Studies on opioid delta receptor mediated antinociception, opioid antinociceptive tolerance and physical dependence.

摘要

The central hypothesis of this dissertation is that agonists and antagonists acting at the {dollar}delta{dollar} opioid receptor will have therapeutic applications in treating acute and chronic pain states and in the treatment of drug addiction. It is further hypothesized that {dollar}delta{dollar} compounds will have better therapeutic profiles than currently available opioids that act predominantly at the {dollar}mu{dollar} receptor. In advancing the central hypothesis, selective nonpeptidic {dollar}delta{dollar} compounds, that readily cross the blood brain barrier after systemic administration, were tested. BW373U86, a nonpeptidic ligand with moderate selectivity and activity at {dollar}delta{dollar} opioid receptors represented a lead compound. A structurally related molecule, SNC80, displayed an improved selectivity and activity profile compared to BW373U86. Importantly, SNC80 produced antinociception following systemic administration which was blocked by {dollar}delta{dollar}, but not {dollar}mu{dollar}, selective antagonists. The pharmacology of {dollar}delta{dollar} opioid receptors was further studied using antisense oligodeoxynucleotides that disrupted the synthesis of {dollar}delta{dollar} receptors in vivo and in vitro. The experiments provided further evidence for distinct {dollar}delta{dollar} receptor subtypes and demonstrated the utility of the antisense approache in studying neurochemical processes in vivo. Several studies addressed the phenomenon of opioid tolerance and physical dependence, two processes which compromise the clinical application of currently available opioid analgesics. The observation that NMDA receptor antagonists block the development of antinociceptive tolerance to repeated administrations of morphine was confirmed. The results were extended by demonstrating that NMDA antagonists did not block antinociceptive tolerance to more selective {dollar}delta{dollar} or {dollar}mu{dollar} agonists. These studies caution against the generalization that an effect seen with morphine is applicable to all opioid agonists. Further hypotheses regarding the mechanisms of opioid tolerance and physical dependence were tested using inhibitors of protein kinases and putative neutral and inverse opioid antagonists. These studies advanced the hypothesis that opioid receptor phosphorylation may play a critical role in the development of opioid antinociceptive tolerance and physical dependence. In summary, this dissertation has provided strong evidence that nonpeptidic {dollar}delta{dollar} selective opioid agonists and antagonists can be developed and that these compounds will have therapeutic applications in the treatment of pain and addictive disorders.