Work in the previous award period demonstrated that persistent inflammatory nociception has important functional consequences for the activity of pain modulatory pathways that originate in the rostral ventromedial medulla (RVM). Persistent inflammatory nociception induced by i.pl. injection of complete Freund's adjuvant (CFA)results in a progressive and time-dependent enhancement of the antihyperalgesic and antinociceptive effects of _ or 5 opioid receptor agonists microinjected in the RVM, in a compensatory activation of opioid-mediated pain inhibitory )athways, and the possible expression of opioid receptors with a novel pharmacology. The overall goals of the next award period are to further examine the neurochemical and cellular mechanisms responsible for the enhancement of opioid mediated actions in the RVM and to begin to determine which characteristics of inflammatory injury are critical to neuronal plasticity in the RVM. The first specific aim will determine whether an increase in opioid receptor affinity and number, or an increase in the potency and efficacy of opioids at their respective receptors in the RVM mediate the enhanced antinociceptive and antihyperalgesic effects of DAMGO and DELT. Opioid receptor autoradiography will be used in conjunction with GTPgammaS autoradiography and binding assays to examine these parameters in saline- and CFA-treated rats and to determine whether decreases in KD or ECs0 or increases in Bmax or Emaxare temporally concordant with the time-dependent enhancement of opioid effects in vivo. The second specific aim will determine whether the presynaptic and postsynaptic inhibitory effects of DAMGO and DELT are enhanced in the RVM of CFA-treated rats and to relate these changes to identified populations of RVM neurons. Whole-cell voltage or current clamp recordings will be made from immunohistochemically identified populations of spinally-projecting neurons in the RVM of saline- and CFA-treated rats to determine whether and in which population of neurons the presynaptic and postsynaptic effects of mu and delta opioid receptor agonists are enhanced as a consequence of inflammatory injury. These studies will also determine how inflammatory injury alters the sensitivity of RVM neurons to endogenous excitatory and inhibitory inputs by construction of input-output curves. The third specific aim will determine to what extent the plasticity of the RVM is dependent on the nociceptive nature and temporal relevance of the inflammatory injury. Local anesthetic blockade at various times before and during the inflammatory process will be used to determine whether an acute noxious stimulus is sufficient or necessary to invoke long-term plasticity of RVM neurons, as well as determine whether these changes require a sustained input from primary afferents. This series of complementary behavioral pharmacological, neurochemical and electrophysiological studies will provide important new information about the mechanisms by which persistent inflammatory nociception alters the pharmacology and physiology of brainstem neurons that comprise an critical efferent pathway for the modulation of nociception and the production of analgesia by opioids.
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