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-simulated 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.

Changes in Brain Size during the Menstrual Cycle

“…There are clear-cut sexual differences in specific cognitive tasks, in behavior and in the vulnerability to depression and anxiety [11], [43], [44]. Furthermore, memory and learning, pain perception, and susceptibility to seizures are among the CNS functions which are modulated by steroids [45], [46], [47], [48]. Some but not all of these effects show menstrual cycle dependent fluctuations.…”

The Physiologic Effects of Pain on the Endocrine System

“…The critical pain-control hormones that are produced in glands outside the CNS are cortisol, pregnenolone, dehydroepiandrosterone (DHEA), progesterone, testosterone, estrogen, and thyroid (Table 1) [31–52]. Among the primary pain-control functions of these hormones are immune and anti-inflammatory actions, cellular protection, tissue regeneration, glucose control, and modulation of CNS receptors, the blood–brain barrier, and nerve conduction (Table 2) [53–63]. Given the CNS effects of certain hormones, analgesics such as anti-depressants, neuropathic agents and opioids, may not achieve maximal analgesic responses without hormone homeostasis [19, 33, 37, 42, 49–53].…”

Estradiol and testosterone differently affect visceral pain‐related behavioural responses in male and female rats

“…Indeed, estrogen receptors (ERs) are present not only in the CNS but in most body structures, including muscle (Wiik et al, 2009;Cheskis et al, 2007). ER in the spinal cord can be directly involved in nociceptive transmission since they are present in the superficial laminae cells, most of which release enkephalin (Amandusson et al, 1996;Dawson-Basoa and Gintzler, 1996). In addition, ER are present in smooth muscle where they have an inhibitory action, probably through increased nitric oxide (NO) production or modulation of calcium homeostasis (Qiao et al, 2008).…”