The studies proposed in this application focus on the mechanisms of excitatory neurotransmission in the nociceptive afferent system in spinal cord dorsal horn of rodents. The goal of these studies is to understand the importance of synaptic transmission and alterations in synaptic efficacy to the overall behavior of the system in the presence of natural nociceptive stimulation and analgesic substances. The hypotheses to be tested address the participation of excitatory amino acids (EAAs), neurokinins and neuronal nitric oxide (NO) in activation of spinal cord neurons and enhancement of synaptic efficacy induced by both acute and chronic sensory and pharmacological stimulation. Some of the excitatory phenomena will be studied in the context of the development of tolerance to acute or chronic analgesics. The proposed experiments are designed to test these hypotheses at several levels of analysis. Some experiments will examine behavior in unanesthetized rodents after intrathecal administration of agents manipulating the transmitters and pathways listed above. Complementary electrophysiological studies will examine the responses of individual neurons in the spinal cord of anesthetized rodents in situ to electrical stimulation of peripheral nerve, natural stimulation of cutaneous receptive fields and iontophoretic application of agents which manipulate the above pathways. In vitro electrophysiological studies of neurons in spinal cord slices will examine cellular, ionic and synaptic mechanisms mediating phenomena seen in the whole animal studies. The experiments will determine if: 1) EAA receptor agonists and antagonists, and NO inhibitors and generators can affect nociceptive neurotransmission in spinal cord; 2) manipulation of NO synthesis can alter SP-induced changes in spinal cord responsiveness; 3) pharmacological removal of inhibitory systems can unmask long term changes in spinal cord synaptic efficacy induced by repeated, intense stimulation; 4) inhibitors of NO prevent or reduce temporary synaptic alterations in spinal sensory circuitry accompanying hyperalgesia and analgesia; 5) manipulation of spinal EAA receptors or NO can alter the development of opioid tolerance. These studies should provide a better understanding at several levels of analysis of the importance of excitatory transmission and synaptic plasticity to spinal nociceptive transmission and opioid action.
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