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subset: commoncrawl


text:
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Date: 12-06-2018
Case Style:
State of New Jersey v. Carlos B. Green
Case Number: 080274
Judge: Lee Solomon
Court: SUPREME COURT OF NEW JERSEY
Plaintiff's Attorney: Theodore N. Stephens, II, Acting Essex County Prosecutor, attorney; Stephen A. Pogany, of counsel and on the briefs
Defendant's Attorney: Joseph E. Krakora, Public Defender, attorney; Molly ODonnell Meng, of counsel and on the briefs
On a late December night in 2014, defendant Carlos B. Green (Green)
struck and killed Billy Ray Dudley (Dudley), who was lying in the road. A
toxicology lab determined Greens blood alcohol concentration (BAC) to be
0.210% at the time of the accident. Pursuant to N.J.S.A. 39:4-50, a person
who operates a motor vehicle with a BAC of 0.08% or more is guilty of
driving while intoxicated.
Green had two prior DWI convictions in 1998 and 2009, for which his
sentences each required completion of an educational course at the Intoxicated
Driving Resource Center (IDRC). The IDRC conducts a post-conviction
intervention program for those convicted of an alcohol or drug-related traffic
offense. The program is designed to educate participants about alcohol and its
effects on motor vehicle safety. At the IDRC, participants attend a series of
educational sessions and discussions in order to successfully complete the
As a result of Dudleys death, Green was charged in a grand jury
indictment with first-degree vehicular homicide while intoxicated and within
1,000 feet of a school, contrary to N.J.S.A. 2C:11-5(b)(3)(a). Before trial, the
State moved in limine to introduce Greens two prior DWI convictions, which
the State argued were relevant to the issue of recklessness. According to the
State, the prior convictions demonstrated that Green had knowledge of the
substantial and unjustifiable risks associated with driving while intoxicated.
The trial court denied the States motion. Applying the factors
established by this Court in State v. Cofield, 127 N.J. 328, 338 (1992), the trial
judge ruled that the evidence was unduly prejudicial because a jury might use
the prior convictions as evidence that Green acted in conformity with that
behavior in this instance. Quoting United States v. Rutherford, 54 F.3d 370,
376 (7th Cir. 1995), the court noted that [a]ny drunk driver who takes to the
road should know he runs a risk of injuring another person. The court also
ruled that the evidence was cumulative because the State had a toxicology
report indicating that Green had a BAC of 0.210% at the time of the incident.
Therefore, the State did not need to rely on defendants prior convictions to
establish recklessness.
The Appellate Division granted the States motion for leave to file an
interlocutory appeal. On appeal, the State primarily relied on State v. Bakka,
176 N.J. 533 (2003), for the proposition that prior unsafe conduct, like driving
while intoxicated, can be highly probative of recklessness. The State also
cited decisions from other jurisdictions that admit evidence of prior DWI
convictions to establish recklessness. Finally, the State argued that because
Green was instructed at the IDRC about the dangers of driving while
intoxicated, evidence of his convictions would tend to prove his awareness and
conscious disregard of the risks of driving while intoxicated when he chose to
drink and drive again.
In response, Green argued that the motion judge correctly applied the
Cofield factors to exclude his prior convictions, which were too remote and
unduly prejudicial. Green stressed that other than his intoxication, there was
no indication that he was operating his vehicle recklessly -- Green was not
swerving or speeding, he had his lights on, and Dudley was lying in the
roadway in the dark. Finally, Green contended that the State could prove his
intoxication with less inflammatory evidence, such as the toxicology results
and police testimony.
The Appellate Division affirmed the trial court, citing this Courts
acknowledgment that [d]riving while intoxicated may alone satisfy the
recklessness required by the death by auto statute. State v. Green, 452 N.J.
Super. 323, 325-26 (App. Div. 2017) (quoting State v. Jamerson, 153 N.J. 318,
335 (1998)). The panel found that Cofield requires trial courts to engage in a
careful and pragmatic evaluation that focuses on the specific context in
which [other-crimes] evidence is offered to determine admissibility. Id. at
326-27 (quoting State v. Stevens, 115 N.J. 289, 303 (1989)). Applying the
Cofield factors, the panel concluded that the trial judge did not abuse his
discretion in excluding Greens two prior DWI convictions. Id. at 328-29.
The State sought leave to appeal, which we granted. 232 N.J. 97 (2018).
We also granted amicus curiae status to the New Jersey Attorney General.
The parties arguments here mirror those raised in the Appellate
Division. In addition, the State urges this Court to join those jurisdictions that
admit evidence of prior bad acts for the purpose of establishing knowledge,
malice, or another state of mind. The State argues that this Court should
therefore hold that Greens prior DWI convictions are admissible for the
limited purpose of establishing his knowledge and recklessness. The State also
contends that there is no reason to believe that the jury would use this evidence
for an improper purpose, particularly because trial courts can alleviate any
prejudicial effect by giving a limiting instruction.
The Attorney Generals arguments largely echo the arguments set forth
by the State. Additionally, the Attorney General asks this Court to revisit
Cofields Rule 404(b) analysis, arguing that the Cofield Court intended to
simply incorporate Rule 403 into the other-crimes test. According to the
Attorney General, the fourth prong has somehow morphed into a more
stringent Rule 404(b) analysis. The Attorney General thus urges this Court to
reevaluate the dramatic shifting of Cofields fourth prong, particularly
because this shift occurred without the issue being litigated.
Green asks this Court to reject the States invitation to follow other
jurisdictions with less-protective rules of evidence. Green also argues that
the States reliance on Bakka is misplaced, as the defendant in Bakka drove
with a suspended license and was charged with aggravated manslaughter,
which requires proof of a higher level of recklessness than does vehicular
homicide. Green further contends that even if Bakka is applicable, the trial
court and Appellate Division decisions were entirely consistent with Bakkas
mandate to apply the Cofield factors on a case-by-case basis.
We begin our discussion by acknowledging that the admissibility of
evidence at trial is left to the sound discretion of the trial court. State v.
Willis, 225 N.J. 85, 96 (2016). A trial courts evidentiary ruling is therefore
reviewed on appeal for abuse of discretion. State v. Rose, 206 N.J. 141, 157
(2011). In addition, sensitive admissibility rulings regarding other-crimes
evidence made pursuant to Rule 404(b) are reversed [o]nly where there is a
clear error of judgment. Id. at 157-58 (alteration in original) (quoting State v.
Barden, 195 N.J. 375, 391 (2008)). However, that deferential approach is
inappropriate when the trial court failed to properly apply Rule 404(b) to the
evidence at trial. Id. at 158. When that occurs, an appellate court may
engage in its own plenary review to determine . . . admissibility. Ibid.
(quoting Barden, 195 N.J. at 391). In other words, appellate review is de novo
when the court should have, but did not perform a Cofield analysis. State v.
Reddish, 181 N.J. 553, 609 (2004).
This appeal focuses on the admission of other-crimes evidence --
specifically, Greens two prior DWI convictions and evidence of his
subsequent participation in IDRC courses. Rule 404(b) bars evidence of
other crimes, wrongs, or acts when used to show that [a] person acted in
conformity therewith. N.J.R.E. 404(b). However, evidence of prior crimes,
wrongs, or acts may be used to show intent, . . . knowledge, . . . or absence
of mistake or accident. Id. Because evidence of a defendants other crimes
has a unique tendency to prejudice the jury, Reddish, 181 N.J. at 608
(quoting Stevens, 115 N.J. at 302), other-crimes evidence proffered under Rule
404(b) must pass [a] rigorous test, State v. Garrison, 228 N.J. 182, 194
(2017) (alteration in original) (quoting State v. Kemp, 195 N.J. 136, 159
In Cofield, we adopted a four-part test to determine the admissibility of
other-crimes evidence:
(1) The evidence of the other crime must be admissible as relevant to a material issue;
(2) It must be similar in kind and reasonably close in time to the offense charged;
(3) The evidence of the other crime must be clear and convincing; and
(4) The probative value of the evidence must not be outweighed by its apparent prejudice.
[127 N.J. at 338.]
Trial courts must apply that test on a case-by-case basis in order to
avoid the over-use of extrinsic evidence of other crimes or wrongs. Ibid. The
four-part Cofield test governing the admissibility of other-crimes evidence is a
well-settled feature of New Jerseys evidence jurisprudence.
To satisfy the first prong of the Cofield test, the proffered evidence
must be relevant to a material issue genuinely in dispute. State v. Gillispie,
208 N.J. 59, 86 (2011) (quoting State v. Darby, 174 N.J. 509, 519 (2002)).
Rule 401 defines relevant evidence as any evidence that has a tendency in
reason to prove or disprove any fact of consequence to the determination of the
action. Darby, 174 N.J. at 519 (quoting N.J.R.E. 401). In determining
relevance, the inquiry should focus on the logical connection between the
proffered evidence and a fact in issue. Ibid. (quoting State v. Hutchins, 241
N.J. Super. 353, 358 (App. Div. 1990)). The required logical connection has
been satisfied if the evidence makes a desired inference more probable than it
would be if the evidence were not admitted. Garrison, 228 N.J. at 195
(quoting State v. Williams, 190 N.J. 114, 123 (2007)).
Here, as a result of his DWI convictions, Green was required to take
courses at the IDRC, where he learned of the dangers of driving while
intoxicated. As such, the proffered evidence supports the States contention
that Green knew of and consciously disregarded the risks of driving while
intoxicated. Thus, Greens previous DWI convictions and compulsory IDRC
participation were relevant to a material issue at trial, namely Greens
The second prong requires that the other acts be similar in kind and
reasonably close in time to the offense charged. Cofield, 127 N.J. at 338.
Application of this prong is limited to cases that replicate the circumstances
in Cofield. Williams, 190 N.J. at 131. Although relevant in Cofield, this
Court has recognized that similarity and temporality are not applicable in
every case. Rose, 206 N.J. at 163. As a result, Cofields second prong may be
eliminated where it serves no beneficial purpose. Williams, 190 N.J. at 131.
We find that to be the case here.
Under the third Cofield prong, the prosecution must establish that the
other crime actually happened by clear and convincing evidence. Rose,
206 N.J. at 160 (quoting Cofield, 127 N.J. at 338). Here, the State offered
judgments of conviction as evidence of Greens prior DWIs. Therefore, the
evidence satisfies Cofields third prong.
Because of the damaging nature of [other crimes] evidence, the fourth
Cofield prong -- [t]he probative value of the evidence must not be outweighed
by its apparent prejudice, 127 N.J. at 338 -- is the most difficult to
overcome. Rose, 206 N.J. at 160 (citing Barden, 195 N.J. at 389). That
prong requires an inquiry distinct from the familiar balancing required under
N.J.R.E. 403: the trial court must determine only whether the probative value
of such evidence is outweighed by its potential for undue prejudice, Barden,
195 N.J. at 389, not whether it is substantially outweighed by that potential as
in the application of Rule 403.1 [I]f other less prejudicial evidence may be
presented to establish the same issue, the balance in the weighing process will
1 The State and the Attorney General cite to authority from other federal and state jurisdictions and ask us to adopt a less stringent standard for analyzing Cofields fourth prong. We decline the invitation to alter New Jerseys wellsettled jurisprudence in this regard.
tip in favor of exclusion. Rose, 206 N.J. at 161 (quoting Barden, 195 N.J. at
392). Therefore, Rule 404(b) is viewed as a rule of exclusion rather than a
rule of inclusion. Reddish, 181 N.J. at 609 (quoting Darby, 174 N.J. at 520).
Nevertheless, some types of evidence, such as evidence of motive or intent,
require a very strong showing of prejudice to justify exclusion. Garrison,
228 N.J. at 197 (quoting State v. Skinner, 218 N.J. 496, 516 (2014)).
To reduce the inherent prejudice in the admission of other-crimes
evidence, trial courts are required to sanitize the evidence when
appropriate, Rose, 206 N.J. at 161 (quoting Barden, 195 N.J. at 390), by
allowing the introduction of only the degree and date of the offense, State v.
Brunson, 132 N.J. 377, 391 (1993).2 To further minimize the inherent
prejudice in the admission of other-crimes evidence, a carefully crafted
limiting instruction must be provided to inform the jury of the purposes for
which it may, and for which it may not, consider the evidence of defendants
[other crimes], both when the evidence is first presented and again as part of
the final jury charge. Rose, 206 N.J. at 161 (citing Barden, 195 N.J. at 390).
However, the inherently prejudicial nature of other-crimes evidence casts
2 Brunson modified this Courts decision in State v. Sands, 76 N.J. 127, 144 (1978), in which we held that the admissibility of a prior conviction to impeach the credibility of a testifying criminal defendant is a decision that rests within the sound discretion of the trial judge.
doubt on a jurys ability to follow even the most precise limiting instruction.
Reddish, 181 N.J. at 611 (quoting State v. Fortin, 162 N.J. 517, 534 (2000)).
The crux of this case is Cofields fourth prong. Greens two prior DWI
convictions and subsequent IDRC participation are probative of his mental
state when he committed the charged vehicular homicide. Specifically, Green
had twice been through the criminal justice process and therefore was
unquestionably aware that driving while intoxicated is an impermissible and
punishable offense. As a result of his convictions, Green was sentenced to
attend courses at the IDRC where he learned of the risks and dangers of
driving while intoxicated. Greens IDRC participation likely gave him a
heightened awareness of those risks and dangers. Therefore, the other-crimes
evidence tends to show that Green was aware of, but consciously disregarded,
the risks of driving while intoxicated, a mental state that is a material element
of vehicular homicide.
Nevertheless, other considerations diminish the probative value of the
evidence at issue. For example, Greens prior DWI convictions were from
1998 and 2009 -- many years before this fatal accident. The lapse of time has
an eroding effect on the instructive impact of the DWI convictions and ensuing
attendance at the IDRC.
Turning to prejudice, admission of the prior DWI convictions suggests to
the jury that Green acted in conformity with his prior behavior. The
circumstances surrounding this vehicular homicide prosecution indicate that,
although intoxicated, Green was not speeding, swerving, or otherwise
committing any traffic infractions. Therefore, the motion court could
reasonably conclude that admission of Greens prior DWI convictions would
confuse or risk misleading the jury, causing it to convict Green based solely on
his propensity to drive while intoxicated.
The potential for jury confusion is especially high when, as here, proof
of causation is tenuous. While Green was indeed intoxicated on the night of
the accident, Dudley was lying in the middle of a dark roadway when he was
struck by Greens vehicle. Even with the most carefully crafted limiting
instruction, admission of Greens two prior DWI convictions could result in
the jurys conflating recklessness and causation.
Additionally, the State possesses a less inflammatory source of probative
evidence -- Greens BAC of 0.210% at the time of the incident. Proof that
the defendant was driving while intoxicated . . . shall give rise to an inference
that the defendant was driving recklessly. N.J.S.A. 2C:11-5(a). In the drunk
driving context, [i]ntoxication in combination with other evidence or standing
alone may satisfy the recklessness element. State v. Stanton, 176 N.J. 75, 84
(2003). Although N.J.S.A. 2C:11-5(a) does not mandate that the jury accept
the inference of recklessness, the jury may infer recklessness based solely on
Greens BAC. Therefore, the State has at its disposal probative and far less
inflammatory evidence of Greens reckless state of mind.
In light of the circumstances present in this case, the risk that a jury
would convict Green based on his propensity to drive while intoxicated
outweighs the probative value of his more than five-year-old DWI convictions.
Therefore, balancing the probative value against the prejudice of admitting
defendants prior DWI convictions and IDRC program participation under
Rule 404(b) favors exclusion of the evidence.
Our independent analysis leads to the conclusion that Greens prior DWI
convictions are inadmissible under Rule 404(b). In that respect, we affirm the
judgment of the Appellate Division.
We acknowledge that the State, relying on Bakka, urges a different
conclusion. In Bakka, the defendant crashed his girlfriends car while
intoxicated, killing a passenger. 176 N.J. at 539. Prior to trial, the court
granted the States motion in limine, allowing it to introduce evidence that the
defendant was driving with a revoked license at the time of the accident. Id. at
543. The jury thereafter convicted the defendant of first-degree aggravated
manslaughter and second-degree vehicular homicide. Ibid. The Appellate
Division found that the trial court improperly admitted the evidence of
revocation and vacated the defendants convictions. Id. at 544.
This Court agreed with the Appellate Division that the mere fact that a
defendant is an unlicensed driver does not by itself suggest an awareness of
risk. Id. at 546. We thus agreed that its admission was error but concluded
that the error was harmless under the circumstances of that case and reinstated
the defendants convictions. Id. at 550-51.
Although we found error, we acknowledged that the reasons for that
revocation may be probative of recklessness when defendant again engages in
unsafe conduct identical or similar to that which resulted in the revocation.
Id. at 547. In other words, the revocation may serve as an additional
warning to the defendant of the risks to others when the proscribed conduct
is repeated and therefore may be probative of recklessness. Ibid.
Likewise, we hold here that the trial court and Appellate Division were
correct to exclude defendants prior DWI convictions. However, as we did in
the circumstances of Bakka, we recognize that there may be a situation in
which prior DWI convictions of a defendant charged with vehicular homicide
while intoxicated would be admissible under Rule 404(b) as evidence of
recklessness, despite the statutory inference of recklessness arising from
evidence that the defendant drove with a BAC over 0.08%. The probative
value of prior DWI convictions close in time to the incident charged may, only
in the rare case, outweigh the potential for undue prejudice. We therefore
encourage trial judges to perform a thorough Cofield analysis and not presume
a per se exclusion of such evidence. The admissibility of Rule 404(b)
evidence must be considered on a case-by-case basis by analyzing the evidence
proffered and the circumstances of the case.
Outcome: For the reasons set forth above, we affirm the judgment of the Appellate
Plaintiff's Experts:
Defendant's Experts:


text:
Original Research ARTICLE
Chronic Stress Is Associated with Pain Precipitation and Elevation in DeltaFosb Expression
- 1Jiangsu Province Key Laboratory of Anesthesiology, College of Anesthesiology, Xuzhou Medical University, Xuzhou, China
- 2College of Medicine, Anhui University of Science and Technology, Huainan, China
- 3School of Basic Medical Sciences, Anhui Medical University, Hefei, China
A number of acute or repeated stimuli can induce expression of DeltaFosB (ΔFosB), a transcription factor derived from the fosB gene (an osteosarcoma viral oncogene) via alternative splicing. ΔFosB protein is currently viewed as a 'molecular switch' to repeated stimuli that gradually converts acute responses into relatively stable adaptations underlying long-term neural and behavioral plasticity. ΔFosB has received extensive attention in drug addition, depression, and stress adaptation, but changes in ΔFosB protein expression during pain is not fully understood. In this study we explored ΔFosB expression in the medial prefrontal cortex (mPFC) of rats experiencing chronic or acute stress-induced pain. Our data reveal that chronic pain induced by neonatal colorectal distension, chronic constriction injury (CCI) of the sciatic nerve, or maternal separation was associated with an increase in ΔfosB protein expression in mPFC, but acute application of acetic acid or zymosan did not alter the ΔFosB protein expression. ΔFosB expression in the rat visual cortex, a non pain-related brain region, did not change in response to (CCI) of the sciatic nerve and acetic acid treatment. In conclusion, our results indicate that ΔFosB protein expression is significantly elevated in rats that have experienced chronic pain and stress, but not acute pain. The ΔFosB protein may serve as an important transcription factor for chronic stress-induced pain. Further research is needed to improve the understanding of both the upstream signaling leading to ΔFosB protein expression as well as the regulation of ΔFosB gene expression in cortical neurons.
Pain is associated with an alteration in gene expression and neuronal plasticity (Baliki et al., 2014) that can result in persistent structural and functional modifications (Woolf and Costigan, 1999; Ji et al., 2014). Transcription factors bridge the pathological events in the central nervous system (CNS) with alterations in gene expression during the pathogenesis of pain (Woolf and Costigan, 1999; Zhang et al., 2015). Transcription factors belonging to the Fos family may be important candidates for pain modulation (Luis-Delgado et al., 2006). Encoded by c-fos, fosB, fra-1, and fra-2 genes (Herdegen and Leah, 1998), Fos family proteins are induced rapidly and transiently in specific brain regions to regulate downstream gene expression in response to environmental factors (Sheng and Greenberg, 1990; Perrotti et al., 2004). These Fos family proteins form heterodimers with Jun family proteins (c-Jun, JunB, or JunD) to form functioning activator protein-1 (AP1) transcription factors that bind to AP1 consensus sites present in the promoters of certain genes to regulate their transcription. The DeltaFosB (ΔFosB) protein is a truncated splice variant of fosB, missing 101 amino acids at the C-terminal of the FosB protein (Nakabeppu and Nathans, 1991). Recently the ΔFosB protein has received extensive attention in drug addition, depression and stress adaptation (McClung and Nestler, 2003; Perrotti et al., 2004).
The ΔFosB protein is encoded by the fosB gene and shares homology with other Fos family proteins (Morgan and Curran, 1995). ΔFosB has the same dimerization and DNA-binding activities of FosB. Upon stress stimulus, the post-translational modifications of ΔFosB protein lead to different protein isoforms with half-lives between 10 h and 8 days (McClung et al., 2004). Therefore, ΔFosB protein is assumed to function as a "molecular switch" that mediates persistent adaptations in the brain's response to repetitive or long-lasting stimuli (Nestler et al., 1999, 2001). In the CNS, ΔFosB has been examined in the context of electroconvulsive treatment and epilepsy (Morris et al., 2000), addiction (McClung and Nestler, 2003; Zhang et al., 2014), compulsive running (Werme et al., 2002), dyskinesia (Andersson et al., 2003), and stress (Perrotti et al., 2004). For instance, Zhang reported that ΔFosB overexpression decreases cocaine self-administration, enhances extinction of cocaine seeking, and decreases cocaine-induced reinstatement of intravenous cocaine self-administration (Zhang et al., 2014). However, limited evidence suggests an involvement of ΔFosB protein in acute or chronic stress-induced pain precipitation. Mice overexpressing the ΔFosB protein in the nucleus accumbens and the dorsal striatum displayed reduced analgesic responses to acute morphine administration as well as faster development of morphine tolerance (Zachariou et al., 2006). Carrageenan-induced inflammation increases ΔFosB protein expression in the spinal cord (Luis-Delgado et al., 2006). These reports suggest that ΔFosB may be an important molecular modulator participating in the pathogenesis of pain. To date, the direct evidence of changes in ΔFosB protein expression in various pain models has not been reported.
Pain is associated with depression and cognitive decline (Metz et al., 2009; Zhang et al., 2015), suggesting an involvement of cortical areas associated with cognitive functions. The medial prefrontal cortex (mPFC) plays a critical role in pain-related depression and anxiety, which are frequent co-morbidities of chronic pain (Guida et al., 2015). Unilateral chronic constriction injury (CCI) to the infraorbital nerve induces a strong, bilateral upregulation of extracellular signal regulated kinases 1/2 (pERK-1/2) in the ventral mPFC in rats (Devoize et al., 2011). Stress induces ΔFosB protein expression in mPFC, and that overexpression of ΔFosB in pre-limbic mPFC enhances stress susceptibility in mice (Vialou et al., 2014). mPFC may be a key brain region through which the ΔFosB protein modulates the establishment and maintenance of pain.
In the present study, we examined ΔFosB protein expression in mPFC in rodents that experienced acute and chronic stress-induced pain. The visual cortex, a non pain-related brain region, was used as a control. Our data reveal that chronic stress-induced pain was associated with an increase in the expression of mPFC ΔFosB protein, but ΔFosB expression did not change in rats that experienced acute stress-induced pain. These results illuminate a new molecular mechanism of pain, and may pave a new avenue for development of therapeutics against pain.
Materials and Methods
Male Sprague-Dawley rats weighing 220 to 250 g and C57B mice weighing 21 to 24 g were obtained from the Experimental Animal Center of Xuzhou Medical University (Xuzhou, China) and housed in groups of four per standard polycarbonate cage and kept on a standard 12 h light/dark cycle (lights on at 07:00 a.m.), constant temperature and humidity (22°C and 50%, respectively) with food provided ad libitum. All procedures were conducted in accordance with the guidelines described in the National Institutes of Health's Guide for the Care and Use of Laboratory Animals (NIH Publication No. 8023, revised 1978) and the International Association for the Study of Pain, and approved by the Institutional Animal Care and Use Committee at Xuzhou Medical College.
Development of Pain Models
Development of Visceral Hypersensitivity Rat Model with Colorectal Distensions
Visceral hypersensitivity was induced by adult colorectal distension (CRD) in rats that experience neonatal CRDs as described previously (Chen et al., 2015; Zhang et al., 2015). In brief, neonatal CRDs were induced on postnatal days 8, 10, and 12 using an angioplasty balloon (length, 20.0 mm; diameter, 3.0 mm) inserted into the upper rectum and descending colon (the section of the large intestine that travels back down toward the rectum). The balloon was distended with 0.3 ml water at a pressure of 60 mm Hg for 1 min before deflation and withdrawal. The distention was repeated twice with a 30-min break. CRD for adult rats was established 8 weeks later in which an 80 mm Hg (1 min) distention was given twice with a 5 min interval. The extent of visceral hypersensitivity was assessed with abdominal withdrawal reflex (AWR) scores, pain threshold, and electromyography activities of oblique muscles as described previously (Zhang et al., 2015).
Chronic Constriction Injury (CCI) Neuropathic Pain Model
The chronic neuropathic pain model was generated using a chronic sciatic nerve compression injury method (Bennett and Xie, 1988). Rats were anaesthetized with intraperitoneal injection of 10% chloral hydrate at 400 mg/kg. After anaesthetization and disinfection, the sciatic nerve trunk was isolated and ligated for a total of four ligations at an interval of 1 mm. The sciatic nerve was exposed without ligation treatment in the control group. Paw withdrawal latency (PWL) was used to evaluate the pain level.
Maternal Separation Model
The protocol of maternal separation was conducted as previously described in detail (Wang et al., 2015). The male and female rats were mated to produce litters. After birth, the pups were randomly divided into two groups: the maternal separation group and the non-maternal separation group. Neonatal mice were separated from mothers for 4 h (10:00 a.m.–2:00 p.m.) per day ranging from postnatal day 1 to day 15, and maintained on a water-heating pad (29 ± 1°C) separately from their littermates. The pups in non-maternal separation group remained in their home cages with their mothers and littermates during the 4 h separation.
Acetic Acid-Elicited Acute Visceral Pain
Intraperitoneal acetic acid-induced abdominal contraction was used to establish the acute pain model (Martinez et al., 1999). In brief, mice were placed individually in a standard polycarbonate cage, and allowed to habituate to the environment for 30 min. Acetic acid (0.6% in distilled water) was injected intraperitoneally in a volume of 10 ml/kg. Immediately after the acetic acid or vehicle injection, pain responses were scored by counting the number of abdominal contractions (writhing test) in 15 min intervals for 1 h. An abdominal contraction was defined as a lengthwise stretching of the torso with a concomitant arching of the back.
Zymosan-Induced Paw Inflammatory Pain
Intraplantar injections of zymosan (1.25 mg/100 μl) were utilized to induce paw inflammation. Sham group received an equal volume of saline. The thermal latencies of the rats were measured pre- and 0.5, 1, 2, 4, 8, and 24 h post-injection.
Immunofluorescence Labeling
Rats were deeply anesthetized with 10% chloral hydrate (250 mg/kg) and perfused transcardially with 300 ml 0.9% saline, followed by 4% paraformaldehyde. The entire brain was quickly removed and further fixed in 4% paraformaldehyde for 48 h at 4°C before being equilibrated in a 30% sucrose solution at 4°C for 2 days. Double immunofluorescence labeling was used to identify ΔFosB protein distribution in particular cell types. The mPFC region was cut in 30-μm thick slices with a cryostat (Leica CM1800; Heidelberg, Germany). Selected sections were washed with PBS for 5 min three times, and then incubated with 10% donkey serum in PBS containing 0.3% Triton-X-100 for 2 h at room temperature before incubation with rabbit anti-delta Fosb antibody (1:500, #9890, Cell Signaling Technology), anti-neuronal nuclei (NeuN) antibody (1:200; MAB377X, Millipore), anti-glial fibrillary acidic protein (GFAP; 1:200; #3670, Cell Signaling Technology), or anti-ionized calcium-binding adaptor molecule 1 (Iba-1; 1:200; ab5076, Abcam) at 4°C for 24 h. Alexa 488 donkey anti-rabbit IgG (1:200), Alexa 594 donkey anti-mouse IgG (1:200), or Alexa 594 donkey anti-goat IgG (1:200) were added to the corresponding sections and incubated for 2 h at room temperature. Tissue sections were mounted with 50% glycerol mounting medium. Layer V of the prelimbic cortex on the left hemisphere in each mouse was visualized with a confocal laser microscope (FV1000; Olympus, Tokyo, Japan). Tissue images were processed using Image Pro-Plus 5.0 software (Media Cybernetics, Silver Spring, MD).
Western Blotting Analysis
The bilateral mPFC and visual cortex were collected from fresh brain and lysed in RIPA lysis buffer containing 50 mM Tris (pH 7.4), 150 mM NaCl, 1% Triton X-100, 1% sodium deoxycholate, 0.1% SDS, 1 mM sodium orthovanadate, and 1 mM Phenylmethanesulfonyl fluoride (PMSF). Homogenates were keep on ice for another 30 min before being centrifuged at 8,000 g for 5 min at 4°C; the supernatant containing the cytoplasmic components was saved at -80°C before analysis. Equal amounts of protein (80 μg) were separated by SDS-PAGE, transferred electrophoretically to nitrocellulose membrane, and incubated with rabbit polyclonal anti-ΔFosB overnight at 4°C. The membrane was washed thoroughly and incubated with AP-conjugated secondary antibody (1:1000) for 2 h at room temperature. Protein bands were visualized using the BCIP/NBT Alkaline Phosphatase Color Development Kit and quantified using Image J software (National Institutes of Health).
Statistical Analysis
Data were expressed as mean ± SEM. The time-course of the number of abdominal contraction was analyzed by a two-way repeated measures ANOVA. Student's t-test, one-way ANOVA, and two-way ANOVA were also used. If significance was found, post hoc Bonferroni multiple comparison was used. All statistical tests were conducted using SPSS 19.0 software package (IBM, Armonk, NY, USA) with p < 0.05 considered statistically significant.
Neonatal CRD Exposure is Associated with an Increase in Adult ΔFosB Protein Expression in mPFC
The ΔFosB protein labeling was compared with neuronal marker NeuN, microglial marker Iba-1 and astrocyte marker GFAP. The top row in Figure 1A shows the ΔFosB and NeuN staining in prelimbic area of drug-naïve rats. Rows 2–4 in Figure 1A illustrate protein staining in rats that had experienced neonatal and adult CRDs. As compared to drug-naïve rats, the rats experienced CRDs presented a significant increase in NeuN and ΔFosB immunoreactivity. ΔFosB was visualized in pyramidal neurons marked by NeuN staining (Figure 1A). A two-way ANOVA on body weight revealed a significant main effect of neonatal CRDs [F(1,8) = 218.56, p < 0.01], a significant main effect of adult CRD [F(1,8) = 8.80, p < 0.05], but not the neonatal × adult CRDs interaction [F(1,8) = 6.39, p = 0.035] (n = 8 in each group; Figure 1B). As compared to naïve rats, there was a significant increase in ΔFosB protein expression in rats that had experienced neonatal CRDs [t(4) = 11.46, p < 0.01], adult CRDs [t(4) = 4.98, p < 0.01] or a combination of neonatal and adult CRDs [t(4) = 11.78, p < 0.01]. Adult CRD rats presented a significantly lower expression of ΔFosB protein levels as compared with rats that had experienced neonatal CRDs [t(4) = 8.99, p < 0.01] or a combination of neonatal and adult CRDs [t(4) = 0.9.35, p < 0.01]. There was no difference between rats that had experienced neonatal CRDs and those with a combination of neonatal + adult CRDs [t(4) = 0.26, p = 0.81] (Figure 1C).
FIGURE 1. Neonatal colorectal distension (CRD) exposure is associated with an increase in adult ΔFosB expression in mFPC. ΔFosB protein labeling was compared with neuronal marker NeuN, microglial marker Iba-1 and astrocyte marker GFAP. ΔFosB was visualized in pyramidal neurons marked by NeuN staining. Row one came from drug-naïve rats, and rows 2 to 4 was from rats that experienced neonatal and adult CRDs. Scale bar = 100 μm (A). Mice received neonatal and/or adult colorectal distension. There was no difference in body weight. (B; n = 8 per group). A two-way ANOVA on ΔFosB expression revealed a significant main effect of neonatal CRDs (p < 0.01) and a significant main effect of adult CRDs (p < 0.05). Rats that experienced neonatal or a combination of neonatal and adult CRDs presented a significant increase in ΔFosB expression compared with rats without CRDs or adult CRD only (C). Data were expressed as mean ± SEM, n = 3 in each group. **p < 0.01.
Chronic Constriction Injury Is Associated with an Increase in Adult ΔFosB Protein Expression in mPFC
The CCI in rats altered the PWL score (Figure 2A). A one-way ANOVA showed a significant difference [F(2,48) = 61.51, p < 0.01]; Post hoc Bonferroni's multiple comparisons showed that CCI rats (n = 17) presented a significant decrease in PWL as compared to control (n = 17; p < 0.01) or sham rats (n = 17; p < 0.01). There was no difference between control and sham rats. The CCI in rats altered the ΔFosB protein expression (Figure 2B). A one-way ANOVA showed a significant difference [F(2,9) = 174.7, p < 0.01]; Post hoc Bonferroni's multiple comparisons CCI rats (n = 4) presented a significant increase in ΔFosB expression as compared to control (n = 4; p < 0.01) and sham rats (n = 4; p < 0.01). Sham rats presented a significant increase in ΔFosB protein expression as compared to control rats (p < 0.01). On the other hand, ΔFosB protein expression in the visual cortex was not statistically different between control, sham and CCI rats [F(2,6) = 0.02, p = 0.98; n = 3 per group; Figure 2C].
FIGURE 2. Chronic constriction injury (CCI) is associated with an increase in adult ΔFosB expression in mPFC. Rats that received CCI of the sciatic nerve presented a significant decrease in paw withdrawal latency (PWL; A; n = 17 per group) and a significant increase in ΔFosB expression. (B; n = 4 per group) compared with control or sham rats. There was no change in ΔFosB expression in the visual cortex between control, sham and CCI groups. (C; n = 3 per group). Data were expressed as mean ± SEM, ∗∗p < 0.01.
Maternal Separation Is Associated with an Increase in Adult ΔFosB Expression in mPFC
Rats that underwent maternal separation presented a significant increase in ΔFosB protein expression in mPFC compared with that in the control group [t(4) = 4.95, p < 0.01, n = 3 per group; Figure 3].
FIGURE 3. Maternal separation is associated with an increase in adult ΔFosB expression in mPFC. Rats exposed to maternal separation exhibited a significant increase in ΔFosB expression in mPFC compared with that in the control group (p < 0.01, n = 3). Data were expressed as mean ± SEM, ∗∗p < 0.01 vs. control.
Acetic Acid-Induced Acute Visceral Pain Does Not Affect ΔFosB Expression in mPFC
Intraperitoneal injection of 0.6% acetic acid increased the number of abdominal contractions compared with that in the control group (Figure 4A). A two-way repeated measures ANOVA revealed a significant main effect of treatment [F(1,18) = 599.51, p < 0.01], a significant main effect of time [F(3,54) = 123.39, p < 0.01], and a significant time × treatment interaction [F(3,54) = 123.39, p < 0.01, n = 10 per group]. There was no significant difference in ΔFosB expression in mPFC between acetic acid group and control group [F(4,19) = 0.32, p = 0.86, n = 3; Figure 4B]. The ΔFosB expression in the visual cortex was not found to be statistically different between vehicle and acetic acid-treated rats [t(4) = 0.14, p = 0.89; n = 3; Figure 4C].
FIGURE 4. Acetic acid-induced acute pain does not affect ΔFosB expression in mPFC. Intraperitoneal injection of 0.6% acetic acid increased the number of abdominal contractions compared with that in control group. (A; n = 10 per group). The ΔFosB expression in mPFC was not significantly altered 15, 30, 45, and 60 min after acetic acid application. (B; n = 3 per group). There was no change in ΔFosB expression in the visual cortex between control and acetic acid-treated groups. (C; n = 3 per group; brain tissues were collected at 45 min after acetic acid treatment). Data were expressed as mean ± SEM, ∗∗p < 0.01 vs. vehicle.
Zymosan-Induced Paw Inflammatory Pain Does Not Affect ΔFosB Expression in mPFC
Intrapaw injection of zymosan decreased the latency of paw withdrawal compared with that in control group (Figure 5A). A two-way repeated measures ANOVA revealed a significant main effect of treatment [F(1,10) = 157.97, p < 0.01], a significant main effect of time [F(6,60) = 37.60, p < 0.01], and significant time × treatment interaction [F(6,60) = 27.84, p < 0.01, n = 6 per group]. There was no significant difference in ΔFosB expression in mPFC between zymosan-group and control group [F(6,14) = 0.97, p = 0.48, n = 3; Figure 5B].
FIGURE 5. Zymosan-induced paw inflammatory pain does not affect ΔFosB expression in mPFC. Intrapaw injection of zymosan decreased the latency of paw withdrawal compared to that in the control group. (A; n = 6 per group). The ΔFosB expression in mPFC was not significantly altered 1, 3, 6, 8, 12, and 24 h after zymosan application. (B; n = 3 per group). Data were expressed as mean ± SEM, ∗∗p < 0.01 vs. saline.
In this study, we examined ΔFosB protein expression in animals that experienced acute or chronic stress-induced pain. Our data reveal an increase in ΔFosB expression in animals with chronic pain induced by CRD, CCI, and maternal separation, but not in acetic acid-induced acute visceral pain and zymosan-induced acute inflammatory pain. ΔFosB protein expression in the visual cortex did not change as a result of CCI or acetic acid-induced pain. These results suggest that ΔFosB may be an important transcriptional factor that modulates neuronal adaptation specifically to chronic stress-induced pain. Elucidation of the molecular mechanisms that are responsible for the specific ΔFosB response to chronic pain provides new opportunities for therapeutic approaches to prevent acute pain translated into chronic pain.
Our data indicate that ΔFosB protein expression is increased in rats that experienced neonatal CRDs. Visceral hypersensitivity is a major contributor to irritable bowel syndrome and other disorders with chronic visceral pain (Chey et al., 2015). The pathogenesis of visceral hypersensitivity remains speculative due to undetectable structural abnormalities in the peripheral organs (Chen et al., 2015). In the present study, visceral hypersensitivity was developed by neonatal and adult CRDs in rats. We did not find any identifiable behavioral abnormalities in adult rats that experienced neonatal CRDs (Chen et al., 2015; Zhang et al., 2015), but adult re-exposure to CRD precipitated behavioral abnormalities and visceral pain hypersensitivity only in rats that experienced neonatal CRDs (Zhang et al., 2015). These results suggest that neonatal CRDs alter the neuronal traits, in spite of the body maintaining a normal phenotype through adaptation. Such a quiescent event can be prompted by a subthreshold stressor imposed late in life, and induces changes in genotype and phenotype, such as fear reaction, cognition, dysthymia, novelty-seeking, and pain perception (Charmandari et al., 2003). Our data indicate that the neonatal CRD is associated with a significant increase in ΔFosB protein expression in mPFC.
Chronic neuropathic pain is a prevalent and debilitating condition, affecting 7–18% of the population (Bouhassira et al., 2008; Toth et al., 2009). Clinical manifestation includes spontaneous pain, dysaesthesia, paraesthesia, allodynia, and hyperalgesia. The sensory symptoms are co-morbid with mental impairments, such as insomnia and depression. CCI of the sciatic nerve is a chronic neuropathic pain resulting from damage to the peripheral nervous system. The CCI model is a popular tool to study mechanisms for chronic neuropathic pain and to identify experimental compounds with analgesic properties that are palliative for chronic neuropathic pain. Unilateral CCI to the infraorbital nerve induces a strong, bilateral upregulation of pERK-1/2 in the ventral mPFC of rats (Devoize et al., 2011). Our data reveal an increase in the expression of ΔFosB in mPFC in rats that experienced CCI. Interestingly, CCI did not alter ΔFosB expression in the visual cortex, a non pain-related brain region.
Early life adversity, such as postnatal maternal separation, plays a central role in the development of psychopathologies during individual ontogeny. The adverse early life event is a risk factor for the development of psychiatric diseases in adult. In rats, maternal separation, which deprives pups of their mothers, has often been used as a model for early life adversity (Hall, 1998). Maternal separation has been demonstrated to induce behavioral and cognitive abnormalities, such as increased depressive and anxiety-like behaviors (Rentesi et al., 2010) and prepulse inhibition and learning deficits (Garner et al., 2007). Maternal separation has also been shown to decrease new born cells in the hippocampus and the granular cell in the dentate gyrus of juvenile and adult rats (Hulshof et al., 2011), and decrease the expression of brain-derived neurotrophic factor (BDNF) in the mPFC in young adult rats (Wang et al., 2015). These findings suggest that maternal separation can affect the neuroplasticity of rats. In line with these results, our data revealed an increase in the expression of ΔFosB in mPFC in rats that experienced maternal separation.
Local or intraperitoneal injection of zymosan, a polysaccharide component of the cell wall from Saccharomyces cerevisiae, or acetic acid, represents a self-resolving model of acute inflammation and pain, which has been widely used for the quantification of particular cell types and inflammation-related soluble factors (Cash et al., 2009). Intraplantar administration of zymosan in the rat hindpaw produces a reliable and quantifiable thermal and mechanical hyperalgesia accompanied by oedema that closely mimics the symptoms of inflammation in humans (Meller and Gebhart, 1997). Our data indicate that the expression of ΔFosB in mPFC is not altered in rats with acetic acid- or zymosan- induced acute pain. Since ΔFosB expression is altered only in chronic or persistent exposure to chronic stimuli, it is not surprising that we did not observe the ΔFosB change in either the acetic acid- or the zymosan-induced acute pain models.
Early life stress, such as neonatal CRD and maternal separation, is a potential contributor to visceral hypersensitivity and pain (Al-Chaer et al., 2000; Zhou et al., 2010). The developing brain undergoes rapid growth and is characterized by high turnover of neuronal wiring. Early life stress affects the developmental trajectory of the neurocircuitry in the CNS and alters vulnerability to subsequent stress during adulthood (Wouters et al., 2012). Early life stress may produce stable changes in neuronal plasticity, function, and communication, and increase susceptibility to developing the enhanced pain-like behavioral profiles and later-life psychopathology (Van den Bergh et al., 2008; Green et al., 2011; Amath et al., 2012). The ΔFosB protein is elevated in chronic, but not acute stress-induced pain models. It is posited that ΔFosB functions as a molecular switch that mediates persistent adaptations in the brain response to chronic pain (Luis-Delgado et al., 2006).
The ΔFosB protein is a unique transcription factor that plays an essential role in long-term adaptive changes in the brain associated with diverse conditions, such as drug addiction, Parkinson's disease, depression, and antidepressant treatment. In CNS, ΔFosB expression is regulated in a regional- and cell-type-specific manner by many types of chronic perturbations (Nestler et al., 2001; Werme et al., 2002). Once induced, it persists for a long period of time due to its unusual stability. The transcriptional effects of ΔFosB are complex, because the protein can function as both a transcriptional activator and repressor. Progress has been made in identifying specific target genes for ΔFosB and in relating some of these genes to the cellular and behavioral actions of the ΔfosB protein. Future studies will help us to better understand the biochemical basis of the ΔfosB protein's unique stability, as well as the precise molecular pathways through which this transcription factor produces its complex effects on neuronal plasticity and complex behavior (McClung et al., 2004).
The upstream and downstream signaling pathways of ΔFosB remain largely unknown. Different stimuli can invoke different molecular mechanisms to induce ΔfosB protein levels. Inflammation is a major contributor to pain. This inflammatory neuroplasticity is the consequence of a combination of activity-dependent changes in the neurons and specific signal molecules initiating particular signal-transduction pathways and altering gene expression (Woolf and Costigan, 1999). We recently demonstrated that activation of microglial toll-like receptor 4 (TLR4)/ myeloid differentiation factor 88 (MyD88)/ nuclear factor κB (NF-κB) signaling, as well as proinflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) facilitated the development of visceral hypersensitivity and pain (Chen et al., 2015; Zhang et al., 2015). The casual relation between inflammatory modulators and the ΔFosB protein needs further exploration.
The downstream of ΔFosB remains elusive. ΔFosB dimerizes predominantly with JunD to form a heterodimerized AP1 complex (Hiroi et al., 1998). Recent in vitro evidence has indicated that ΔFosB can also form homodimers (Jorissen et al., 2007). ΔFosB acts as either a transcriptional repressor or activator (McClung and Nestler, 2003). A plethora of factors participate in hyperalgesia and allodynia following peripheral tissue inflammation, including cyclin-dependent kinase 5 (CDK5; Chen et al., 2000), cholecystokinin (CCK)-B receptor, (Covington et al., 2010) NMDA receptor subunit 1 (NR1; Hiroi et al., 1998) and AMPA ionotropic glutamate receptor subunit 2 (GluR2; Kelz et al., 1999; Rygh et al., 2001). Such data from the literature suggest that the above target genes could be candidates of interest for future studies to understand the action of the ΔFosB protein in the CNS.
The chronic conditions tested here do not allow separation of pain processing in the mPFC due to stress, depression or anxiety. ΔFosB is a transcriptional regulator of stress (Nestler, 2015). Stress, e.g., pain, physical abuse, neonatal maternal separation, or exposure to an immune challenge can induce genetic, physiological and behavioral changes (Mayer and Collins, 2002). The ΔFosB protein accumulates within the same brain regions after repeated stress exposure, whereas other Fos family members show desensitization [i.e., reduced induction compared with initial drug exposures (Perrotti et al., 2004; Lehmann and Herkenham, 2011)]. Such accumulation of ΔFosB has been observed due to several forms of active stress, such as chronic restraint stress, chronic unpredictable stress, and chronic social defeat stress, whereas chronic social isolation decreases ΔFosB levels in nucleus accumbens (Vialou et al., 2010). Stress induces ΔFosB expression in mPFC, and that overexpression of ΔFosB in pre-limbic mPFC enhances stress susceptibility in mice (Vialou et al., 2014). The mPFC shows lower basal levels of ΔFosB immunoreactivity, but almost a threefold induction after chronic restraint stress in rats (Perrotti et al., 2004). We found rats that experienced neonatal CRD and maternal separation showed an elevation in the ΔfosB protein levels. Maladaptation of the stress system may impair neuronal development, and account for a number of endocrine, metabolic, autoimmune, and psychiatric disorders (Green et al., 2011; Amath et al., 2012). Antidepressants can reverse this social withdrawal syndrome by boosting ΔFosB. Moreover, ΔFosB is conspicuously depleted in brains of people who suffered from depression. Thus, induction of ΔFosB is a positive adaptation for coping with stress. Under most circumstances, stress, depression, anxiety and pain share common contributors and neurobiological inhibitors. In this study, we reported that chronic pain rat models presented an elevation of ΔFosB protein level in mFPC. Interestingly, the ΔFosB expression in the visual cortex, a non pain-related region of the brain did not change due to CCI or acetic acid treatments, suggesting that ΔFosB expression to stress and pain presents a regional specificity. The casual relationship between chronic pain and the ΔFosB protein need further exploration.
A number of immunostaining studies show that ΔFosB expresses predominately in projection neurons (Perrotti et al., 2004; Lobo et al., 2013; Nomaru et al., 2014). In the prefrontal cortex, ΔFosB exists in several layers of the cortex, in particular in layers II/III and V. The ΔFosB staining was again localized in the neurons, with no colocalization with GFAP, an astroglial marker seen primarily within cortical pyramidal neurons; over 90% of the ΔFosB+ cells colabeled with vesicular glutamate transporter 1 (vGluT1; a marker of glutamatergic neurons), with little colabeling seen with markers for various GABAergic interneurons (i.e., calbindin, parvalbumin, or calretinin; Perrotti et al., 2004). Based on these data, we predict that chronic stress elevates the ΔFosB protein expression in pyramidal neurons in mPFC.
Our results clearly show the expression of ΔFosB was significantly elevated in rats undergoing chronic, but not acute, stress-induced pain. The ΔFosB protein expression profile to different stimuli supports the role of ΔFosB in neuronal plasticity and suggests that it could be a useful molecular marker of sustained pain. Further research is needed to improve our understanding of both the upstream mechanism leading to ΔFosB protein production and the downstream mechanism by which the ΔFosB protein might participate in plasticity.
Author Contributions
Y-MZ and GZ conceived the idea, supervised the research, analyzed the data, and wrote the manuscript. HW conducted the research and wrote the manuscript. All other authors conceived the idea, analyzed the data, and wrote the manuscript. We thank Dr. Diane Baronas-Lowell for proofreading this manuscript.
This project was supported by grants from the National Natural Science Foundation of China (81171041 to Y-MZ, 81271217 to GZ, 31200836 to YS and 81471161 to XT), Key Subject of Colleges and Universities Natural Science Foundation of Jiangsu Province (13KJA320001 to Y-MZ), and sponsored by the Qing Lan Project.
Conflict of Interest Statement
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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Keywords: Deltafosb, ΔFosB, medial prefrontal cortex, pain, western blot
Citation: Wang H, Tao X, Huang S-T, Wu L, Tang H-L, Song Y, Zhang G and Zhang Y-M (2016) Chronic Stress Is Associated with Pain Precipitation and Elevation in DeltaFosb Expression. Front. Pharmacol. 7:138. doi: 10.3389/fphar.2016.00138
Received: 08 January 2016; Accepted: 11 May 2016;
Published: 30 May 2016.
Edited by:Catherine Cahill, University of California, Irvine, USA
Reviewed by:Philippe Seguela, McGill University, Canada
Li Zhang, National Institute on Alcohol Abuse and Alcoholism – National Institutes of Health, USA
Copyright © 2016 Wang, Tao, Huang, Wu, Tang, Song, Zhang and Zhang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Gongliang Zhang, firstname.lastname@example.com; Yong-Mei Zhang, email@example.com
†These authors have contributed equally to this work.


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Holá, I'm Mish. I'm visual designer and imagination engineer. My main focus is combining different visual disciplines to achieve better and enjoyable user experiences through design. I love what I do since 2012. I'm currently working with the multidisciplinary team at White Brick, a design and communications studio based in the sunny island of Cebu, Philippines.
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After launching the disastrous missile strikes against Syrian military forces that resulted in the killing of Syrian soldiers, civilians, and children as well as sending ships toward North Korea in a flagrant act of aggression and dropping the largest known non-nuclear bomb on Afghanistan, the Trump administration is now taking aim at Iran.
Sounding much like it did after its bizarre and unprovoked "putting Iran on notice" speech made by former Trump administration official Michael Flynn, the United States is now "reviewing its policy" on Iran and warning the world of the dangers of a nuclear Iran.
Ironically, the United States is warning of an Iran terrorizing the world with its bombs, funding "militias" across the world, and expanding its influence in the region by force as well as unprovoked aggression against specific countries. If there were a field of psychology for geopolitics, these statements would be classified as a clear example of projection if ever there was one.
"Whether it be assassination attempts, support of weapons of mass destruction, deploying destabilizing militias, Iran spends its treasure and time disrupting peace," Tillerson said. "An unchecked Iran has the potential to travel the same path as North Korea ‒ and take the world along with it."
"Iran is the world's leading state sponsor of terrorism, and is responsible for intensifying multiple conflicts and undermining US interests in countries such as Syria, Yemen, Iraq and Lebanon, and continuing to support attacks against Israel."
"An unchecked Iran has the potential to travel the same path as North Korea ‒ and take the world along with it," he added.
"A comprehensive Iran policy requires that we address all of the threats posed by Iran, and it is clear there are many," he said.
Tillerson then turned to the Iran nuclear deal which has been the target of both the Trump administration and traditional Republicans since day one, claiming that it "fails to achieve the objective of a non-nuclear Iran ‒ it only delays their goal of becoming a nuclear state. This deal represents the same failed approach of the past that brought us to the current imminent threat that we face from North Korea."
Tillerson added that "The Trump administration has no intention of passing the buck to a future administration on Iran. The evidence is clear: Iran's provocative actions threaten the United States, the region and the world." In addition, he stated that the United States will "meet the challenges Iran poses with clarity and conviction" after the policy review is over.
Tillerson echoed statements uttered by Defense Secretary James Mattis earlier in the week, who accused Iran of trying destabilize the Middle East. "Everywhere you look if there is trouble in the region, you find Iran. We will have to overcome Iran's efforts to destabilize yet another country and create another militia in their image of Lebanese Hezbollah but the bottom line is, we are on the right path for it." Mattis' statement came after meeting with senior Saudi officials in Riyadh.
The Path To Persia
The plan for a Western or a Western/Israeli attack on Iran, along with the theatre of alleged US-Israeli tensions leading up to a strike and outright war, has been in the works for some time. For instance, in 2009, the Brookings Institution, a major banking, corporate, and military-industrial firm, released a report entitled "Which Path To Persia? Options For A New American Strategy For Iran," in which the authors mapped out a plan which leaves no doubt as to the ultimate desire from the Western financier, corporate, and governing classes.
The plan involves the description of a number of ways the Western oligarchy would be able to destroy Iran including outright military invasion and occupation. However, the report attempts to outline a number of methods that might possibly be implemented before direct military invasion would be necessary. The plan included attempting to foment destabilization inside Iran via the color revolution apparatus, violent unrest, proxy terrorism, and "limited airstrikes" conducted by the US, Israel or both.
Interestingly enough, the report states that any action taken against Iran must be done after the idea that Iran has rejected a fair and generous offer by the West has been disseminated throughout the general public. The report reads,
…any military operation against Iran will likely be very unpopular around the world and require the proper international context— both to ensure the logistical support the operation would require and to minimize the blowback from it. The best way to minimize international opprobrium and maximize support (however, grudging or covert) is to strike only when there is a widespread conviction that the Iranians were given but then rejected a superb offer—one so good that only a regime determined to acquire nuclear weapons and acquire them for the wrong reasons would turn it down. Under those circumstances, the United States (or Israel) could portray its operations as taken in sorrow, not anger, and at least some in the international community would conclude that the Iranians "brought it on themselves" by refusing a very good deal.
Ironically, it is admitted by the authors of the report that the Iranians are not governed by lunatics intent on nuking the world but by entirely rational players. Still, they move forward with a number of options for attacking Iran. It should thus be obvious to anyone reading this report that the US, NATO, and Israel are uninterested in peace with Iran and are entirely focused on war and Iranian destruction.
"The so-called "Iran deal," introduced during the administration of US President Barack Obama, represents precisely this "superb offer," with Flynn's accusations serving as the "turn down" ahead of the "sorrowful" war and attempted regime change the US had always planned to target Tehran with," writes Tony Cartalucci of Land Destroyer Report.
The report continues to discuss the citations that could be used for an attack on Iran, clearly stating its intentions to create a plan to goad a non-threatening nation into war. It states,
The truth is that these all would be challenging cases to make. For that reason, it would be far more preferable if the United States could cite an Iranian provocation as justification for the airstrikes before launching them. Clearly, the more outrageous, the more deadly, and the more unprovoked the Iranian action, the better off the United States would be. Of course, it would be very difficult for the United States to goad Iran into such a provocation without the rest of the world recognizing this game, which would then undermine it. (One method that would have some possibility of success would be to ratchet up covert regime change efforts in the hope that Tehran would retaliate overtly, or even semi-overtly, which could then be portrayed as an unprovoked act of Iranian aggression.)
The question of the Israeli role in the possible attack against Iran is also mentioned by Brookings. In fact, in the chapter entitled, "Allowing or Encouraging An Israeli Military Strike," Brookings not only outlines a potential strategy but essentially admits that the US-Israeli tension being hyped in the Western media is nothing more than a farce. It says,
..the most salient advantage this option has over that of an American air campaign is the possibility that Israel alone would be blamed for the attack. If this proves true, then the United States might not have to deal with Iranian retaliation or the diplomatic backlash that would accompany an American military operation against Iran. It could allow Washington to have its cake (delay Iran's acquisition of a nuclear weapon) and eat it, too (avoid undermining many other U.S. regional diplomatic initiatives).
Why Iran?
There are a number of reasons why the United States and the NATO imperial army would like to see Iran destroyed over the coming years. Geopolitical reasons are, of course, front and center.
On one level, the Israeli connection stands as one obvious reason the United States has maintained an anti-Iran posture for nearly two decades. Iran not only stands as a regional opponent to the whims and aims of the Israeli settler state, but it also bankrolls and supports one of the greatest forces of opposition to Israel directly due to its close proximity and the militia's military prowess. Indeed, Israel was humiliated by Hezbollah in front of the world in 2006. Thus, if Iran is destroyed, Hezbollah goes with it and two of Israel's biggest and most effective opponents disappear from the game board.
The United States also sees Iran as an opponent due to Iran's resistance to the Anglo-American insistence on global hegemony of its "Western" system of financial and corporate overseers in a plantation owned by a world oligarchy. Iran stands in opposition to the Western system because it refuses to engage in a system private central banking as well as corporate and private financier domination of its society and culture. Maintaining its own national bank has long been a source of irritation for Wall Street and City of London vampires eager to sink their fangs into the blood supply of every nation on earth. In addition, Iran has recently announced that it would be dropping the U.S. dollar for some other currency or basket of currencies beginning March 21, a sure sign that a Western war of aggression is most definitely on the horizon.
Iran also remains a close Russian ally and the last domino that needs to fall before the great Anglo-American army can march forward directly into Russia and break the largest country in the world into "manageable" parts.[1] Once Iran is destroyed, Russia will be largely isolated and left to face the NATO alliance which has been slowly surrounding Russia over the last two decades.
The Trump Administration's false labeling of Iran as the biggest sponsor of terrorism, ignoring the fact that Iran is one of the most important players in the fight against ISIS and Sunni Islamic extremism in the Middle East as well as the fact that American ally Saudi Arabia is perhaps the biggest purveyor of terrorism in the world, tells everyone what we need to know going forward – the plan to destroy Iran is marching forward without a hitch in another example of seamless transition.
Of course, Iran is opposing America's policies in Yemen, Syria, Iraq, and Lebanon. It should. The United States' policy is that of funding, directing, and manipulating terrorists for the purpose of destroying sovereign countries, backing a brutal racist Israeli regime that continually attacks its neighbors, and supporting an equally brutal Saudi dictatorship intentionally slaughtering the Yemeni people. If this is what Iran is opposing, the world owes it a debt of gratitude.
[1] Brzezinski, Zbigniew. The Grand Chessboard. Basic Books. 1st Edition. 1998.
Image Credit: Cato.org
25 Comments on "U.S. Threatens Iran: Plans To "Review Policy" And Deal With Them Before New Administration Comes To Power"
Iran is a sovereign nation that intends to be sovereign and that has the bankers pants in a wad, just like any person or nation that intends to be sovereign and self sufficient. BRICS should invite Iran to join and should consider inviting people all over the world in every nation to join. Let's petition, as individuals, to join BRICS.
The BRICS banking is a Rothschild construct (and UN & IMF), it's umbilicus tightly secured to the Rothschilds Bank of International Settlements granddaddy central bank of all central banks.
Iran has been working closely with BIS officials in Iran to bring Iran's central banking into full BIS Basel II compliance. According to Iran's central banking spokesperson writing a recent op ed in Financial Times, BIS and US officials have given wink and nod approval to Iran's maneuvers to work around the sanctions to transact with banks in other nations, all of them being subject to BIS control.
A repeat history post cuz truth doesn't lie or get old…
*Between 1898 and 1934 the Marines invaded: Cuba 4 times; Nicaragua 5 times; Honduras 7 times; the Dominican Republic 4 times; Haiti twice; Guatemala once; Panama twice; Mexico 3 times; and Colombia 4 times. All done for the corporations to get natural resorces and farm land for them.
*Eisenhower murdered over one million innocent Germans in open field prison camps, AFTER the war's end.
*President Truman dropped atomic bombs on Hiroshima and Nagasaki murdering over 100,000 innocent people.
*Johnson, Nixon, and J. Edgar Hoover were at Clint Murcheson's ranch finalizing JFK's murder the night before.
*George Bush allowed 9/11 to occur then murdered a million Iraqi innocents.
*Obama dropped over 26 thousand bombs in 2016 on innocents plus allowed the drone murder of wedding parties.
*Dropping more bombs in Yemen in one week than the annual total for any prior year, or loosening the standards for "acceptable" civilian casualties.
*And now Trump has increased drone misdions 400% thst we know of, along with all the other madness.
Candidate Trump somehow never showed up. He is either a liar or hostage.
George Bush was in on 9/11 from the start. the FPOS needs to hang.
http //www thelibertybeacon com/2014/12/14/4-generations-of-treason-the-royalnazizionistbush-connection/
Hi Joe, that's quite the unsavory list of psychopathic misdeeds, going back to the formation of the City of London, which was behind the devastating US civil war, as you know, and operating well before that in various guises. They surely are an evil bunch of megalomaniacs.
An important history lesson here would also be the extensive use of the Hegelian Dialetic to perpetuate the classic Strategy of Tension. Iran being another example beginning with the overthrowing of the Shah puppet, with Khomeini, in friendly contact with the US since at least 1963 through back channels, taking over Iran. We have clear documented evidence Khomeini was a US asset further bolstering whistle blowers who revealed the embassy hostage crisis was a joint US-Iran false flag.
Then we have the Clinton admin 'accidentally' transferring classified military technology to Iran, under Operation Merlin, which accelerated Iran's nuclear weapons program.
More recently, there was the revelation a few years ago that since at least the early to mid 2000s, both the US and Israel were quietly transferring advanced military weapons and parts to Iran (mostly for fighter jets) that was in turn being given to Syria! So much for Iran being part of the "axis of evil". BTW, Sibel Edmonds has shared some amazing deep insight on this general issue involving Iran.
Iran is rapidly implementing UN Agenda 2030 and began the process with Agenda 21 in the 1990s, including adopting IMF restructuring guidelines. Also, western educated President Rouhani has all the earmarks of being a globalist.
I'm proposing if we reveal to a critical mass of thinkers all of these so-called nemeses (except possibly N. Korea) are actually stem to stern globalist constructs, then TPTB's pounding of war drums will be recognized as ludicrous thus there would be no point to a theatrical "demonstration" of antagonism hurting innocents. Fear based control would also lose its grip.
George H. W. Bush´s use of the MOSSAD to organize the "October Surprise of 1980", controlling the date of release of the embassy employees, takes the cake. Suppressing his whereabouts during the in-Paris-organized plan, reflects the disguised, secretive history of George H. W. Bush.
Good example of the Hidden Hand. No doubt you know Bush Sr. was directly involved in JFK's assassination and CIA cocaine trafficking in the US. That he went on to become POTUS epitomizes the powerful criminality of the cabal he serves.
Here is something that might interest you, drbhelthi. It's Sibel Edmonds' historical overview of the deposing of the shah and how, in the resulting power vacuum, Iranian political factions began to cannibalize smaller factions (expunging and executing them). She also mentions Iranian whistle blowers came forward in 1981, 1982 with information about Khomeimi's ties to the US & UK governments and CIA for over a decade. Corbett's article cites US documents showing friendly cables from Khomeini to US officials going back to 1963*. Edmonds' description of testimonial evidence that the taking of the hostages was re-planned by the US govt (false flag) begins at the ~ 18:35 mark.
BTW, the behind the scenes background on the Vati-leaks situation as a self-styled 'crisis' apparently used to shake up the Vatican to culturally swing Catholics toward the NWO religion might be a window into last year's US leaking of Khomeini cables for Iranian public consumption. The Pope's butler as whistle blower being a cover story, a facade, to sow the ground with new memes for cultural liberalization (admitted in a BBC documentary on YT). The Saudi royals, as well, are radically liberalizing social norms, shifting into high gear last year with the unveiling of the new Ministry of Entertainment (no pun, that's the real name). Perhaps more Iranians being aware an iconic Ayatollah was in a long standing cooperative relationship with the US will serve as a type of tabula rasa cognitive dissonance shock reshaping the views of rigid Islamists.
* https://www.corbettreport.com/another-conspiracy-confirmed-khomeini-had-a-secret-channel-with-the-us/
Being a hostage has broad limitations.
"The Secret Team, the CIA and Its Allies in Control of the United States and the World".
These days of the truth/lie nexus approaching no one can be sure of just "who" is pulling the strings. Everyone seems to have a favorite bad guy…Jesuits, J ews, NWO, Majestic 12, just name your favorite. Secret societies by their very nature are secret so what is offered in the public trough is mearly deception.
To borrow a phrase from Winston Churchill, Iran is the soft underbelly of Russia. If the mass-murdering American gangsters ever get to take it (and they appear to have backed down to Kim Jong-Un if that US fleet is nowhere near Korea), they could use the Indian Ocean to move men and materiél in through their '-stan' allies and seriously destabilize the Caucasus countries. All for degenerate Israel of course.
After seeing how Kim could stand up to the US because of his nukes Iran should consider buying some.
A 'war on bankers' should be declared.
Iran never did anything to the U.S.
Very true.
Fact is: The US has been engaging in terrorism against Iran since 1952 when the CIA and MI6 overthrew the democratically elected prime minister. The US periodically has periodically interfered with Iran ever since.
I don't like Islam and I really don't care for those nation-states that allow this backwards cult. But Iran is the victim here and I believe they are absolutely entitled to any payback they choose. The world will never achieve stability as long as Washington is allowed to engage in terrorism against the entire world.
Iranian elites were completely subsumed after Mossadegh was overthrown.
Khomeini was a US asset and the embassy hostage crisis was a joint US-Iran false flag operation. The revelations by whistle blowers received further confirmation last year with the release of old classified US gov documents.
USA tradicionalmente não cumpre acordos… governo não respeita leis acordadas internacionalmente… não vale a pena acreditar no governo… tem que ser colocado de lado, pois não representa o povo norte-americano… são colocados no poder através de eleições fajutas, indicados pela máfia khazarian sionista-banksters-midia corrupta-ISISraHELL, a fim de cumprir as ordens de guerras contra adversários da quadrilha… envolvidos em todo tipo de roubo e expoliação… não representa o povo norte-americano, que ainda não conseguiu livrar-se desse cancer que está destruindo os USA… estão nos estertores…
Donald Trump and his band of tiresome men have literally become nothing more than a source of endless noise.
There is now a complete lack of creative or original thought.
Policy towards Iran determined in Tel Aviv. My how refreshing.
Trump is proving the greatest political bad joke played on America and the poor world in recent history.
Israel is merely a tentacle of the Beast, having been created in 1948. The Beast itself having manipulated geopolitics for centuries, is the one in the driver's seat.
US And Israel Quietly Provide Military Support And Parts To Iran, Which In Turn Is Arming Syria
zerohedge . com/ news/ 2014-02-23/ us-israel-providing-military-supports-and-parts-iran-which-turn-arming-syria
Sibel Edwards also explained some simple examples of the ongoing Kabuki theater she saw when she was in the FBI. For instance, the political rhetoric in Iran was they would accept no products whatsoever from in Isra-hell. However, the reality was food produced in Israel was being sold in Iran with an end run being done of having it first shipped to Jordan and then to Iran, merely increasing the cost for Iranians. Iranian officials were well aware of the origins of these products.
Sorry, I just do not follow your meaning.
I was trying to demonstrate the narrative that Iran and Israel as nemeses is a Kabuki stage performance, otherwise Israel would not, for example, be sending Iran advanced military parts and weapons.
The neozio cabal bankers are hellbent on world government, it is they who orchestrate global conflicts between typically faux enemies, as they did in WWl and WW2, Korea, and Vietnam, having created and supported both fascism, communism, and the rise of the Third R3ich.
There's a lot more strong evidence than the ZH article that Iranian elites are already cooperating with the Globalists taking a deep dive into the NWO paradigm.
Who's Sibel Edwards??LOL
Thanks for the heads up on the typo.
Donald Dunce's gone Nuking FUT$ !
Iran has never been a threat to the US. If it was, why then were the US and Israel quietly sending Iran advanced military parts and weapons for years, despite the sanctions?
Same reason the Clinton administration, under Operation Merlin, transferred classified information to Iran advancing its nuclear weapons program.
Is it possible that if we reach a critical mass level of consciousness recognizing behind-the-curtain Iranian and Russian elites are tightly intercalated with the Globalists, fully cooperating with TPTB, then there can be no excuses to harm innocent people for "Strategy of Tension" fear based elite control?
We are dealing with same psychopathic mindset unleashing engineered Al-CIA-duh & ISIS terrorism, "climate change" doomsday threats, Ebola & Zika, engineered or fake scarcity, and deliberate economic crises. Likely Fukushima and the Gulf oil spill too.
The zionist beast and its criminal allies will fall…..and it will be messy , but as we all know now, an essential judgement will come.
Politicians campaign on Peace and prosperity at home and abroad – they know Zionist Washington won't allow their silly campaign promises. What they know is once in power , they will be approached with tons of money to do a 180 on their speeches and promises. It happens every time whether you're a Representative or the President. There is only Honor amongst the Honorable – and their is no Honorable ones left.


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Meet the chef: Heather Terhune
At the tender age of 4, Heather Terhune had just a couple of requests for her birthday: artichokes and spare ribs. It was then that her family realized they might have a foodie on their hands. Although she grew up in New England, Chef Terhune went to high school and college in Missouri and considers herself a proud Midwesterner. With the move to Milwaukee, she's back to her roots after leading the charge for BDK Restaurant & Bar in San Francisco. At Tre Rivali, the memorable Top Chef contestant will use her venerable background — she's worked everywhere from Jean Louis at The Watergate Hotel in Washington, D.C., to Atwood and Sable Kitchen + Bar, both respected Chicago restaurants part of the Kimpton family — to create Mediterranean-inspired modern American fare.


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Adirondack Country Homes Realty Inc.
Presented by our Schroon Lake Regional Office
Inventory #RF0121 - SOLD
Summer Fun on 6.7+/- Private Acres
Seasonal Cabins
This property has all the charm of an old-time "roughing it" Adirondack Mountain Summer Camp, but with the potential for building a modern year-round home. There are two seasonal cabins, a storage shed, and a large restored barn. The property has a dug well with running water and a septic system in place. Located on 6.73 acres with 286' frontage on Paradox Creek, the property is only a stones throw by boat from Paradox Lake via the creek. A mixture of woods and clearings, the parcel offers a nice setting to enjoy as is, or to build on in the future. View the beautiful sunsets from the creek side clearing, where there is a marina channel to the creek, offering access to and views of Paradox Lake to the west. Come boat, kayak or fish from your own waterfront property. Located on a paved town-maintained road, the property offers easy access to I-87 at exit 28, only an hour and a half from Albany.
Offered at Only $159,000 USD
|Fantastic Barn
|Paradox Creek to Paradox Lake
|Run Roughing It
|Enjoy the Adirondacks in the Woods on 6.6 acres!
Call your ACHR Agent, or Listing Agent Jeri Heinzelman for more information, and pictures!
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