Estrogen and progesterone activate spinal kappa-opiate receptor analgesic mechanisms

Abstract

Rats and humans manifest elevated response thresholds to aversive stimuli during gestation and parturition. This pregnancy-associated antinociception is mediated, in part, by a spinal cord dynorphin/kappa antinociceptive system. Simulating the maternal pregnancy blood concentration profile (in non-pregnant animals) of 17-beta-estradiol (E2) and progesterone (P) produces an opioid antinociception which closely approximates that of actual pregnancy. The current study was initiated in order to determine whether sex steroid-induced antinociception involves a spinal cord kappa-opiate receptor-coupled system (as does the antinociception of actual gestation). Additionally, sex steroid modulation of the intrathecal (i.t.) antinociceptive effectiveness of a kappa agonist was investigated. The opioid antinociception associated with simulating the pregnancy blood concentration profile of E2 and P (hormone-stimulated pregnancy, HSP) is significantly antagonized by i.t. administration of nor-binaltorphimine, an antagonist highly specific for the kappa-opiate receptor. This indicates that exposure (of non-pregnant animals) to the pregnancy blood profile of E2 and P activates a spinal cord kappa-opiate receptor analgesic system, as occurs during actual gestation. Furthermore, during HSP, antinociceptive responsiveness to i.t. U50,488H (kappa-selective) is significantly enhanced (approximately 40%). This effect is abolished in animals treated concomitantly with steroid hormones and systemic naltrexone or i.t. nor-binaltorphimine. In contrast to the effects of steroid treatment on antinociceptive responsiveness to i.t. U50,488H, no alteration in antinociceptive responsiveness to i.t. sufentanil was observed on day 19 of HSP over all doses tested (0.1-1 nmol). Thus, during HSP (and actual gestation), a less robust constituent of intrinsic opioid pain-attenuating systems in the spinal cord is recruited. pF to mediate, at least in part, the maternal antinociception of gestation. pF, positive modulation of the spinal cord kappa analgesic system occurs post-synaptically. This laboratory previously reported that simulating the pregnancy blood concentration profile of E2 and P also positively modulates spinal dynorphin content and the processing of its precursor, suggesting a presynaptic loci of action. Thus, female rats possess a spinal dynorphin/kappa analgesic system that can be positively modulated, pre-synaptically as well as post-synaptically, by circulating sex steroids.