We have previously demonstrated that afferent input will result in a Ca++ dependent increase in the levels of met-enkephalin like immunoreactivity in spinal and mesencephalic periaqueductal (PAG) perfusates. A principal source of metenkephalin, proenkephalin A, is, however, known to possess several carboxy extended forms of met-enkephalin and a variety of large sequences (greater than 2000 Da). The fact that these forms, do gain access to the brain and spinal cord extracellular space and do have biological activity emphasizes their possible function as neurohormones. Though the several roles played by these enkephalin-secreting systems is not known, the physiological effect of activating receptors in these regions suggests these systems may play a prominent role in the processing of nociceptive information. Given the differential receptor preferences of the extended opioid peptides and the different systems associated with the several opioid receptors, it might be hypothesized that the release of the extended forms may reflect distinguishable functions. To investigate this issue we will assess in halothane anesthetized cats the release from spinal cord and PAG of: YGGFM, YGGFMR, YGGFMRF, YGGFMRGL and metorphamide. The concurrent assay of these several fragments will be made using a sequential protocol we have quantitatively characterized involving: a) ultrafiltration, b) HPLC, c) trypsin/carboxypeptidase B cleavage, and d) met-enkephalin specific radioimmunoassay. The concurrent release of these several opioid peptides from brain and spinal cord will be examined as a function of: the activation of somatic and visceral afferents; direct spinal stimulation using putative afferent transmitters (glutamate, substance P, vasoactive intestinal polypeptide) or agents which depolarize afferent terminals/ganglion cells (capsaicin). Electrical stimulation thresholds and frequency dependency of the release and the effects of opioid agonists and antagonists on release will be examined. Where practical, the effects of these manipulations on enkephalin secretion will be correlated with the effects on a thermally evoked nociceptive reflex. These studies will thus provide insight regarding the physiology and pharmacology of PAG and spinal cord systems, activity in which results in the local secretion of opioid peptides. Given the powerful effects produced by the action of exogenously administered opioids in these same regions, we must conclude that stimuli producing such enkephalin secretion also activate a powerful modulation.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
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Neurological Sciences Subcommittee 1 (NLS)
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University of California San Diego
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