Melanocortin-1 receptor gene variants affect pain and mu-opioid analgesia in mice and humans.
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.
Department of Psychology and Centre for Research on Pain, McGill University, Montreal, Canada. jeffrey.mogil@mcgill.ca
J S
JS
Mogil
J
J
Ritchie
S B
SB
Smith
K
K
Strasburg
L
L
Kaplan
M R
MR
Wallace
R R
RR
Romberg
H
H
Bijl
E Y
EY
Sarton
R B
RB
Fillingim
A
A
Dahan
D000293:Adolescent; D000328:Adult; D000698:Analgesia; D000701:Analgesics, Opioid / Q000493:pharmacokinetics / Q000627:therapeutic use; D000818:Animals; D004305:Dose-Response Relationship, Drug; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D006200:Hair Color / Q000235:genetics; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009020:Morphine / Q000493:pharmacokinetics / Q000627:therapeutic use; D009022:Morphine Derivatives / Q000493:pharmacokinetics / Q000627:therapeutic use; D010146:Pain / Q000188:drug therapy / Q000235:genetics*; D010147:Pain Measurement / Q000187:drug effects; D017288:Pain Threshold / Q000187:drug effects; D044102:Receptor, Melanocortin, Type 1 / Q000235:genetics*; D017450:Receptors, Opioid, mu / Q000187:drug effects*; D012016:Reference Values
D000701:Analgesics, Opioid; D009022:Morphine Derivatives; D044102:Receptor, Melanocortin, Type 1; D017450:Receptors, Opioid, mu; C035349:morphine-6-glucuronide; D009020:Morphine