NOCICEPTIVE TRANSMISSION IN THE SPINAL CORD

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The long term goal of this plan is to clarify, in discrete areas of the spinal cord, the interrelationships of transmitter candidates that appear to be involved in pain and analgesia. Substance P (SP) and excitatory amino acids (EAA) appear to participate in pain- transmission and endogenous analgesia. We are currently using a combination of biochemical, anatomical and behavioral approaches to focus on the roles of these compounds in pain and analgesia. The goal of our present work on SP is to determine the mechanism of desensitization to SP. Analgesic drugs may then be designed which mimic or exploit such desensitization. The specific objectives are to correlate changes in desensitization to SP with changes in the concentration of specific SP metabolites and in SP binding. The goals of our EAA studies are to elucidate the role that EAAs play in transmission along primary afferent and/or centrally projecting fibers involved in pain-transmission and to determine whether such EAA neurotransmission is specifically affected by opioid and non-opioid compounds. The specific objectives are to characterize the distribution (immunostaining), concentration (HPLC) and release (potassium-evoked changes in extracellular fluid) of EAAs in areas of the CNS presumed to be involved in pain transmission and their relation to endogenously occurring antinociceptive mechanisms. Our long term plans are to extend our present research examining transmitter release during nociceptive and antinoceptive processing in discrete areas of the spinal cord. The system currently in use in our laboratory involves the implantation of a semipermeable dialysis tubing through the spinal cord and provides us with an excellent method of examining extracellular fluid as a reflection of transmitter release. Compounds or mainpulations presumed to alter pain or transmitter release can then be tested in vivo. While our present studies focus on EAA release in the rat spinal cord, our long term goal is to use larger species, such as cat, to examine the release of not only EAAs but also that of SP, SP metabolites and serotonin from even more discrete regions and from any two distinct areas simultaneously. The experiments described will integrate our current research programs and expand their scope. This research will contribute to our understanding of neurotransmission by SP and EAAs.