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Brain and plasma concentrations of morphine during the development of physical dependence and tolerance

The subcutaneous implantation of a morphine pellet has been used to produce physical dependence and tolerance to morphine in mice (Maggiolo & Huidobro, 1961 ; Way, Loh & Shen, 1969) and rats (Cicero & Meyer, 1973). The degree of physical dependence and tolerance which develops in mice (Way & others, 1969) and rats (Cicero & Meyer, 1973) is comparable to that produced by an injection schedule of morphine. Recently, Patrick, Dewey & others (1975) reported that the concentration of morphine in the mouse brain increases rapidly and is maintained at a high level through the third day following morphine pellet implantation. This study was initiated in an effort to further quantify the technique of pellet implantation in the rat so that this model could be used for additional studies in our laboratory. Male, Sprague-Dawley derived rats (Laboratory Supply Co., Indianapolis, IN) six to eight weeks old (180-200 g) were employed. Food and water were freely available and animals were housed in community cages unless otherwise noted. Temperature was maintained between 21-23” and a 14 h light cycle (0600 to 2000 h) was employed. Two morphine pellets, each containing 103.5 mg morphine base and formulated according to the procedure of Gibson & Tingstad (1970), were implanted subcutaneously 2-4 cm posterior to the shoulders on the back of the animals under light ether anaesthesia. The mortality following implantation of two morphine pellets was between 3-5 % for all experiments provided that the animals were housed individually for at least 24 h following pellet implantation. Morphine pellets remained implanted in the rats during all experimental procedures except where noted. The degree of physical dependence on morphine was determined using a modification of the procedure of Cicero & Meyer (1973). Acute morphine withdrawal was precipitated by the administration of naloxone hydrochloride (0.4 mg kg-l, s.c.) and the number of ‘wet dog’ shakes were counted for a period of 30 min (a shorter period than that used by Cicero & Meyer but the results of the test are not affected). Symptoms of the withdrawal syndrome included writhing, salivation, lacrimation, teeth chattering, profuse diarrhoea, ejaculate-like discharge, hostility, bursts of activity which included escape behaviour and ‘wet dog’ shakes. Physical dependence, as determined by the number of ‘wet dog’ shakes, reached the highest level four to five days after implantation of 207 mg morphine base (ave. of 29 shakes per rat in 30 min on both days four and five). The number of ‘wet dog’ shakes per rat in 30 min