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The Journal of Neuroscience, December 13, 2006, 26(50):13048-13053; doi:10.1523/JNEUROSCI.4783-06.2006

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Behavioral/Systems/Cognitive
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

Jomo Claiborne, Subodh Nag, and Sukhbir S. Mokha

Division of Neurobiology and Neurotoxicology, Department of Biomedical Sciences, Meharry Medical College, Nashville, Tennessee 37208

Correspondence should be addressed to Dr. Sukhbir S. Mokha, Division of Neurobiology and Neurotoxicology, Department of Biomedical Sciences, Meharry Medical College, 1005 D. B. Todd Boulevard, Nashville, TN 37208. Email: smokha{at}mmc.edu

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 µg 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.

Key words: orphanin FQ; opioid receptor like-1 receptor; ORL₁; sex differences; pain; tail flick; analgesia

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Received June 14, 2006; revised Nov. 9, 2006; accepted Nov. 9, 2006.

Correspondence should be addressed to Dr. Sukhbir S. Mokha, Division of Neurobiology and Neurotoxicology, Department of Biomedical Sciences, Meharry Medical College, 1005 D. B. Todd Boulevard, Nashville, TN 37208. Email: smokha{at}mmc.edu

This article has been cited by other articles:

				A. Dahan, B. Kest, A. R. Waxman, and E. Sarton Sex-Specific Responses to Opiates: Animal and Human Studies Anesth. Analg., July 1, 2008; 107(1): 83 - 95. [Abstract] [Full Text] [PDF]

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