Sex differences in morphine-induced analgesia of visceral pain are supraspinally and peripherally mediated

Abstract

Increasing evidence suggests there is a sex difference in opioid analgesia of pain arising from somatic tissue. However, the existence of a sex difference in visceral pain and opioid analgesia is unclear. This was examined in the colorectal distention (CRD) model of visceral pain in the current study. The visceromotor response (vmr) to noxious CRD was recorded in gonadally intact male and female rats. Subcutaneous injection of morphine dose-dependently decreased the vmr in both groups without affecting colonic compliance. However, morphine was significantly more potent in male rats than females. Because systemic morphine can act at peripheral tissue and in the central nervous system (CNS), the source of the sex difference in morphine analgesia was determined. The peripherally restricted mu-opioid receptor (MOR) antagonist naloxone methiodide dose-dependently attenuated the effects of systemic morphine. Systemic administration of the peripherally restricted MOR agonist loperamide confirmed peripherally mediated morphine analgesia and revealed greater potency in males compared with females. Spinal administration of morphine dose-dependently attenuated the vmr, but there was no sex difference. Intracerebroventricular administration of morphine also dose-dependently attenuated the vmr with significantly greater potency in male rats. The present study documents a sex difference in morphine analgesia of visceral pain that is both peripherally and supraspinally mediated.

Estrogen alters spinal NMDA receptor activity via a PKA signaling pathway in a visceral pain model in the rat

“…We have previously reported that the magnitude of the visceromotor response (a suprathreshold response) does not fluctuate with the estrous cycle (Ji et al 2006), although the threshold to evoke the visceromotor response does fluctuate across the estrous cycle (Sapsed-Byrne et al, 1996;Holdcroft et al 2000). These data and our previous reports that E2 replacement reverses the antinociceptive effect of ovariectomy (Ji et al, 2003b;Ji et al, 2005), suggests female gonadal hormones modulate visceral nociceptive processing.…”

Estrogen Modulation of Morphine Analgesia of Visceral Pain in Female Rats Is Supraspinally and Peripherally Mediated

“…20 In the present experiment, we provide evidence that estradiol is 1 of the key factors that mediates the observed sex differences in morphine analgesia. Specifically, OVx rats had similar dose-response curves and ED 50 s to morphine as male rats, whereas E2-replaced rats had similar dose-response curves and ED 50 s to morphine as intact female rats (compare with Table 1 in Reference 20).…”

“…Seven days after ovariectomy (5 to 7 days before testing), rats were anesthetized with halothane, and electromyogram electrodes made from Tefloncoated, 32-gauge stainless steel wire (Cooner Wire Co, Chatsworth, CA) were implanted in the lateral abdominal wall and exteriorized at the back of the neck. 20,33,47 Rats were subsequently singly housed. All rats were fasted 18 to 24 hours before testing to facilitate balloon placement.…”

“…20 In the present study, we tested the hypothesis that the gonadal hormone estradiol plays an important role in modulating the effect of morphine and may contribute to the observed sex difference in morphine potency. Aspects of this work have been published in abstract form.…”

Sexually Dimorphic Recruitment of Spinal Opioid Analgesic Pathways by the Spinal Application of Morphine

“…These results are consistent with an earlier report that, in contrast to systemic and i.c.v. administration of morphine, its spinal administration dose dependently attenuates the visceromotor response to colorectal distention with equal potency in male and female rats (Ji et al, 2006).…”