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Strain Differences in Response to Opioids

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Recent advances in genomics have brought to the forefront the fact that the mouse has been drastically underutilized in the behavioral aspects of drug abuse research. The use of operant schedules of reinforcement has played a significant role in our understanding of drugs of abuse and the addictive process in both humans and laboratory species. However, until recently there have been only a small number of laboratories that have attempted to utilize the mouse in experiments involving operant schedules of reinforcement. Many years of research on the genetics of the mouse has supplied the scientific community with a tremendous number of inbred strains. Many of these strains have well defined genetic differences that result in significant differences in drug effects. For example, it has been shown that marked differences exist between C57Bl/6 and DBA/2 mice in response to many effects of morphine including analgesia, locomotor activity, hypothermia, Straub-tail, and voluntary oral morphine consumption. Similarly, although tolerance to the analgesic and locomotor response to morphine has been observed to be about equal in C57Bl/6 and DBA/2 mice, tolerance to the analgesic effects of morphine has been reported not to occur following chronic administration in 129 mice. Whether strain differences exist in the stimulus or reinforcing properties as measured by drug discrimination or IV self-administration procedures in response to opioid drugs in these strains is not known. Knowledge of such differences may provide significant insight into the role of genetic differences in opioid addiction and the mechanisms of drug action. The present study will use three inbred strains of mice (C57Bl/6J, DBA/2J and 129P3/J). The study will examine the ability of receptor subtype specific opioid agonists to function as discriminative stimuli, the degree to which the drug stimulus generalizes to agonists specific for other receptor subtypes, and the ability of antagonists to block the stimulus properties. Hopefully, by utilizing these well-defined strains, it will be possible to use the known differences in genetics to provide new insight into the abuse of opioids.

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