title: The melanocortin-1 receptor gene mediates female-specific mechanisms of analgesia in mice and humans.
abstract: 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 kappa-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 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.
authors.affiliation: Department of Psychology, McGill University, Montreal, QC, Canada H3A 1B1. jeffrey.mogil@mcgill.ca
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Mogil
authors.forename: Sonya G
authors.initials: SG
authors.lastname: Wilson
authors.forename: Elissa J
authors.initials: EJ
authors.lastname: Chesler
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Rankin
authors.forename: Kumar V S
authors.initials: KV
authors.lastname: Nemmani
authors.forename: William R
authors.initials: WR
authors.lastname: Lariviere
authors.forename: M Kristina
authors.initials: MK
authors.lastname: Groce
authors.forename: Margaret R
authors.initials: MR
authors.lastname: Wallace
authors.forename: Lee
authors.initials: L
authors.lastname: Kaplan
authors.forename: Roland
authors.initials: R
authors.lastname: Staud
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Ness
authors.forename: Toni L
authors.initials: TL
authors.lastname: Glover
authors.forename: Magda
authors.initials: M
authors.lastname: Stankova
authors.forename: Alexander
authors.initials: A
authors.lastname: Mayorov
authors.forename: Victor J
authors.initials: VJ
authors.lastname: Hruby
authors.forename: Judith E
authors.initials: JE
authors.lastname: Grisel
authors.forename: Roger B
authors.initials: RB
authors.lastname: Fillingim
mesh_terms: D000293:Adolescent; D000328:Adult; D000483:Alleles; D000698:Analgesia; D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D005260:Female; D014644:Genetic Variation; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008817:Mice, Mutant Strains; D010146:Pain / Q000235:genetics* / Q000503:physiopathology; D010423:Pentazocine / Q000494:pharmacology; D018043:Receptors, Corticotropin / Q000235:genetics* / Q000502:physiology; D044101:Receptors, Melanocortin; D017473:Receptors, Opioid, kappa / Q000187:drug effects; D012727:Sex Characteristics
chemical_list: D000701:Analgesics, Opioid; D018043:Receptors, Corticotropin; D044101:Receptors, Melanocortin; D017473:Receptors, Opioid, kappa; D010423:Pentazocine