This is a revised application to study the analgesic effects of novel non-peptidic and systemically-active delta opioid agonists in rhesus monkeys. The use of morphine-like analgesics, which act primarily on mu opioid receptors, is limited by their high abuse potential and by other side-effects such as respiratory depression. Studies with peptidic delta opioids suggest that delta agonists may produce clinically relevant analgesic effects without producing morphine-like side effects. Recently developed non-peptidic delta agonists, such as SNC80 and TAN67, now make it possible for the first time to examine the analgesic effects of systemically-administered delta-selective agonists in primates. Many of these compounds have not been administered before to primates, so the time course, potency and delta-receptor selectivity of novel compounds will first be examined in an assay of food-maintained operant responding. Drugs that function as delta-selective agonists in the assay of food-maintained responding will then be evaluated for their analgesic effects using two assays of analgesia: (1) a model of thermal nociception, and (2) a model of inflammatory pain. We propose to compare the effects of acute and chronic administration of novel delta agonists in these two complementary assays because they model different aspects of pain that are mediated by different mechanisms. Moreover, thermal nociception and inflammatory pain respond differently to analgesic drugs, and initial studies indicate that delta agonists may be especially effective against inflammatory pain. In view of recent evidence that there are gender differences in opioid antinociception in primates, this application also proposes to study novel delta agonists in both male and female monkeys. The proposed studies will evaluate the role of gonadal hormones at different phases of the menstrual cycle in the mediation of delta opioid analgesic effect. Convulsant activity is the single most severe side-effect that has been associated with some novel delta agonists. Preliminary findings show that SNC80 does not produce convulsions in rhesus monkeys even at high doses, but this potentially severe side-effect warrants careful study, because convulsant activity could seriously compromise the clinical usefulness of delta agonists. Accordingly, the proposed studies would also examine the effects of acute and chronic administration of selected delta agonists on electroencephalographic (EEG) activity in male and female rhesus monkeys to assess the degree to which these compounds produce abnormal EEG activity, EEG seizures and/or behavioral convulsions.
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