Estrogen-dependent, sex-specific modulation of mustard oil-induced secondary thermal hyperalgesia by orphanin FQ in the rat.

Activation of opioid receptor-like 1 receptor (ORL(1)) by intrathecal administration of orphanin FQ (OFQ), an endogenous ligand for the ORL(1) receptor, has been shown to produce antinociception. In addition, we have recently shown gonadal hormone-dependent, sex-specific modulation of acute spinal nociception such that estrogen attenuated OFQ-induced antinociception in the female whereas testosterone was required for the expression of antinociception in the male. However, sex-related differences in the role of OFQ under hyperalgesic conditions are unknown. Hence, we investigated whether OFQ produces sex-specific modulation of mustard oil-induced secondary thermal hyperalgesia in the rat. Mustard oil application to the hind limb significantly reduced the tail-flick latencies (TFL) in male, and ovariectomized (OVX), estradiol treated ovariectomized (OVX+E), proestrous (ProE) and diestrous (DiE) females. Intrathecal administration of OFQ not only attenuated mustard oil-induced decrease in TFLs, i.e. reversed hyperalgesia, but also led to a significant increase in TFLs above the baseline, i.e. produced antinociception in male, OVX, and diestrous rats. However, OFQ failed to alter TFLs in proestrous or OVX+E females, thus these two groups with elevated estrogen levels remained hyperalgesic following mustard oil treatment. These findings demonstrate that OFQ modulates mustard oil-induced secondary hyperalgesia in an estrogen-dependent, sex-specific manner.

Activation of opioid receptor like-1 receptor in the spinal cord produces sex-specific antinociception in the rat: estrogen attenuates antinociception in the female, whereas testosterone is required for the expression of antinociception in the male.

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 (ORL1) 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 microg of estradiol. The antinociceptive effects of OFQ were dose dependent in male and OVX animals and were reversibly antagonized by UFP-101 ([Nphe1,Arg14,Lys15]N/OFQ(1-13)-NH2), an ORL1 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.