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Research ArticleNeuropharmacology

Sex, Pain, and Opioids: Interdependent Influences of Sex and Pain Modality on Dynorphin-Mediated Antinociception in Rats

Nai-Jiang Liu, Stephen Schnell, Martin W. Wessendorf and Alan R. Gintzler
Journal of Pharmacology and Experimental Therapeutics February 2013, 344 (2) 522-530; DOI: https://doi.org/10.1124/jpet.112.199851
Nai-Jiang Liu
Department of Obstetrics and Gynecology, State University of New York, Downstate Medical Center, Brooklyn, New York (N.-J.L., A.R.G.); and Department of Neuroscience, University of Minnesota, Minneapolis, Minnesota (S.S., M.W.W.)
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Stephen Schnell
Department of Obstetrics and Gynecology, State University of New York, Downstate Medical Center, Brooklyn, New York (N.-J.L., A.R.G.); and Department of Neuroscience, University of Minnesota, Minneapolis, Minnesota (S.S., M.W.W.)
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Martin W. Wessendorf
Department of Obstetrics and Gynecology, State University of New York, Downstate Medical Center, Brooklyn, New York (N.-J.L., A.R.G.); and Department of Neuroscience, University of Minnesota, Minneapolis, Minnesota (S.S., M.W.W.)
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Alan R. Gintzler
Department of Obstetrics and Gynecology, State University of New York, Downstate Medical Center, Brooklyn, New York (N.-J.L., A.R.G.); and Department of Neuroscience, University of Minnesota, Minneapolis, Minnesota (S.S., M.W.W.)
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Abstract

The role of dynorphin A (1-17; Dyn) and its associated kappa opioid receptor (KOR) in nociception represents a longstanding scientific conundrum: Dyn and KOR (Dyn/KOR) have variously been reported to inhibit, facilitate, or have no effect on pain. We investigated whether interactions between sex and pain type (which are usually ignored) influenced Dyn/KOR-mediated antinociception. Blockade of the spinal α2-noradrenergic receptor (α2-NAR) using yohimbine elicited comparable spinal Dyn release in females and males. Nevertheless, the yohimbine-induced antinociception exhibited sexual dimorphism that depended on the pain test used: in the intraperitoneal acetic acid–induced writhing test, yohimbine produced antinociception only in females, whereas in the intraplantar formalin-induced paw flinch test, antinociception was observed only in males. In females and males, both intrathecal Dyn antibodies and spinal KOR blockade eliminated the yohimbine-induced antinociception, indicating that Dyn/KOR mediated it. However, despite the conditional nature of spinal Dyn/KOR-mediated yohimbine antinociception, both intraplantar formalin and intraperitoneal acetic acid activated spinal Dyn neurons that expressed α2-NARs. Moreover, Dyn terminals apposed KOR-expressing spinal nociceptive neurons in both sexes. This similar organization suggests that the sexually dimorphic interdependent effects of sex and pain type may result from the presence of nonfunctional (silent) KORs on nociceptive spinal neurons that are responsive to intraplantar formalin (in females) versus intraperitoneal acetic acid (in males). Our findings that spinal Dyn/KOR-mediated antinociception depends on interactions between sex and pain type underscore the importance of using both sexes and multiple pain models when investigating Dyn/KOR antinociception.

Footnotes

  • dx.doi.org/10.1124/jpet.112.199851.

  • Received September 5, 2012.
  • Accepted December 7, 2012.
  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 344 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 344, Issue 2
1 Feb 2013
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Research ArticleNeuropharmacology

Sex and Pain Interaction and Kappa-Opioid Antinociception

Nai-Jiang Liu, Stephen Schnell, Martin W. Wessendorf and Alan R. Gintzler
Journal of Pharmacology and Experimental Therapeutics February 1, 2013, 344 (2) 522-530; DOI: https://doi.org/10.1124/jpet.112.199851

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Research ArticleNeuropharmacology

Sex and Pain Interaction and Kappa-Opioid Antinociception

Nai-Jiang Liu, Stephen Schnell, Martin W. Wessendorf and Alan R. Gintzler
Journal of Pharmacology and Experimental Therapeutics February 1, 2013, 344 (2) 522-530; DOI: https://doi.org/10.1124/jpet.112.199851
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