The melanocortin-1 receptor gene mediates female-specific mechanisms of analgesia in mice and humans

Jeffrey S. Mogil, Sonya G. Wilson, Elissa J. Chesler, Andrew L. Rankin, Kumar V.S. Nemmani, William R. Lariviere, M. Kristina Groce, Margaret R. Wallace, Lee Kaplan, Roland Staud, Timothy J. Ness, Toni L. Glover, Magda Stankova, Alexander Mayorov, Victor J. Hruby, Judith E. Grisel, Roger B. Fillingim

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433 Scopus citations


Sex specificity of neural mechanisms modulating nociceptive information has been demonstrated in rodents, and these qualitative sex differences appear to be relevant to analgesia from κ-opioid receptor agonists, a drug class reported to be clinically effective only in women. Via quantitative trait locus mapping followed by a candidate gene strategy using both mutant mice and pharmacological tools, we now demonstrate that the melanocortin-1 receptor (Mclr) gene mediates K-opioid analgesia in female mice only. This finding suggested that individuals with variants of the human MC1R gene, associated in our species with red hair and fair skin, might also display altered κ-opioid analgesia. We found that women with two variant MC1R alleles displayed significantly greater analgesia from the κ-opioid, pentazocine, than all other groups. This study demonstrates an unexpected role for the MC1R gene, verifies that pain modulation in the two sexes involves neurochemically distinct substrates, and represents an example of a direct translation of a pharmacogenetic finding from mouse to human.

Original languageEnglish (US)
Pages (from-to)4867-4872
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number8
StatePublished - Apr 15 2003

ASJC Scopus subject areas

  • General


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