Melanocortin-1 receptor gene variants affect pain and μ-opioid analgesia in mice and humans
- ️Fri Jul 01 2005
Melanocortin-1 receptor gene variants affect pain and μ-opioid analgesia in mice and humans
- J S Mogil1,
- J Ritchie1,
- S B Smith1,
- K Strasburg1,
- L Kaplan2,
- M R Wallace2,
- R R Romberg3,
- H Bijl3,
- E Y Sarton3,
- R B Fillingim4,
- A Dahan3
- 1Department of Psychology and Centre for Research on Pain, McGill University, Montreal, Canada
- 2Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, FL, USA
- 3Department of Anesthesiology, Leiden University Medical Center, Leiden, The Netherlands
- 4University of Florida College of Dentistry and Gainesville VA Medical Center, Gainesville, FL, USA
- 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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