Substantial evidence indicates that the antinociceptive effects of mu and delta opioid receptor agonists are enhanced under conditions of inflammatory pain, such as that induced by injection of complete Freund's adjuvant (CFA) in the hindpaw of the rat. Alterations in both the peripheral and spinal actions of opioids have been implicated as the basis for this enhancement which occurs after local, systemic or intrathecal administration of the agonists. By comparison, virtually nothing is known about the effects of opioids at supraspinal sites under conditions of inflammatory pain. The overall aim of this proposal is to characterize the suprespinal actions of mu and delta opioid receptor agonists under conditions of inflammatory pain. This proposal will determine whether the antinociceptive effects of mu and delta opioid receptor agonists microinjected in the ventromedial medulla (VMM) are enhanced by comparison of dose-response relationships for these agonists determined in control rats and at various times after injection of CFA in one hindpaw. This proposal will also determine whether neurons of the VMM are subject to enhanced opioid inputs using microinjection of mu and delta opioid receptor antagonists in the VMM of control or CFA-treated rats. As the enhanced effects of mu opioid receptor agonist can result from a synergistic interaction with enkephalins acting at delta opioid receptors,this study will determine whether microinjection of a delta opioid receptor antagonist in the VMM reverses the enhanced antinociceptive effect of a mu opioid receptor agonist in CFA-treated rats as compared to control rats. Finally, this study will determine whether unilateral inflammation induces the synthesis of endogenous opioid peptides and alters opioid receptor binding at supraspinal sites using in situ hybridization and in vitro autoradiography.

5F30DA005784-05

2001-04-01