Gestation, in laboratory animals and women, is accompanied by a hormonally activated antinociception that is predominantly driven by spinal dynorphin/K- and enkephalin/6- analgesic systems. Notably, this antinociception appears not to be subject to tolerance lormation. Spinal dynorphin tone, augmented during pregnancy and its hormonal simulation (HSP), results from the offset of its negative modulation by endogenous spinal opioids and nociceptin (orphanin FQ; N/OFQ). In fact, in HSP animals, the delta-opioid inhibition of dynorphin release reverses to an enhancement. This renewal application proposes to build on these observations to elucidate mechanistic underpinnings of the antinociception of pregnancy and HSP. The organizing hypothesis is that interactions between visceral afferent input and ovarian sex steroids are causally associated with altered regulation of spinal opioid action. This results in the reciprocal feed-forward regulation of dynorphin/K and enkephalin/delta spinal opioid pathways and the ovarian steroid-dependent amplification of opioid neuronal transmission. The specific objectives are to (1) Determine the influence of pregnancy and 17-betaestradiol (E2) and progesterone (P) on analgesic responsiveness to intrathecal (i.t.) delta-opioid agonists and the receptor profile thereof, (2) Determine whether or not the pregnancy profile of E2/P activates an enkephalin spinal antinociceptive system analogous to its effects on spinal dynorphin; the influence of E2/P, N-OFQ, opioids and interactions thereof on the in vitrorelease of lumbar spinal enkephalin will be investigated, (3) Determine the sequelae of sustained ovarian sex steroid treatment of orchidectomized sexually mature male rats on spinal opiold release: compare and contrast with females, (4) Determine the relevance of augmented afferent tone to the blunted formation of tolerance to endogenous opioids and the recently discovered E2/P-induced 'feed forward' opioid antinociception and (5) Determine the effect of the pregnancy profile of E2/P on opioid tolerance development to i.t. opiolds. Insights obtained from these experiments should point the way to the development of gender-based pharmacotherapies for the treatment of chronic pain (notoriously more prevalent in women than men), the usefulness of which is not restricted by the extreme loss of potency over time, the bane of narcotic utilization.
