Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 100, Issue 8, Pages 4867-4872Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0730053100
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Funding
- NIDA NIH HHS [R01 DA015191, DA15191] Funding Source: Medline
- NIDCR NIH HHS [DE12735] Funding Source: Medline
- NIDDK NIH HHS [DK17420] Funding Source: Medline
- NINDS NIH HHS [R01 NS041670, NS41670] Funding Source: Medline
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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 kappa-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 (Mc1R) 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 kappa-opioid analgesia. We found that women with two variant MC1R alleles displayed significantly greater analgesia from the kappa-opioid, pentazocine, than all other groups. This study demonstrates an unexpected role for the MOR 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.
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