Sex-related differences in the perception and modulation of pain have been reported. The present study is the first to investigate systematically whether activation of opioid receptor-like 1 receptor (ORL 1 ) by orphanin FQ (OFQ) produces sex-specific modulation of spinal nociception and whether estrogen or testosterone contributes to these differences using the rat as an experimental animal. Two behavioral models, the NMDA and heat-induced nociceptive tests, were used to examine sex-specific modulation of spinal nociception. Intrathecal microinjection of OFQ in male, ovariectomized (OVX), and diestrous rats produced a significant antinociceptive effect on both tests. However, OFQ failed to produce antinociception in proestrous rats, the phase of the estrous cycle with the highest levels of circulating estradiol, and produced a dose-dependent effect in OVX females treated with 1 ng to 100 g of estradiol. The antinociceptive effects of OFQ were dose dependent in male and OVX animals and were reversibly antagonized by UFP-101 ([Nphe 1 ,Arg ,Lys 15]N/ OFQ(1-13)-NH 2 ), an ORL 1 receptor-selective antagonist. Interestingly, OFQ was ineffective in gonadectomized (GDX) males, whereas testosterone replacement restored the antinociceptive effect of OFQ in GDX males. We conclude that OFQ produces sex-specific modulation of spinal nociception; estrogen attenuates antinociception in the female in parallel with normal cycling of estrogen levels, and testosterone is required for the expression of antinociception in the male; thus, the sensitivity of the male to the antinociceptive effects of OFQ is not simply attributable to the intrinsically low estrogen levels in these animals.

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Sex-related differences in antinociception produced by the activation of α 2 -adrenoceptors (α 2 -ARs) have been reported, however, the precise role of gonadal steroids is still unknown. Hence, we hypothesized that estrogen and testosterone modulate antinociceptive effects of clonidine (an α 2 -AR agonist) on N-methyl-D-aspartate (NMDA)-and heat-induced spinal nociception. We also investigated whether estrogen-or testosterone alter the expression of α 2A -adrenoceptors in the spinal cord. Sprague-Dawley (SD) rats were implanted with PE10 cannulae in the intrathecal space of the lumbosacral spinal cord and divided into male, proestrous and diestrous female, ovariectomized (OVX), estradiol-treated OVX (OVX+E), castrated male (GDX), testosterone (GDX+T) and estrogen-treated GDX (GDX+E) groups. Clonidine dose-dependently inhibited NMDA-induced scratching behavior in the male and OVX groups but to a significantly lesser extent in the OVX+E group. It also increased the tail withdrawal latency in the male, OVX, diestrous and GDX+T groups but not in the OVX+E, proestrous, GDX and GDX+E groups. Levels of α 2A -AR mRNA were significantly higher in the OVX, estradiol-treated OVX, GDX and GDX+E animals. In contrast, α 2A -AR protein levels were higher in estradiol-treated OVX, GDX, GDX+T and GDX+E animals as compared to the male. Indeed, no correlations were observed between changes in the mRNA or protein levels of α 2A -AR and behavioral observations. These results support our hypothesis that sex-related differences in α 2 -AR-mediated modulation of spinal nociception are gonadal hormone-dependent: estrogen attenuates antinociceptive effects in females whereas testosterone is required for the expression of antinociception in males. In addition, results also revealed that the mechanism of action of gonadal hormones may not involve a global alternation in expression of α 2A -AR in the spinal cord. Estrogen-induced attenuation of α 2 -AR-mediated inhibition of nociception could contribute to the higher prevalence of pain syndromes in women. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Sex-related differences in the perception of pain and the response to analgesics have been reported with females having lower thresholds for pain (Notermans, 1966;Neri et al., 1984;Berkley, 1997;Riley et al., 1999;Rollman et al., 2000; reviewed in Keogh et al., 2002) and a larger number of pain sites as compared to males (Fillingim and Maixner, 1995;Berkley, 1997;Fillingim et al., 1999). In addition, many pain syndromes/disorders such as fibromyalgia, rheumatoid arthritis, irritable bowel syndr...

This investigation determined whether activation of the kappa opioid receptor (KOR) in the spinal cord produces estrogen-dependent, sex-specific modulation of acute and inflammation-induced persistent nociception. We demonstrate for the first time that KOR antinociception and gene expression are enhanced by exogenous or endogenous estrogen in the female. The lack of KOR antinociception and KOR gene expression are not altered by hormonal status (testosterone or estrogen) in males. Cannulae were implanted intrathecally in male, gonadectomized male (GDX), intact and ovariectomized female (OVX) Sprague-Dawley rats. Estradiol was injected subcutaneously, 48 h before testing (GDX+E and OVX+E). Intrathecal injection of U50, 488H, a selective KOR agonist, dose dependently increased heat-evoked tail flick latencies (TFLs) in proestrous and OVX+E groups, but not in male, GDX, GDX+E, OVX, and diestrous groups. Further, estrogen dose-dependently enhanced the effect of U50,488H in OVX rats. KOR selective antagonist, nor-binaltorphimine (Nor-BNI), blocked the antinociceptive effect of U50,488H. U50,488H reversed the carrageenan-induced thermal hyperalgesia in OVX+E rats, but not in male or OVX rats. However, U50,488H treatment did not alter mechanical thresholds in any group, with or without inflammation. KOR gene expression was enhanced in proestrous and OVX+E groups as compared to any other group. We conclude that selective activation of KOR in the spinal cord produces sex-specific, stimulus-and estrogen-dependent attenuation of acute and inflammatory pain in the rat via estrogeninduced upregulation of the KOR gene expression in the spinal cord. These findings may further implicate estrogen dependence of KOR effects in learning, epilepsy, stress response, addiction etc.Selective activation of the kappa opioid receptor by intrathecal U50,488H produces antinociception and antihyperalgesia which are sex-specific, stimulus dependent and require the presence of estrogen.

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