This is a revised, competing renewal application to study the behavioral effects of delta opioid receptor agonists in rhesus monkeys. Two major findings of the last project period were that (a) SNC80 and other non-peptidic delta agonists produced anti-allodynic effects in a model of inflammatory pain, and (b) SNC80 enhanced the analgesic effects but not the sedative effects of mu agonists. These results suggest that delta agonists may be useful in the treatment of inflammatory pain, and combinations of delta and mu opioids may produce enhanced analgesic effects with reduced side effects in comparison to delta or mu agonists alone. We now propose to extend these findings according to four specific aims. First, we propose to examine the delta-receptor pharmacology of delta/mu interactions in assays of sedation and thermal pain. We hypothesize that delta/mu analgesic interactions are stereoselective and dependent on the efficacy of the delta opioid. Second, we propose to examine delta/mu interactions in our assay of inflammatory pain, which models some types of clinical pain commonly treated with opioids (e.g. post-surgical pain). Delta/mu analgesic interactions may vary as a function of the type of pain, and the extent of delta/mu interactions in assays of inflammatory pain is unknown. We hypothesize that delta/mu interactions will be synergistic in assays of inflammatory pain. Third, we propose to examine delta/mu interactions on operant behavioral measures of drug reward. Abuse liability limits the clinical utility of mu agonists, and the discovery of strong analgesics with low abuse liability would be a significant advance in pain treatment. We hypothesize that co-activation of delta receptors will reduce the abuse-related effects of mu agonists. Finally, we propose to evaluate peripheral and spinal mechanisms of delta agonist- induced anti-allodynia in the model of inflammatory pain. Localized peripheral drug injections will be used to test the hypothesis that peripheral delta opioid receptors at the site of inflammation are necessary and/or sufficient for delta agonist-induced anti-allodynia. Intrathecal drug injections will be used to test the hypothesis that spinal delta opioid receptors are necessary and/or sufficient for delta agonist-induced anti-allodynia. We suggest that the proposed studies would enhance understanding of the pharmacological, behavioral and neurobiological determinants of opioid analgesia in non-human primates and may contribute to the development of improved analgesic medications.
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