Recent studies of neuropathic or inflammatory injury have revealed an unexpected plasticity in the physiology and pharmacology of afferent pain pathways, and concomitant changes in the antinociceptive effects of opioids. To date, these studies have focused predominantly on neurons of the periphery and spinal cord. Little is known about the changes that occur at supraspinal sites such as the NRM and NGCp-alpha (NGCpa)the ventromedial medulla. Yet, spinally-projecting neurons in these nuclei are an important, common efferent pathway for the modulation of nociception and are also implicated in opioid-mediated antinociception. The goal of this proposal is to understand how persistent inflammatory nociception alters the response properties and synaptic pharmacology of neurons in the ventromedial medulla, and the functional consequences of these changes for opioid-mediated antinociception. In vivo behavioral pharmacological studies will further characterize the enhanced antihyper-algesic and antinociceptive effects of mu, delta, and kappa opioid receptor agonists microinjected in the NRM and NGCpa of rats in which inflammatory nociception has been induced by i.pl. injection of complete Freunds' adjuvant (CFA) in one hindpaw. The potency and efficacy of these agonists will be determined as a function of time after injection of CFA and compared to their effects in the un-inflamed condition. Microinjection of mu, delta, kappa, GABAA, AMPA and NMDA receptor antagonists or agonists will determine how opioid, GABAergic and glutamatergic inputs to these neurons are altered by persistent inflammatory nociception. Finally, in vitro whole-cell patch clamp recordings from NRM and NGCpa neurons will characterize the membrane properties and sensitivity of these neurons to excitatory and inhibitory synaptic inputs under conditions of inflammatory nociception and in the presence of opioid agonists and antagonists, and thereby establish the cellular mechanisms responsible for the enhanced effects of opioid agonists in the brainstem. The results of these complementary behavioral, pharmacological and electrophysiological investigations will provide important insights into the effects of persistent inflammatory nociception on the pharmacology and physiology of supraspinal neurons that comprise an important, common efferent pathway for the modulation of nociception and a key site for the production of antinociception by opioids. Understanding these mechanisms will aid the development of improved therapies for the treatment of chronic pain.
Showing the most recent 10 out of 28 publications
