David J. Mayer - US grants

Broadly stated, this research project has two goals. First, I plan to investigate behavioral, neurophysiological, neuroanatomical, and neurochemical aspects of analgesia produced by focal electrical stimulation of the brain and to compare this phenomenon to analgesia produced by morphine micro-injection. Some of the specific goals subsumed under this project include: 1) To precisely describe the neuroanatomical pathways utilized and the ultimate sites and mechanisms of analgesic action. 2) To further describe the involvement of endogenous opiate substances in analgesia resulting from certain environmental manipulations. 3) To examine the functional neurochemistry of narcotic and non-narcotic analgesia systems. 4) To examine behavioral manifestations of tolerance and physical dependence to the analgesia produced by these procedures and to relate these findings to the general problem of opiate addiction. 5) To be able to suggest new and practical treatment procedures for difficult or intractable pain syndromes in man. Secondly, I proposed to identify, employing electrophysiological techniques, brain areas with behaviorally significant involvement in pain perception. Stimulation-produced analgesia, morphine analgesia, and behavioral manipulation of pain perception will be utilized as tools to achieve this goal.

This is a Shannon Award providing partial support for research projects that fall short of the assigned institute's funding range but are in the margin of excellence. The Shannon award is intended to provide support to test the feasibility of the approach; develop further tests and refine research techniques; perform secondary analysis of available data sets; or conduct discrete projects that can demonstrate the PI's research capabilities or lend additional weight to an already meritorious application. Further scientific data for the CRISP System are unavailable at this time.

The long term goal of this research project is to characterize spinal cord spatial and temporal neural mechanisms that encode information related to acute and chronic pain. Progress during the last 3 years of this project has resulted in evidence that both spatial recruitment and impulse frequencies in spinal nociceptive neurons are likely to be critical factors in encoding nociceptive stimulus intensity as well as in encoding the distinction between non-nociceptive and nociceptive somatosensory events. The proposed continuation of these efforts will rely on the utilization of [14C]-2-deoxyglucose mapping procedures and electrophysiological recordings from dorsal horn nociceptive neurons to accomplish 7 SpecifiC aims: (1) To provide electrophysiological mapping of L2 to L5 neural activity under stimulus conditions used in the [14C]-2- deoxyglucose experiments so as to provide functional interpretations of our results with metabolic imaging analysis; (2) To more precisely delineate the rostral-caudal extent of elevated neural activity elicited by graded nociceptive thermal stimuli; (3) To determine the similarities and differences in the rat spinal cord of spatial patterns of elevated neural activity in response to nociceptive stimulation in spinalized, decerebrate, and intact preparations; (4) To determine how spatial recruitment and/or integration at the level of single spinal cord nociceptive neurons Can account for spatial summation of heat induced pain; (5) To compare the patterns of [14C]-2-deoxyglucose activity within the spinal cord across two types of nociceptive stimuli: thermal stimulation (45 degrees-49 degrees C) and formalin injection into the foot and to relate such patterns of activity with areas of spinal gray matter (at cervical levels and contralateral dorsal horn regions) known to be either inhibited or excited by the types of stimuli to be used ; (6) To further examine the spatial patterns of elevated neural activity in the spinal cords of rats experiencing experimental painful peripheral mononeuropathy and to compare such patterns with electrophysiological recordings of neural activity from L2 to L5; (7) To examine the effects of antagonists of the glutamate/aspartate receptor and local anesthetic agents on behavioral indexes of pain and spatial distributions of elevated neural activity within spinal cords of rats with a painful mononeuropathy. The results of this proposed work will provide an extensive characterization of the role of spatial and temporal factors in encoding nociceptive information under both acute and pathophysiological conditions. Finally, the analysis of pharmacological interventions on spatial recruitment and on abnormal pain-related behavior in a model of neuropathic pain may be helpful in providing new therapeutic approaches to treat neuropathic pain and perhaps other chronic pain disorders in man.

The goal of this research project is to understand neural and molecular mechanisms of thermal hyperalgesia associated with narcotic tolerance. Recent investigations have indicated that thermal hyperalgesia develops in association with the development of narcotic tolerance and that excitatory amino acid (EAA) receptor activation and subsequent intracellular second messenger systems may play a critically important role in central nervous system mechanisms of thermal hyperalgesia associated with narcotic tolerance. Thus, multidisciplinary approaches including behavioral, pharmacological, autoradiographic, and immunocytochemical methods will be used to accomplish 3 specific aims: (l) To clarify the time course and dose-response relationships of morphine treatment as well as the role of the opiate kappa receptor in the development of thermal hyperalgesia associated with narcotic tolerance; (2) To determine the role of EAA receptors (both ionotropic and metabotropic EAA receptors) and their relationships in the development and expression of the thermal hyperalgesia; and (3) To determine the role of EAA receptor mediated changes in intracellular protein kinase C and nitric oxide and their relationships in the development and expression of the thermal hyperalgesia. This proposed work will provide novel and important information on neural and molecular mechanisms of hyperalgesia that may be common to thermal hyperalgesia associated with the development of narcotic tolerance in particular and with neurogenic and inflammatory etiologies in general. Because of the intimate relationship between narcotic tolerance and associated thermal hyperalgesia as well as potential interrelations between hyperalgesia induced by narcotic treatment and nerve (tissue) injury or inflammation, the results of this work may help to improve clinical utility of narcotic analgesics in treatment of chronic pain states. In addition, the results from assessment of the roles of EAA receptors, protein kinase C, and nitric oxide will provide insights into the neurobiology of narcotic tolerance which could result in additional clinical applications.