Promoting peripheral opioid analgesia: The role of interactions between mu- and delta-opioid receptor agonists

Targeting of peripheral opioid receptors has been investigated as a pain treatment strategy to avoid some of the centrally-mediated adverse side effects and abuse potential that limit conventional opioid therapy. Although animal studies have indicated that the ability of peripheral opioid receptors to reduce sensitivity to noxious stimuli is enhanced following injury or inflammation, clinical results of peripheral opioid treatment have been inconsistent and often modest. Thus, the development of strategies to improve peripheral opioid receptor function remains an important area of investigation.;Interactions between agonists acting at central mu- and delta-opioid receptors have been demonstrated to augment opioid analgesia. The work presented in this thesis tests the overall hypothesis that interactions between agonists for the two receptor types enhance measures of peripheral opioid receptor function as well. The effect of delta- and mu-opioid receptor agonists alone and in combination on behavioral measures of mechanical and thermal sensitivity in both naive rats and in a model of inflammatory pain were tested. In addition, the effects of combined opioid administration were evaluated in vitro using inhibition of CGRP release from hind paws and sciatic nerves of naive animals as a functional assay. We observed that combination opioid administration enhanced peripherally-mediated thermal analgesia in naive rats and inhibition of CGRP release from naive peripheral tissue. Some evidence for enhanced antinociceptive effects against inflammatory pain was also observed; however, the effects of combined opioid administration were less robust under these conditions.