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| PREGNANCY-INDUCED ANTINOCICEPTION: INSIGHTS INTO GENDER-SPECIFIC ENDOGENOUS ANALGESIC PATHWAYS AND SUGGESTIONS FOR NOVEL PHARMACOTHERAPIES FOR PAIN Alan Gintzler, Ph.D., Department of Biochemistry, State University of New York Health Science Center, Brooklyn, New York In all cultures and societies, pain is a primary component of late pregnancy and labor. Additionally, these physiological states are mediated by stressful, energy-consuming physiological processes that are often associated with pronounced circulatory, respiratory and metabolic responses that can confound the orderly progression of normal child birth. For example, excessive stress-induced catecholamine output may cause dysfunctional labor as well as uteroplacental vasoconstriction leading to decreased blood flow and fetal deterioration. Thus, proper management of the pain of late pregnancy and labor is necessitated not only by humanistic considerations but physiological concerns as well. Appropriate pain management produces physiologic effects which are salutary for mother and infant. Thus, the presence of intrinsic pregnancy-activated analgesic processes would seem to have been critical to the evolution of all species. Indeed, there have evolved endogenous pain attenuating pathways which become activated during gestation and parturition, as a consequence of which the pain and discomfort of pregnancy and labor is mitigated. This phenomenon, pregnancy-induced analgesia, is manifest in response to somatic as well as visceral noxious stimuli. Gestational analgesia involves both peripheral and central systems. Spinal opioids acting via spinal cord k and d opioid receptors in a synergistic fashion, are the final mediator of this analgesia. Additionally, recent evidence suggests the reciprocal regulation of the spinal 'anti-opioid' orphanin FQ/ORL1 system during gestation. In addition to central antinociceptive systems, there are peripheral components that are essential to gestational analgesia. These include the hypogastric nerve, transection of which attenuates the analgesia of pregnancy, as well as circulating ovarian sex steroids. Simulation of the pregnancy profile of circulating 17-b -estradiol and progesterone results in elevated pain thresholds that closely parallel that associated with physiological pregnancy in its magnitude and temporal pattern, associated neurochemical changes in the spinal cord and the pharmacology of participating spinal opioid receptors. These data indicate that the mechanisms that underlie the analgesic adaptation to the 'stress' of pregnancy is multifactorial. They suggest that epidural application of combinations of k and d opioid agonists might be particularly efficacious in managing pain in women, especially during pregnancy. The gender-selectivity of the physiological relevance of a spinal antinociceptive system that is activated by estrogen and progesterone does not negate the possibility that an analogous system, although vestigial under normal circumstances, could also be present in males. Activation of such analgesic systems via novel pharmacotherapie could prove to be clinically advantageous. These considerations underscore the importance of the hormonal milieu to modulation of nociceptive transmission.
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