Pregnancy is associated with an antinociception that is multifactorial and results from spinal (kappa/delta) opioid antinociceptive pathways as well as peripheral processes (ovarian sex steroids, uterine afferent neurotransmission). The present results provide the first indication that the full manifestation of pregnancy-induced analgesia also requires a supraspinal component. The analgesia of gestation or its hormonal simulation (via estrogen and progesterone administration; HSP) is substantially attenuated (>/=60%) following blockade of spinal alpha(2) (but not alpha(1)) adrenergic receptors. HSP antinociception is also attenuated by transection of the hypogastric nerve, the magnitude of which is indistinguishable from that produced by spinal alpha(2) receptor blockade. Additionally, hypogastric neurectomy abolishes the component of the antinociception associated with HSP that is mediated by spinal alpha(2) receptors. This suggests that the augmented spinal noradrenergic activity during HSP is not due to activation at the terminal of noradrenergic spinal projection neurons but requires supraspinal activity. It is suggested that enhanced spinal noradrenergic activity amplifies ongoing spinal kappa/delta antinociception as has been observed following the concomitant intrathecal application of alpha(2) and opioid agonists. The current observations underscore the importance of visceral afferent activity as well as its modulation by a female-specific hormonal milieu to the efficacy of endogenous spinal opioid antinociception.