsewhere [98], on 40 μm transverse sections obtained with a cryostat (Leica CM 1850) from L2-L3 spinal cord segments. The tissue sections were successively washed and incubated for 1 h in goat anti-rabbit biotinylated antibody (1:400 in PBS; Vector Laboratories, Burlingame, CA). They were then processed by the avidin-biotin immunoperoxidase method (Vectastain ABC kit, Vector Lab, Burlingame, CA, U.S.A.), and then Fos-like immunoreactivity (FLI) was revealed by the addition of chromogen diaminobenzidin (Sigma).
All reactions were performed at room temperature. Fos-like immunoreactivity was quantified using an image analysis system (Leica, Quantimet 500, Leica Microsystems Inc. Cambridge, UK) that identified and counted immunostained neurons according to a gray level that was empirically determined prior to analysis. The number of Fos-like immunoreactive (Fos-LI) neurons/section was calculated as the mean of the three sections examined for each rat. For analysis of the laminar distribution of Fos-LI neurons, the spinal cord gray matter was divided into three regions (laminae I-II, V, and X). Assessment of Fos-like immunoreactivity was conducted in a blind manner.
The number of Fos-LI neurons per region on both the ipsilateral and contralateral slides was counted in fixed area sizes (0.2 mm2 for spinal cord laminae I/II, V or X), using a software 9.0 image analysis system (W. Rasband, National Institute of Health). Only rats showing catheter tip positioned at the dorsal spinal cord were considered for data analysis.
Atropine sulfate, a non selective muscarinic cholinergic antagonist, phenoxybenzamine hydrochloride, a non selective α-receptor antagonist, methysergide, a 5-HT1/2B/2C antagonist [99], ketanserin, a 5-HT2A antagonist [100], methiothepin, a 5-HT1/2A/2C/5/6/7 antagonist [101], and LY 278,584, a 5-HT3 antagonist [102, 103], were purchased from Sigma (St Louis, MO, USA) and diluted in sterile isotonic saline at the moment of the injection.
Experimental design
All animals were anesthetized and allocated to one of four experimental groups. A group for the overall control of the experiment had non-incised and non-catheterized anesthetized rats (group A), which were sacrificed 2 h after the beginning of anesthesia. A group for control of the effects of intrathecal catheterization had non-incised rats treated intrathecally with saline (5 μl) and were sacrificed 2 h later (group AS). A group for control of the effects of the hind paw incision had rats treated intrathecally with saline and submitted to the surgical incision of the right hind paw performed 15-min later (group ASI). Test groups had rats submitted to paw incision carried out 3 h after intrathecal phenoxybenzamine or 15-min after methysergide, atropine, LY 278,584, ketanserin or methiothepin. Animals from group ASI and test groups were sacrificed 2 h after the incision.
The mean (± SEM) of the number Fos-LI cells/0.2 mm2 of 3 sections from the spinal cord of 4 - 8 animals per group was taken to allow comparisons among the different treatments. Comparisons of groups were made using one-way ANOVA followed by the Tukey's Multiple Comparison test. The level of significance was set at P < 0.05 in all cases.
This study was supported by FAPESP. JWSS and QMD were the recipients of CNPq fellowships. We gratefully acknowledge MA Carvalho and PR Castania for skillful technical assistance. Dr A Leyva helped with English editing of the manuscript.
Authors' Affiliations
- Gebhart GF: Descending modulation of pain. Neurosci Biobehav Rev 2004, 27: 729–737. 10.1016/j.neubiorev.2003.11.008PubMedGoogle Scholar
- Fields HL, Heinricher MM, Mason P: Neurotransmitters in nociceptive modulatory circuits. Annu Rev Neurosci 1991, 14: 219–245. 10.1146/annurev.ne.14.030191.001251PubMedGoogle Scholar
- Kovelowski CJ, Ossipov MH, Sun H, Lai J, Malan TP, Porreca F: Supraspinal cholecystokinin may drive tonic descending facilitation mechanisms to maintain neuropathic pain in the rat. Pain 2000, 87: 265–273. 10.1016/S0304-3959(00)00290-6PubMedGoogle Scholar
- Pertovaara A, Wei H, Hamalainen MM: Lidocaine in the rostroventromedial medulla and the periaqueductal gray attenuates allodynia in neuropathic rats. Neurosci Lett 1996, 218: 127–130. 10.1016/S0304-3940(96)13136-0PubMedGoogle Scholar
- Vaccarino AL, Melzack R: Temporal processes of formalin pain: differential role of the cingulum bundle, fornix pathway and medial bulboreticular formation. Pain 1992, 49: 257–271. 10.1016/0304-3959(92)90150-APubMedGoogle Scholar
- Wiertelak EP, Roemer B, Maier SF, Watkins LR: Comparison of the effects of nucleus tractus solitarius and ventral medial medulla lesions on illness-induced and subcutaneous formalin-induced hyperalgesias. Brain Res 1997, 748: 143–150. 10.1016/S0006-8993(96)01289-9PubMedGoogle Scholar
- Pertovaara A: A neuronal correlate of secondary hyperalgesia in the rat spinal dorsal horn is submodality selective and facilitated by supraspinal influence. Exp Neurol 1998, 149: 193–202. 10.1006/exnr.1997.6688PubMedGoogle Scholar
- Zhuo M, Gebhart GF: Biphasic modulation of spinal nociceptive transmission from the medullary raphe nuclei in the rat. J Neurophysiol 1997, 78: 746–758.PubMedGoogle Scholar
- Calejesan AA, Ch'ang MH, Zhuo M: Spinal serotonergic receptors mediate facilitation of a nociceptive reflex by subcutaneous formalin injection into the hindpaw in rats. Brain Res 1998, 798: 46–54. 10.1016/S0006-8993(98)00394-1PubMedGoogle Scholar
- Wei F, Dubner R, Ren K: Nucleus reticularis gigantocellularis and nucleus raphe magnus in the brain stem exert opposite effects on behavioral hyperalgesia and spinal Fos protein expression after peripheral inflammation. Pain 1999, 80: 127–141. 10.1016/S0304-3959(98)00212-7PubMedGoogle Scholar
- Millan MJ: Descending control of pain. Prog Neurobiol 2002, 66: 355–474. 10.1016/S0301-0082(02)00009-6PubMedGoogle Scholar
- Millan MJ, Girardon S, Bervoets K: 8-OH-DPAT-induced spontaneous tail-flicks in the rat are facilitated by the selective serotonin (5-HT)2C agonist, RO 60–0175: blockade of its actions by the novel 5-HT2C receptor antagonist SB 206,553. Neuropharmacology 1997, 36: 743–745. 10.1016/S0028-3908(97)00071-3PubMedGoogle Scholar
- Stanfa LC, Dickenson AH: Enhanced alpha-2 adrenergic controls and spinal morphine potency in inflammation. Neuroreport 1994, 5: 469–472. 10.1097/00001756-199401120-00025PubMedGoogle Scholar
- Eisenach JC: Muscarinic-mediated analgesia. Life Sci 1999, 64: 549–554. 10.1016/S0024-3205(98)00600-6PubMedGoogle Scholar
- Zahn PK, Brennan TJ: Incision-induced changes in receptive field properties of rat dorsal horn neurons. Anesthesiology 1999, 91: 772–785. 10.1097/00000542-199909000-00030PubMedGoogle Scholar
- Villarreal CF, Del Bel EA, Prado WA: Involvement of the anterior pretectal nucleus in the control of persistent pain: a behavioral and c-Fos expression study in the rat. Pain 2003, 103: 163–174. 10.1016/S0304-3959(02)00449-9PubMedGoogle Scholar
- Hunt SP, Pini A, Evan G: Induction of c-fos-like protein in spinal cord neurons following sensory stimulation. Nature 1987, 328: 632–634. 10.1038/328632a0PubMedGoogle Scholar
- Hughes P, Dragunow M: Induction of immediate-early genes and the control of neurotransmitter-regulated gene expression within the nervous system. Pharmacol Rev 1995, 47: 133–178.PubMedGoogle Scholar
- Coggeshall RE: Fos, nociception and the dorsal horn. Prog Neurobiol 2005, 77: 299–352.PubMedGoogle Scholar
- Sandkuhler J: The organization and function of endogenous antinociceptive systems. Prog Neurobiol 1996, 50: 49–81.PubMedGoogle Scholar
- Sun X, Yokoyama M, Mizobuchi S, Kaku R, Nakatsuka H, Takahashi T, Morita K: The effects of pretreatment with lidocaine or bupivacaine on the spatial and temporal expression of c-Fos protein in the spinal cord caused by plantar incision in the rat. Anesth Analg 2004, 98: 1093–1098. 10.1213/01.ANE.0000104580.89717.A2PubMedGoogle Scholar
- Tsuda M, Koizumi S, Inoue K: Role of endogenous ATP at the incision area in a rat model of postoperative pain. Neuroreport 2001, 12: 1701–1704. 10.1097/00001756-200106130-00036PubMedGoogle Scholar
- Nicholas AP, Zhang X, Hokfelt T: An immunohistochemical investigation of the opioid cell column in lamina X of the male rat lumbosacral spinal cord. Neurosci Lett 1999, 270: 9–12. 10.1016/S0304-3940(99)00446-2PubMedGoogle Scholar
- Hamalainen MM, Gebhart GF, Brennan TJ: Acute effect of an incision on mechanosensitive afferents in the plantar rat hindpaw. J Neurophysiol 2002, 87: 712–720.PubMedGoogle Scholar
- Leonard PA, Arunkumar R, Brennan TJ: Bradykinin antagonists have no analgesic effect on incisional pain. Anesth Analg 2004, 99: 1166–1172. 10.1213/01.ANE.0000130348.85587.BEPubMedGoogle Scholar
- Pogatzki-Zahn EM, Shimizu I, Caterina M, Raja SN: Heat hyperalgesia after incision requires TRPV1 and is distinct from pure inflammatory pain. Pain 2005, 115: 296–307. 10.1016/j.pain.2005.03.010PubMedGoogle Scholar
- Wieseler-Frank J, Maier SF, Watkins LR: Central proinflammatory cytokines and pain enhancement. Neurosignals 2005, 14: 166–174. 10.1159/000087655PubMedGoogle Scholar
- Kina VA, Villarreal CF, Prado WA: The effects of intraspinal L-NOARG or SIN-1 on the control by descending pathways of incisional pain in rats. Life Sci 2005, 76: 1939–1951. 10.1016/j.lfs.2004.08.038PubMedGoogle Scholar
- Villarreal CF, Kina VA, Prado WA: Participation of brainstem nuclei in the pronociceptive effect of lesion or neural block of the anterior pretectal nucleus in a rat model of incisional pain. Neuropharmacology 2004, 47: 117–127. 10.1016/j.neuropharm.2004.03.002PubMedGoogle Scholar
- Villarreal CF, Prado WA: Modulation of persistent nociceptive inputs in the anterior pretectal nucleus of the rat. Pain 2007, 132: 42–52. 10.1016/j.pain.2007.01.021PubMedGoogle Scholar
- Stamford JA: Descending control of pain. Br J Anaesth 1995, 75: 217–227.PubMedGoogle Scholar
- Lavand'homme PM, Eisenach JC: Sex differences in cholinergic analgesia II: differing mechanisms in two models of allodynia. Anesthesiology 1999, 91: 1455–1461. 10.1097/00000542-199911000-00039PubMedGoogle Scholar
- Satoh M, Oku R, Akaike A: Analgesia produced by microinjection of L-glutamate into the rostral ventromedial bulbar nuclei of the rat and its inhibition by intrathecal alpha-adrenergic blocking agents. Brain Res 1983, 261: 361–364. 10.1016/0006-8993(83)90646-7PubMedGoogle Scholar
- Iwamoto ET, Marion L: Characterization of the antinociception produced by intrathecally administered muscarinic agonists in rats. J Pharmacol Exp Ther 1993, 266: 329–338.PubMedGoogle Scholar
- Li DP, Chen SR, Pan YZ, Levey AI, Pan HL: Role of presynaptic muscarinic and GABA(B) receptors in spinal glutamate release and cholinergic analgesia in rats. J Physiol 2002, 543: 807–818. 10.1113/jphysiol.2002.020644PubMed CentralPubMedGoogle Scholar
- Zhuo M, Gebhart GF: Tonic cholinergic inhibition of spinal mechanical transmission. Pain 1991, 46: 211–222. 10.1016/0304-3959(91)90078-CPubMedGoogle Scholar
- Hoyer D, Hannon JP, Martin GR: Molecular, pharmacological and functional diversity of 5-HT receptors. Pharmacol Biochem Behav 2002, 71: 533–554. 10.1016/S0091-3057(01)00746-8PubMedGoogle Scholar
- Hamon M, Gallissot MC, Menard F, Gozlan H, Bourgoin S, Verge D: 5-HT3 receptor binding sites are on capsaicin-sensitive fibres in the rat spinal cord. Eur J Pharmacol 1989, 164: 315–322. 10.1016/0014-2999(89)90472-XPubMedGoogle Scholar
- Thor KB, Nickolaus S, Helke CJ: Autoradiographic localization of 5-hydroxytryptamine1A, 5-hydroxytryptamine1B and 5-hydroxytryptamine1C/2 binding sites in the rat spinal cord. Neuroscience 1993, 55: 235–252. 10.1016/0306-4522(93)90469-VPubMedGoogle Scholar
- Danzebrink RM, Gebhart GF: Evidence that spinal 5-HT1, 5-HT2 and 5-HT3 receptor subtypes modulate responses to noxious colorectal distension in the rat. Brain Res 1991, 538: 64–75. 10.1016/0006-8993(91)90377-8PubMedGoogle Scholar
- Giordano J: Analgesic profile of centrally administered 2-methylserotonin against acute pain in rats. Eur J Pharmacol 1991, 199: 233–236. 10.1016/0014-2999(91)90462-YPubMedGoogle Scholar
- Radhakrishnan R, King EW, Dickman JK, Herold CA, Johnston NF, Spurgin ML, Sluka KA: Spinal 5-HT(2) and 5-HT(3) receptors mediate low, but not high, frequency TENS-induced antihyperalgesia in rats. Pain 2003, 105: 205–213. 10.1016/S0304-3959(03)00207-0PubMed CentralPubMedGoogle Scholar
- Zhuo M, Gebhart GF: Spinal serotonin receptors mediate descending facilitation of a nociceptive reflex from the nuclei reticularis gigantocellularis and gigantocellularis pars alpha in the rat. Brain Res 1991, 550: 35–48. 10.1016/0006-8993(91)90402-HPubMedGoogle Scholar
- Jeong CY, Choi JI, Yoon MH: Roles of serotonin receptor subtypes for the antinociception of 5-HT in the spinal cord of rats. Eur J Pharmacol 2004, 502: 205–211. 10.1016/j.ejphar.2004.08.048PubMedGoogle Scholar
- Liu FY, Xing GG, Qu XX, Xu IS, Han JS, Wan Y: Roles of 5-hydroxytryptamine (5-HT) receptor subtypes in the inhibitory effects of 5-HT on C-fiber responses of spinal wide dynamic range neurons in rats. J Pharmacol Exp Ther 2007, 321: 1046–1053. 10.1124/jpet.106.115204PubMedGoogle Scholar
- Urban MO, Gebhart GF: Supraspinal contributions to hyperalgesia. Proc Natl Acad Sci USA 1999, 96: 7687–7692. 10.1073/pnas.96.14.7687PubMed CentralPubMedGoogle Scholar
- Pogatzki EM, Urban MO, Brennan TJ, Gebhart GF: Role of the rostral medial medulla in the development of primary and secondary hyperalgesia after incision in the rat. Anesthesiology 2002, 96: 1153–1160. 10.1097/00000542-200205000-00019PubMedGoogle Scholar
- Vanegas H, Schaible HG: Descending control of persistent pain: inhibitory or facilitatory? Brain Res Brain Res Rev 2004, 46: 295–309. 10.1016/j.brainresrev.2004.07.004PubMedGoogle Scholar
- Wang Y, Feng C, Wu Z, Wu A, Yue Y: Activity of the descending noradrenergic pathway after surgery in rats. Acta Anaesthesiol Scand 2008, 52: 1336–1341. 10.1111/j.1399-6576.2007.01525.xPubMedGoogle Scholar
- Villarreal CF, Kina VA, Prado WA: Antinociception induced by stimulating the anterior pretectal nucleus in two models of pain in rats. Clin Exp Pharmacol Physiol 2004, 31: 608–613. 10.1111/j.1440-1681.2004.04057.xPubMedGoogle Scholar
- Hayashida K, DeGoes S, Curry R, Eisenach JC: Gabapentin activates spinal noradrenergic activity in rats and humans and reduces hypersensitivity after surgery. Anesthesiology 2007, 106: 557–562. 10.1097/00000542-200703000-00021PubMedGoogle Scholar
- Basbaum AI, Fields HL: Endogenous pain control mechanisms: review and hypothesis. Ann Neurol 1978, 4: 451–462. 10.1002/ana.410040511PubMedGoogle Scholar
- Eide PK, Hole K: The role of 5-hydroxytryptamine (5-HT) receptor subtypes and plasticity in the 5-HT systems in the regulation of nociceptive sensitivity. Cephalalgia 1993, 13: 75–85. 10.1046/j.1468-2982.1993.1302075.xPubMedGoogle Scholar
- Millan MJ: Endorphins and nociception: an overview. Methods Find Exp Clin Pharmacol 1982, 4: 445–462.PubMedGoogle Scholar
- Millan MJ: The induction of pain: an integrative review. Prog Neurobiol 1999, 57: 1–164. 10.1016/S0301-0082(98)00048-3PubMedGoogle Scholar
- Colpaert FC, Tarayre JP, Koek W, Pauwels PJ, Bardin L, Xu XJ, Wiesenfeld-Hallin Z, Cosi C, Carilla-Durand E, Assie MB, Vacher B: Large-amplitude 5-HT1A receptor activation: a new mechanism of profound, central analgesia. Neuropharmacology 2002, 43: 945–958. 10.1016/S0028-3908(02)00119-3PubMedGoogle Scholar
- Fasmer OB, Berge OG, Hole K: Changes in nociception after lesions of descending serotonergic pathways induced with 5,6-dihydroxytryptamine. Different effects in the formalin and tail-flick tests. Neuropharmacology 1985, 24: 729–734. 10.1016/0028-3908(85)90006-1PubMedGoogle Scholar
- Millan MJ, Seguin L, Honore P, Girardon S, Bervoets K: Pro- and antinociceptive actions of serotonin (5-HT)1A agonists and antagonists in rodents: relationship to algesiometric paradigm. Behav Brain Res 1996, 73: 69–77. 10.1016/0166-4328(96)00073-3PubMedGoogle Scholar
- Laporte AM, Doyen C, Nevo IT, Chauveau J, Hauw JJ, Hamon M: Autoradiographic mapping of serotonin 5-HT1A, 5-HT1D, 5-HT2A and 5-HT3 receptors in the aged human spinal cord. J Chem Neuroanat 1996, 11: 67–75. 10.1016/0891-0618(96)00130-5PubMedGoogle Scholar
- Bonaventure P, Voorn P, Luyten WH, Jurzak M, Schotte A, Leysen JE: Detailed mapping of serotonin 5-HT1B and 5-HT1D receptor messenger RNA and ligand binding sites in guinea-pig brain and trigeminal ganglion: clues for function. Neuroscience 1998, 82: 469–484. 10.1016/S0306-4522(97)00302-3PubMedGoogle Scholar
- Waeber C, Moskowitz MA: [3H]sumatriptan labels both 5-HT1D and 5-HT1F receptor binding sites in the guinea pig brain: an autoradiographic study. Naunyn Schmiedebergs Arch Pharmacol 1995, 352: 263–275. 10.1007/BF00168556PubMedGoogle Scholar
- Oyama T, Ueda M, Kuraishi Y, Akaike A, Satoh M: Dual effect of serotonin on formalin-induced nociception in the rat spinal cord. Neurosci Res 1996, 25: 129–135.PubMedGoogle Scholar
- Robles LI, Barrios M, Del Pozo E, Dordal A, Baeyens JM: Effects of K+ channel blockers and openers on antinociception induced by agonists of 5-HT1A receptors. Eur J Pharmacol 1996, 295: 181–188. 10.1016/0014-2999(95)00643-5PubMedGoogle Scholar
- Yoshimura M, Furue H: Mechanisms for the anti-nociceptive actions of the descending noradrenergic and serotonergic systems in the spinal cord. J Pharmacol Sci 2006, 101: 107–117. 10.1254/jphs.CRJ06008XPubMedGoogle Scholar
- Ali Z, Wu G, Kozlov A, Barasi S: The actions of 5-HT1 agonists and antagonists on nociceptive processing in the rat spinal cord: results from behavioural and electrophysiological studies. Brain Res 1994, 661: 83–90. 10.1016/0006-8993(94)91184-3PubMedGoogle Scholar
- Zhang Y, Yang Z, Gao X, Wu G: The role of 5-hydroxytryptamine1A and 5-hydroxytryptamine1B receptors in modulating spinal nociceptive transmission in normal and carrageenan-injected rats. Pain 2001, 92: 201–211. 10.1016/S0304-3959(01)00259-7PubMedGoogle Scholar
- Alhaider AA, Wilcox GL: Differential roles of 5-hydroxytryptamine1A and 5-hydroxytryptamine1B receptor subtypes in modulating spinal nociceptive transmission in mice. J Pharmacol Exp Ther 1993, 265: 378–385.PubMedGoogle Scholar
- Xu W, Qiu XC, Han JS: Serotonin receptor subtypes in spinal antinociception in the rat. J Pharmacol Exp Ther 1994, 269: 1182–1189.PubMedGoogle Scholar
- Cornea-Hebert V, Riad M, Wu C, Singh SK, Descarries L: Cellular and subcellular distribution of the serotonin 5-HT2A receptor in the central nervous system of adult rat. J Comp Neurol 1999, 409: 187–209. 10.1002/(SICI)1096-9861(19990628)409:2<187::AID-CNE2>3.0.CO;2-PPubMedGoogle Scholar
- Maeshima T, Ito R, Hamada S, Senzaki K, Hamaguchi-Hamada K, Shutoh F, Okado N: The cellular localization of 5-HT2A receptors in the spinal cord and spinal ganglia of the adult rat. Brain Res 1998, 797: 118–124. 10.1016/S0006-8993(98)00360-6PubMedGoogle Scholar
- Fonseca MI, Ni YG, Dunning DD, Miledi R: Distribution of serotonin 2A, 2C and 3 receptor mRNA in spinal cord and medulla oblongata. Brain Res Mol Brain Res 2001, 89: 11–19. 10.1016/S0169-328X(01)00049-3PubMedGoogle Scholar
- Wu S, Zhu M, Wang W, Wang Y, Li Y, Yew DT: Changes of the expression of 5-HT receptor subtype mRNAs in rat dorsal root ganglion by complete Freund's adjuvant-induced inflammation. Neurosci Lett 2001, 307: 183–186. 10.1016/S0304-3940(01)01946-2PubMedGoogle Scholar
- Kjorsvik A, Tjolsen A, Hole K: Activation of spinal serotonin(2A/2C) receptors augments nociceptive responses in the rat. Brain Res 2001, 910: 179–181. 10.1016/S0006-8993(01)02652-XPubMedGoogle Scholar
- Obata H, Saito S, Sasaki M, Ishizaki K, Goto F: Antiallodynic effect of intrathecally administered 5-HT(2) agonists in rats with nerve ligation. Pain 2001, 90: 173–179. 10.1016/S0304-3959(00)00401-2PubMedGoogle Scholar
- Sasaki M, Ishizaki K, Obata H, Goto F: Effects of 5-HT2 and 5-HT3 receptors on the modulation of nociceptive transmission in rat spinal cord according to the formalin test. Eur J Pharmacol 2001, 424: 45–52. 10.1016/S0014-2999(01)01117-7PubMedGoogle Scholar
- Cardenas CG, Del Mar LP, Scroggs RS: Two parallel signaling pathways couple 5HT1A receptors to N- and L-type calcium channels in C-like rat dorsal root ganglion cells. J Neurophysiol 1997, 77: 3284–3296.PubMedGoogle Scholar
- Cardenas CG, Mar LP, Vysokanov AV, Arnold PB, Cardenas LM, Surmeier DJ, Scroggs RS: Serotonergic modulation of hyperpolarization-activated current in acutely isolated rat dorsal root ganglion neurons. J Physiol 1999,518(Pt 2):507–523. 10.1111/j.1469-7793.1999.0507p.xPubMed CentralPubMedGoogle Scholar
- Bervoets K, Millan MJ, Colpaert FC: Agonist action at 5-HT1C receptors facilitates 5-HT1A receptor-mediated spontaneous tail-flicks in the rat. Eur J Pharmacol 1990, 191: 185–195. 10.1016/0014-2999(90)94146-OPubMedGoogle Scholar
- Bardin L, Schmidt J, Alloui A, Eschalier A: Effect of intrathecal administration of serotonin in chronic pain models in rats. Eur J Pharmacol 2000, 409: 37–43. 10.1016/S0014-2999(00)00796-2PubMedGoogle Scholar
- Laporte AM, Koscielniak T, Ponchant M, Verge D, Hamon M, Gozlan H: Quantitative autoradiographic mapping of 5-HT3 receptors in the rat CNS using [125I]iodo-zacopride and [3H]zacopride as radioligands. Synapse 1992, 10: 271–281. 10.1002/syn.890100402PubMedGoogle Scholar
- Morales M, McCollum N, Kirkness EF: 5-HT(3)-receptor subunits A and B are co-expressed in neurons of the dorsal root ganglion. J Comp Neurol 2001, 438: 163–172. 10.1002/cne.1307PubMedGoogle Scholar
- Ali Z, Wu G, Kozlov A, Barasi S: The role of 5HT3 in nociceptive processing in the rat spinal cord: results from behavioural and electrophysiological studies. Neurosci Lett 1996, 208: 203–207. 10.1016/0304-3940(95)12600-7PubMedGoogle Scholar
- Garraway SM, Hochman S: Serotonin increases the incidence of primary afferent-evoked long-term depression in rat deep dorsal horn neurons. J Neurophysiol 2001, 85: 1864–1872.PubMedGoogle Scholar
- Suzuki R, Rahman W, Hunt SP, Dickenson AH: Descending facilitatory control of mechanically evoked responses is enhanced in deep dorsal horn neurones following peripheral nerve injury. Brain Res 2004, 1019: 68–76. 10.1016/j.brainres.2004.05.108PubMedGoogle Scholar
- Green GM, Scarth J, Dickenson A: An excitatory role for 5-HT in spinal inflammatory nociceptive transmission; state-dependent actions via dorsal horn 5-HT(3) receptors in the anaesthetized rat. Pain 2000, 89: 81–88. 10.1016/S0304-3959(00)00346-8PubMedGoogle Scholar
- Li P, Kerchner GA, Sala C, Wei F, Huettner JE, Sheng M, Zhuo M: AMPA receptor-PDZ interactions in facilitation of spinal sensory synapses. Nat Neurosci 1999, 2: 972–977. 10.1038/14771PubMedGoogle Scholar
- Li P, Zhuo M: Silent glutamatergic synapses and nociception in mammalian spinal cord. Nature 1998, 393: 695–698. 10.1038/31496PubMedGoogle Scholar
- Fu KY, Light AR, Maixner W: Long-lasting inflammation and long-term hyperalgesia after subcutaneous formalin injection into the rat hindpaw. J Pain 2001, 2: 2–11. 10.1054/jpai.2001.9804PubMedGoogle Scholar
- Curtin LI, Grakowsky JA, Suarez M, Thompson AC, DiPirro JM, Martin LB, Kristal MB: Evaluation of buprenorphine in a postoperative pain model in rats. Comp Med 2009, 59: 60–71.PubMed CentralPubMedGoogle Scholar
- Pogatzki EM, Niemeier JS, Brennan TJ: Persistent secondary hyperalgesia after gastrocnemius incision in the rat. Eur J Pain 2002, 6: 295–305. 10.1053/eujp.2002.0339PubMedGoogle Scholar
- Zahn PK, Brennan TJ: Primary and secondary hyperalgesia in a rat model for human postoperative pain. Anesthesiology 1999, 90: 863–872. 10.1097/00000542-199903000-00030PubMedGoogle Scholar
- Jones TL, Lustig AC, Sorkin LS: Secondary hyperalgesia in the postoperative pain model is dependent on spinal calcium/calmodulin-dependent protein kinase II alpha activation. Anesth Analg 2007, 105: 1650–1656. 10.1213/01.ane.0000287644.00420.49PubMedGoogle Scholar
- Pogatzki EM, Niemeier JS, Sorkin LS, Brennan TJ: Spinal glutamate receptor antagonists differentiate primary and secondary mechanical hyperalgesia caused by incision. Pain 2003, 105: 97–107. 10.1016/S0304-3959(03)00169-6PubMedGoogle Scholar
- Pogatzki-Zahn EM, Niemeier JS, Sorkin LS, Brennan TJ: [Spinal glutamate receptor antagonists differentiate primary and secondary mechanical hyperalgesia caused by incision]. Schmerz 2006, 20: 245–253. 10.1007/s00482-006-0481-8PubMedGoogle Scholar
- Zimmermann M: Ethical guidelines for investigations of experimental pain in conscious animals. Pain 1983, 16: 109–110. 10.1016/0304-3959(83)90201-4PubMedGoogle Scholar
- Prado WA: Antinociceptive potency of intrathecal morphine in the rat tail flick test: a comparative study using acute lumbar catheter in rats with or without a chronic atlanto-occipital catheter. J Neurosci Methods 2003, 129: 33–39. 10.1016/S0165-0270(03)00197-3PubMedGoogle Scholar
- Brennan TJ, Vandermeulen EP, Gebhart GF: Characterization of a rat model of incisional pain. Pain 1996, 64: 493–501. 10.1016/0304-3959(95)01441-1PubMedGoogle Scholar
- Lino-de-Oliveira C, Sales AJ, Del Bel EA, Silveira MC, Guimaraes FS: Effects of acute and chronic fluoxetine treatments on restraint stress-induced Fos expression. Brain Res Bull 2001, 55: 747–754. 10.1016/S0361-9230(01)00566-4PubMedGoogle Scholar
- Silberstein SD: Methysergide. Cephalalgia 1998, 18: 421–435. 10.1046/j.1468-2982.1998.1807421.xPubMedGoogle Scholar
- Glennon RA, Metwally K, Dukat M, Ismaiel AM, De los Angeles J, Herndon J, Teitler M, Khorana N: Ketanserin and spiperone as templates for novel serotonin 5-HT(2A) antagonists. Curr Top Med Chem 2002, 2: 539–558. 10.2174/1568026023393787PubMedGoogle Scholar
- Hoyer D, Clarke DE, Fozard JR, Hartig PR, Martin GR, Mylecharane EJ, Saxena PR, Humphrey PP: International Union of Pharmacology classification of receptors for 5-hydroxytryptamine (Serotonin). Pharmacol Rev 1994, 46: 157–203.PubMedGoogle Scholar
- Miller K, Weisberg E, Fletcher PW, Teitler M: Membrane-bound and solubilized brain 5HT3 receptors: improved radioligand binding assays using bovine area postrema or rat cortex and the radioligands 3H-GR65630, 3H-BRL43694, and 3H-LY278584. Synapse 1992, 11: 58–66. 10.1002/syn.890110108PubMedGoogle Scholar
- Wong DT, Robertson DW, Reid LR: Specific [3H]LY278584 binding to 5-HT3 recognition sites in rat cerebral cortex. Eur J Pharmacol 1989, 166: 107–110. 10.1016/0014-2999(89)90689-4PubMedGoogle Scholar
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You can extend the Support & Update License for 1 or 2 years at once. For this, you just need to select the necessary Support & Update License validity term during the checkout process. The price of the product with the extended License will not change. Thus, you will not only save money on further License extension, but make us sure that our products are useful for you.
Discount on the Support & Update License
You will have a chance to extend the Support & Update License with a 50% discount throughout all your Support & Update License validity term. The week before the Support & Update License expiry, you will receive a notification about it on your e-mail.You will also have an opportunity to extend the License for half-off the product price during the following week after its expiry.
And what about Support & Update License for previously purchased products?
We haven't forgotten about the customers who purchased our products before the new Support & Update License introduction. All of them will get free 3-month term of support and updates. It will be added to the remaining part of the previous 12-month Support & Update License after it terminates.
We realize that some questions may arise. That's why we've prepared FAQ where you can find answers concerning the new Policy. If you have any further questions, please feel free to ask them on email@example.com.
Thank you for understanding. We hope our Magento tools will encourage your business growth.
Best regards, Anastasia Pletneva


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February 14th MCAH Closed 12:30 - 2:30 for Staff Meeting26-Dec-2017
MCAH Staff Meeting
We will be closed from 12:30 to 2:30 PM on Wednesday February 14th for our monthly staff meeting.
As always, one of our doctors is always on call in the event of an emergency. Please dial the main number at 410-343-0200 and follow the prompts to reach the doctor on call.
Mount Carmel Animal Hospital16904 York Road • Monkton, MD 21111
Monday - Friday 7:30am - 8:00pm
Saturday - Sunday 8:00am - 3:00pm
"In times of joy, we all wish we had a tail we could wag…"
- Alden