Given the need for improved analgesic medications with reduced abuse liability and reduced side effects relative to currently available opiate pharmacotherapies, this proposal is designed to elucidate the role of delta opioid receptors in pain, drug abuse, and respiratory depression. The primary hypothesis under examination is that stimulation of delta opioid receptors in the central nervous system may differentially result in analgesia with limited addiction liability and side effects such as respiratory depression. This hypothesis is supported by previous research in which delta-selective agonists appeared to produce antinociception with less associated adverse side- effects. Importantly, recent evidence supports the existence of at least tow delta receptor subtypes (isoreceptors) with different physiological profiles. In addition, the first generation of novel systemically-active non-peptide delta-preferring agonists recently have become available. An understanding of the relative role(s) of the delta isoreceptors in antinociception relative to abuse liability and undesirable side effects such as respiratory depression, and characterization of the receptor profiles of the novel systemically- active delta agonists, may be critical to identifying a new class of opioid analgesics with a more favorable therapeutic profile. Accordingly, the three specific Aims of this proposal are to elucidate the role of delta opioid receptors in 1) antinociception; 2) drug reinforcement; and 3) respiratory function in conscious intact rats. Antinociception will be tested using paw withdrawal to a noxious thermal stimulus. The model for the drugs' reinforcing effects will be intravenous self-administration. Respiratory function will be assessed using total body plethysmography and arterial blood gas analysis. In each specific aim, delta agonist dose-effect curves will first be obtained for each dependent measure. Then, for each agonist with demonstrated activity, a separate group of animals will be pretreated with intracerebroventricular injections of different receptor-selective competitive antagonists. Differential antagonist effects on the delta agonist dose-effect curves will elucidate the CNS opioid receptor(s) responsible for the effects of each agonist. The results of these experiments will not only enhance our understanding of brain mechanisms of opiate action and the role of delta opioid receptors in normal physiology and behavior but could also have implications for the development of new opiate drugs with more favorable clinical profiles.
