Rapid Regulation of Pain by Estrogens Synthesized in Spinal Dorsal Horn Neurons

Abstract

In addition to exerting genomic actions via nuclear receptors within hours to days, estrogens also regulate neuronal activity much faster (within seconds) by activating neuronal membrane receptors coupled to intracellular second-messenger pathways. To date, the origin of estrogens inducing rapid effects in the brain remains unclear, although it is often ascribed to the gonads. We report here that an acute blockade of the endogenous synthesis of estrogens in the quail spinal dorsal horn markedly reduced, within 1 min, the behavioral responsiveness to a thermal painful stimulus. Similar rapid effects in the opposite direction were induced by estradiol. This finding identifies a new paracrine and nongenomic mechanism for the regulation of pain by estrogens. Such regulation was assumed previously to result only from slow genomic actions of estrogens arising from the ovaries. Also, quite importantly, this finding suggests that the numerous rapid nongenomic effects of estrogens in the CNS could depend on their immediate local production by the enzyme aromatase, independently from the gonads.

Functional significance of the rapid regulation of brain estrogen action: Where do the estrogens come from?

“…Rapid effects on nociception of intrathecal injections of aromatase inhibitors (vorozole™ and ATD) are also observed: the foot withdrawal latency from a hot water bath is markedly increased 1 and 5 min after an intrathecal injection of the aromatase inhibitor, ATD or Vorozole™, and this effects has disappeared 30 min after the injection. These acute effects of a systemic injection of vorozole™ are inhibited by a concurrent injection of E 2 [85]. Similar effects were reported recently in rats [86].…”

“…These acute effects of a systemic injection of vorozole™ are inhibited by a concurrent injection of E 2 [85]. Similar effects were reported recently in rats [86]. Together these data indicate that the rapid effects of locally produced estrogens on neuronal physiology and behavior do not only concern the brain but also the spinal cord.…”

“…Central aromatization also plays a role in the control of aggressive behaviors [227][228][229]247,258], neuroprotection [10], nociception [43, [83][84][85], the development of sexual preferences [214] and synaptic plasticity [197]. Most of these studies, however, concern relatively slow, presumably genomic, effects of estrogens.…”

Studying sex and gender differences in pain and analgesia: A consensus report

“…Likewise, 500 μg of s.c. progesterone is a reasonable starting point for progestin replacement, with testing beginning 4-6 h later [58]. Of course, these testing intervals assume a nuclear steroid receptor-mediated (genomic) effect, whereas recent reports indicate that gonadal steroids may modulate pain thresholds at considerably shorter intervals [57]. Thus, it is important to consider shorter treatment-test intervals as well.…”

“…For example, changes in spinal aromatase activity dramatically and immediately affected pain thresholds in the Japanese quail, without changes in plasma levels of gonadal steroids [56,57]. Future studies in which various steroidogenic enzyme inhibitors (or hormone agonists or antagonists) are locally infused would contribute to our understanding of how local changes in hormone action result in behavioral changes in sensitivity to pain and analgesia.…”