Despite the concerted efforts of numerous investigators, the role of the delta opioid receptor in central mechanisms of antinociception remains controversial. The pharmacologic specificity of the antinociception attributed to activation of delta opioid receptors has not been rigorously examined due to a lack of potent, selective antagonists of the various subtypes of the opioid receptor. Moreover, the physiological relevance of delta opioid receptors to the production of antinociception by endogenous pain modulatory pathways has not been determined. However, recent advances in the pharmacology of both delta and mu opioid receptors now provide the necessary tools with which to address these issues. This proposal will systematically characterize the involvement of delta opioid receptors in central mechanisms of antinociception in the rat with particular emphasis on the role of the spinal delta opioid receptor. These studies will first assess the efficacy of a series of intrathecally administered delta-selective agonists using both reflexive and behavioral models of nociception and hyperalgesia. Subsequent studies will characterize the pharmacologic specificity of the antinociception produced by intrathecally administered delta-selective agonists using (1) naltrindole, a competitive delta-selective receptor antagonist; (2) SUPERFIT or trans-SUPERFIT, which irreversibly acylate the delta receptor; (3) CTAP, a competitive mu-selective receptor antagonist; and (4) Beta-FNA, an irreversible mu-selective receptor antagonist. Finally, the physiological relevance of the delta opioid receptor will be evaluated by assessing the ability of delta-selective or mu-selective receptor antagonists to attenuate the antinociception produced by activation of endogenous pain modulatory pathways. The results of these studies will (1) provide new insights into opioid mechanisms of antinociception and the development of novel agents for the treatment of pain and (2) guide future investigations of the role of the spinal delta opioid receptor in functions other than antinociception.
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