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Melanocortin-1 receptor gene variants affect pain and μ-opioid analgesia in mice and humans
  1. J S Mogil1,
  2. J Ritchie1,
  3. S B Smith1,
  4. K Strasburg1,
  5. L Kaplan2,
  6. M R Wallace2,
  7. R R Romberg3,
  8. H Bijl3,
  9. E Y Sarton3,
  10. R B Fillingim4,
  11. A Dahan3
  1. 1Department of Psychology and Centre for Research on Pain, McGill University, Montreal, Canada
  2. 2Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, FL, USA
  3. 3Department of Anesthesiology, Leiden University Medical Center, Leiden, The Netherlands
  4. 4University of Florida College of Dentistry and Gainesville VA Medical Center, Gainesville, FL, USA
  1. Correspondence to:
 Jeffrey S Mogil
 Department of Psychology, McGill University, 1205 Dr. Penfield Ave, Montreal, QC, Canada H3A 1B1; jeffrey.mogilmcgill.ca

Abstract

Background: A recent genetic study in mice and humans revealed the modulatory effect of MC1R (melanocortin-1 receptor) gene variants on κ-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 μ-opioid receptor.

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

Methods: Comparisons of spontaneous mutant C57BL/6-Mc1re/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-Mc1re/e mutant mice and human redheads—both with non-functional MC1Rs—display reduced sensitivity to noxious stimuli and increased analgesic responsiveness to the μ-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.

  • AD, antinociceptive dose
  • α-MSH, α-melanocyte stimulating hormone
  • AUEC, area under the time-effect curve
  • M6G, morphine-6-glucuronide
  • MC1R, melanocortin-1 receptor
  • melanocortin-1 receptor
  • morphine-6-glucuronide
  • opioid
  • pharmacogenetics
  • redheads
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Footnotes

  • This work was supported by US PHS grant DA15191 and the Canada Research Chairs and Canada Foundation for Innovation programs (JSM), the Children’s Miracle Network, UF Research Opportunity Fund and the Hayward Foundation (MRW), and US PHS grant NS41670 (RBF). CeNeS Ltd provided financial support for the measurement of the human M6G blood concentrations.

  • Competing interests: none declared

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