The maternal spinal cord: biochemical and physiological correlates of steroid-activated antinociceptive processes.

Physiological gestation, as well as the simulation of the associated changes in estrogen and progesterone, is associated with significant elevations in nociceptive response thresholds. This is mediated by spinal cord kappa- and delta-opIoid systems. The predominant spinal mu-opioid system does not appear to participate. One hallmark of pregnancy- and hormonally-induced antinociception is the multiplicative interaction among its components. Approximately 40% results from spinal kappa/delta analgesic synergy on which is superimposed an additional increment (approximately 60%) of synergy that results from the interaction between descending spinal alpha 2-noradrenergic and spinal kappa/delta activities. An intact hypogastric nerve is required for the spinal alpha 2-noradrenergic component. This would explain the requirement for an intact hypogastric nerve in order for the antinociception of pregnancy and its hormonal simulation to be fully manifest. The predominant means by which spinal dynorphin-containing neurons adjust to increased demand is increased post-translational processing of dynorphin precursor intermediates which are present at approximately 10x the concentration of mature dynorphin peptides (1-17 and 1-8). This is indicated by the concomitant decline (approximately 50%) in the spinal cord content of dynorphin precursors and increase (approximately 87%) in the content of prohormone convertase 2, a processing enzyme sufficient to generate mature dynorphin peptides from prodynorphin. The presence of 'high gain' multiplicative spinal opioid antinociceptive pathways that can be activated by estrogen and progesterone has hyperalgesic implications as well, i.e. it could result in disproportionately increased pain responsiveness. This might explain, in part, findings that women are more prone to recurrent pain and pain of greater duration and intensity than men. The underlying mechanisms of gestational antinociception could point the way to pain pharmacotherapies that are gender-based.