SEX STEROIDS MODULATE NOCICEPTION, AND ESTROGEN MODIFIES SUPRASPINAL NOCICEPTIVE ACTIVATION

Abstract

Chronic pain leads neurological disorders in the US both in terms of numbers of cases and economic cost. The understanding of sex differences in the sensory experience of pain is emerging. For example, the incidence of many, but not all, chronic pain disorders is higher in women than men. There is considerable evidence that sex steroids can modulate pain processing and may contribute to sex differences in chronic pain. However, there are no reports of direct, systematic investigation into the anatomical sites of action in the nervous system of the enhancement of pain by estrogen. Thus, this research program aimed to determine the potential contribution of activational effects of sex hormones to pain sensation and was designed to test the overall hypothesis that sex differences in pain sensation are due, at least in part, to activational effects of sex hormones on peripheral, spinal and/or supraspinal sites involved in the transmission and perception of pain. To test this hypothesis, established rodent models of pain were employed, and biochemical and behavioral end points were quantified. Initial experiments used gonadectomy and testosterone supplementation to manipulate androgen status in adult, male rats, testing the impact of androgen manipulation on behavioral responses in several pain models. Results revealed activational effects on pain of phasic thermal and persistent neuropathic origin, but perhaps not persistent inflammatory origin, providing evidence that androgens can contribute to sex differences in pain sensation. Further experiments used ovariectomy and estradiol supplementation to manipulate estrogen status in adult, female rats, testing its impact on nociception-related behavior and neuronal activation in response to formalin-evoked inflammatory nociception. Results of behavioral analyses showed that estradiol increases persistent, inflammatory nociception in an activational manner. Results of quantification of nociception-evoked neuronal activation (measurement of numbers of neurons expressing the protein Fos) showed that estrogen enhances inflammatory nociception primarily at higher brain centers, specifically the nucleus accumbens and the ventral hippocampal CA1 region. These activational effects of estrogen may contribute to sex differences in pain sensation and/or the disproportionate severity or incidence of some pain syndromes in women.