Melanocortin-1 receptor gene variants affect pain and mu-opioid analgesia in mice and humans

J Med Genet. 2005 Jul;42(7):583-7. doi: 10.1136/jmg.2004.027698.


Background: A recent genetic study in mice and humans revealed the modulatory effect of MC1R (melanocortin-1 receptor) gene variants on kappa-opioid receptor mediated analgesia. It is unclear whether this gene affects basal pain sensitivity or the efficacy of analgesics acting at the more clinically relevant mu-opioid receptor.

Objective: To characterise sensitivity to pain and mu-opioid analgesia in mice and humans with non-functional melanocortin-1 receptors.

Methods: Comparisons of spontaneous mutant C57BL/6-Mc1r(e/e) mice to C57BL/6 wildtype mice, followed by a gene dosage study of pain and morphine-6-glucuronide (M6G) analgesia in humans with MC1R variants.

Results: C57BL/6-Mc1r(e/e) mutant mice and human redheads--both with non-functional MC1Rs--display reduced sensitivity to noxious stimuli and increased analgesic responsiveness to the mu-opioid selective morphine metabolite, M6G. In both species the differential analgesia is likely due to pharmacodynamic factors, as plasma levels of M6G are similar across genotype.

Conclusions: Genotype at MC1R similarly affects pain sensitivity and M6G analgesia in mice and humans. These findings confirm the utility of cross species translational strategies in pharmacogenetics.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adolescent
  • Adult
  • Analgesia*
  • Analgesics, Opioid / pharmacokinetics
  • Analgesics, Opioid / therapeutic use
  • Animals
  • Dose-Response Relationship, Drug
  • Female
  • Genetic Variation*
  • Genotype
  • Hair Color / genetics
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Mutant Strains
  • Morphine / pharmacokinetics
  • Morphine / therapeutic use
  • Morphine Derivatives / pharmacokinetics
  • Morphine Derivatives / therapeutic use
  • Pain / drug therapy
  • Pain / genetics*
  • Pain Measurement / drug effects
  • Pain Threshold / drug effects
  • Receptor, Melanocortin, Type 1 / genetics*
  • Receptors, Opioid, mu / drug effects*
  • Reference Values


  • Analgesics, Opioid
  • Morphine Derivatives
  • Receptor, Melanocortin, Type 1
  • Receptors, Opioid, mu
  • morphine-6-glucuronide
  • Morphine