title: 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.
abstract: 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.
authors.affiliation: Division of Neurobiology and Neurotoxicology, Department of Biomedical Sciences, Meharry Medical College, Nashville, Tennessee 37208, USA.
authors.forename: Jomo
authors.initials: J
authors.lastname: Claiborne
authors.forename: Subodh
authors.initials: S
authors.lastname: Nag
authors.forename: Sukhbir S
authors.initials: SS
authors.lastname: Mokha
mesh_terms: D000700:Analgesics / Q000008:administration & dosage / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004967:Estrogens / Q000502:physiology*; D005260:Female; D008297:Male; D009292:Narcotic Antagonists; D018847:Opioid Peptides / Q000008:administration & dosage* / Q000378:metabolism / Q000494:pharmacology; D009919:Orchiectomy; D010052:Ovariectomy; D010146:Pain / Q000188:drug therapy / Q000378:metabolism; D010147:Pain Measurement / Q000187:drug effects / Q000379:methods; D051381:Rats; D017207:Rats, Sprague-Dawley; D011957:Receptors, Opioid / Q000819:agonists / Q000378:metabolism* / Q000502:physiology; D012727:Sex Characteristics; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism*; D013739:Testosterone / Q000502:physiology*; D000094942:Nociceptin Receptor; D000097629:Nociceptin
chemical_list: D000700:Analgesics; D004967:Estrogens; D009292:Narcotic Antagonists; D018847:Opioid Peptides; D011957:Receptors, Opioid; D013739:Testosterone; D000094942:Nociceptin Receptor; D000097629:Nociceptin; C479838:(Nphe(1),Arg(14),Lys(15))N-OFQ NH(2); C000722285:Oprl1 protein, rat