PROLONGED TOLERANCE, DEPENDENCE AND ABSTINENCE FOLLOWING SUBCUTANEOUSMORPHINE PELLET IMPLANTATION IN THE RAT

Opiate withdrawal is a common occurrence in human opiate addicts that is not life threatening but is hypothesized to be a significant factor which may contribute to drug taking behavior in these opiate dependen t individuals. The purpose of this study was to compare the time cours e for the development of tolerance, dependence and abstinence using a rat model. Rats were made dependent by implantation of 2 morphine pell ets s.c. (75 mg morphine base). Morphine implanted rats exhibited anal gesia as measured in a tail-dip assay, for up to 12 h post-implant aft er which the development of tolerance resulted in tail-flick latencies returning to the level of control rats. Withdrawal was evaluated by i njection of the opiate antagonist, naloxone (1 mg/kg s.c.). Rating of the abstinence syndrome revealed significant withdrawal signs by 3 h p ost-implant which became increasingly intense up to 24 h post-implant. Withdrawal could be precipitated for at least 13 days post-implant, w hile by 18 days post-implant almost no abstinence signs were observed. Plasma morphine levels following implantation of 2 pellets remained r elatively stable from 3-12 days post-implantation. These results furth er extend the characterization of opiate abstinence following subcutan eous pellet implantation. These results also suggest that opiate absti nence develops within the first 24 h and follows the time course of th e development of tolerance. The characterization of the evolution of o piate tolerance, physical dependence and abstinence under similar expe rimental conditions is critical to the design of future studies to exa mine the neural bases for these phenomena.