In view of the many undesirable actions of morphine and other opium derivatives, considerable research efforts has been devoted to developing drugs that retain morphine's analgesic efficacy but are less likely to result in abuse and physical dependence. As class of drugs that was developed specifically for these reasons are the partial u (opioid) agonists. Unlike full u agonists (e.g. morphine), partial u agonists require activation of a relatively large fraction of the total pool in order to produce a behavioral or physiological response. A consequence of this unique pharmacological action is that responsiveness to these drugs can be used as an extremely sensitive model to study the factors (e.g. gender, genetics) that contribute to individual differences in drug sensitivity as well as individual vulnerability to drug abuse. There is ample evidence indicating that both inbred and outbred strains of rats display profound differences in their responsiveness to the antinociceptive effects of partial u agonists. In may instances, these differences are as large or larger than those observed in divergent lines of rodents selected for low and high sensitivity to a particular opioid effect. For our first specific aim we are proposing to determine if partial u agonists can be used to evaluate the genetic (rat strains) determinants of the reinforcing effects of opioids and the development of tolerance to their antinociceptive effects. A final goal will be to determine if the mechanism underlying strain-specific sensitivity to opioids is related to the intrinsic efficacy of opioids at the u receptor. There is an emerging body of clinical evidence indicating that human males and females differ in their responsiveness to the antinociceptive effects of opioids and it has been postulated that these differences are most pronounced with partial u agonists and opioids with activity at the k receptor site. For our second specific aim we are proposing to evaluate gender differences in the antinociceptive effects of partial u and k agonists, determine if gender differences are apparent at the spinal and supraspinal levels, and provide a quantitative comparison of the intrinsic efficacy of selected u agonists in males and females of rat strains known for their differential sensitivity to the antinociceptive effects of opioids. Recent clinical studies indicate that chronic opioid treatment* does not produce adequate levels of analgesia in female patients and that females differ from males in terms of the maximum dosage of opioids required during chronic treatment. For our third specific aim we are proposing to determine if there are gender differences in responsiveness to chronic opioid challenge and thus in the extent that tolerance develops to opioid-induced antinociception. As chronic opioid treatment has a profound effect on the activity of partial u agonists, responsiveness to these opioids should provide an extremely sensitive index of gender differences.
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