Gonadal Hormone Modulation Of Visceral Pain

The preponderance of evidence suggests that females are more sensitive to pain than males and several chronic pain syndromes including IBS, fibromyalgia, and temporomandibular disorders are more prevalent in women than in men (197-199). Furthermore, nociceptive thresholds are lowest and pain responses highest during periods of elevated estrogen (199-204), strongly suggesting that sex hormones modulate pain sensation.

Several labs have demonstrated that gonadal hormones modulate behavioral responses to noxious visceral stimuli and there is a large body of evidence that estrogen increases nociceptive sensitivity. From most studies it cannot be determined where the gonadal hormones are exerting their influence, be it peripherally or centrally, and a full discussion of this topic is beyond the scope of this chapter. There are, however, a few studies indicating hor-monally mediated nociceptive plasticity is spinally mediated. Dorsal horn neurons express estrogen receptors (ERs) (205-207), providing an anatomical framework for estrogen modulation of viscerosensory processing at the level of the dorsal horn. Additionally, the cytostolic estrogen receptor (ER) concentration in the spinal cord is positively correlated with the serum estrogen concentration (208), further suggesting that estrogen can increase nociceptive sensitivity by modulating activity in dorsal horn neurons. Indeed, it was recently demonstrated that spinal aromatase converts testosterone to estrogen and increases sensitivity to noxious somatic stimuli (209). CRD induces Fos expression in spinal neurons that coexpress ER (unpublished observations) and the threshold for the visceromotor response to CRD is lowest when estrogen levels peak during proestrus (210,211). In complementary studies, ovariectomy decreased behavioral and dorsal horn neuronal responses to CRD. These responses were restored to levels observed in intact female rats by estrogen replacement, suggesting estrogen is pronociceptive (105). This estrogen-induced hypersensitivity may be partially mediated by increased activity at NMDA receptors. ER a colocalizes with the NMDA receptor in dorsal horn neurons (unpublished) and estrogen decreases the potency of NMDA receptor antagonists in attenuating the visceromotor response to CRD (150).

Estrogen also contributes to sex differences in opioid analgesia. Systemic morphine attenuates the CRD-evoked visceromotor response in male rats with a greater potency than in intact female rats (191). In the female rat, this sex difference correlates with the plasma estrogen concentration because ovariectomy increases the potency and subsequent estrogen replacement decreases the potency (Ji et al., submitted). In addition, estrogen decreases the potency of morphine in attenuating reflex responses to uterine-cervix distention although estrogen does not modulate the response itself (181,182).

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