The long term objective is to understand central nervous system mechanisms of pain modulation. This knowledge provides the basis for understanding the mechanisms of action of analgesic drugs, such as opioids. The objective of this research proposal is to characterize the contribution of central descending pain modulatory systems from the rostral ventromedial medulla (RVM) to primary and secondary cutaneous hyperalgesia following peripheral inflammation.
The specific aims are: 1. Characterization of the contribution of supraspinal sites, the RVM, and the dorsolateral funiculi (DLF) to primary and secondary hyperalgesia by determining the effects of spinal transection, RVM lesion, or DLF lesion, respectively, on the facilitation of spinal nociceptive withdrawal reflexes following peripheral inflammation in awake rats. The model of primary hyperalgesia (noxious stimulation at the site of injury) will involve carrageenan injection into the planter surface of the hind foot, and models of secondary hyperalgesia (noxious stimulation distant from the site of injury) will involve carrageenan/kaolin injection into the knee joint cavity or topical mustard oil applied to the hind leg. The thermal nociceptive tail-flick, or paw withdrawal reflex will be used to measure nociception following mustard oil or carrageenan, respectively. 2. Characterization of the neurotransmitters and receptors in the RVM which modulate behavioral hyperalgesia by determining the effects of microinjection of receptor selective antagonists into the RVM on the facilitation of nociceptive withdrawal responses following inflammation. Receptor selective antagonists to those receptors implicated in descending facilitation of spinal nociception will be used in those models in which the RVM was determined to contribute to hyperalgesia. 3. Characterization of the involvement of """"""""on-cells"""""""", """"""""off-cells"""""""", and """"""""neutral-cells"""""""" in the RVM in primary and secondary hyperalgesia using extracellular single unit recording in lightly anesthetized rats. The effects of peripheral inflammation on unit activity and behavioral nociceptive withdrawal reflexes will be concurrently determined. Local infusion of receptor selective antagonists will be used to characterize the neurotransmitters and receptors that modulate changes in RVM neuron activity following inflammation.
