Chronic visceral pain, especially pain from irritable bowel syndrome or visceral cancer pain, results in major social and health problems and represents one of the most common causes of work absenteeism, long term suffering and disability. Recently, midline myelotomy, a neurosurgical intervention which severs midline axons in the spinal dorsal column, has proved to be successful in alleviating otherwise visceral cancer pain. This approach is based on the interruption of a newly discovered pathway, the postsynaptic dorsal column (PSDC) pathway that transmits visceral painful information. However, the neurobiology of this pathway for visceral nociceptive transmission is inadequately understood. The major objective of this grant application is to examine the role of the immediate early gene, c-Jun, and its regulatory N-terminal protein kinase (JNK) and JNK subunits, in spinal PSDC neurons that process visceral nociceptive information. We hypothesize that the response of spinal viscero-sensitive neurons, especially PSDC neurons, involves the enhancement of c-Jun and phospho-c-Jun and that their activation is regulated by JNK phosphorylation. We will use multidisciplinary approaches, including morphological, molecular, electrophysiological and pharmacological approaches as well as behavioral tests to examine whether the JNK/c-Jun cascade is involved in central visceral nociception, especially in the PSDC pathway, in a rat model of experimentally induced visceral pain. To test our hypothesis, the specific aims of our studies are to measure during visceral pain stimulation: I) the activation of the transcription factor c-Jun and its phosphorylation in the rat spinal cord and specifically in the PSDC pathway; II) the changes in expression of p-c-Jun by inhibition of JNK/c-Jun cascade following visceral pain and determine if changes occur in cellular response of PSDC neurons, as well as in exploratory behavior; III) the expression of neurokinin NK1 receptors in spinal cord and PSDC neurons following inhibition of JNK activity. These studies are important because they should elucidate the signal-transduction mechanisms involved in the processing of visceral nociception that may, in turn, lead to development of drugs selective for management of visceral pain.
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