Sex-specific mediation of opioid-induced hyperalgesia by the melanocortin-1 receptor.
BACKGROUND
N-Methyl-D-aspartate receptor antagonists reverse hyperalgesia during morphine infusion in male mice only. Because the melanocortin-1 receptor can act as a female-specific counterpart to N-methyl-D-aspartate receptors in kappa-opioid analgesic mechanisms, the authors assessed the contribution of melanocortin-1 receptors to the sex-specific mechanisms underlying morphine hyperalgesia.


METHODS
The tail-withdrawal test was used to compare the nociceptive responses of male and female C57BL/6J (B6) mice with those of C57BL/6J-Mc(1r(e/e)) mice, spontaneous mutants of the B6 background lacking functional melanocortin-1 receptors, during continuous morphine infusion (1.6 and 40.0 mgkg(-1) . 24 h(-1)). Separate groups of hyperalgesic B6 and outbred CD-1 mice were injected with MK-801 or MSG606, selective N-methyl-D-aspartate and melanocortin-1 receptor antagonists, respectively.


RESULTS
Morphine infusion (40.0 mg . kg(-1) . 24 h(-1)) reduced baseline withdrawal latencies by 45-55% in B6 mice of both sexes, indicating hyperalgesia; this increased nociception was manifest in male e/e mice only. Although MK-801 reversed hyperalgesia in male mice only, increasing latencies by 72%, MSG606 increased latencies by approximately 60% exclusively in females. A lower morphine infusion dose (1.6 mg . kg(-1) . 24 h(-1)) reduced baseline withdrawal latencies by 45-52% in B6 and e/e mice of both sexes, which was reversed by MK-801, but not MSG606, in both male and female B6 mice.


CONCLUSIONS
The data indicate the sex-specific mediation of high-dose morphine-induced hyperalgesia by N-methyl-d-aspartate and melanocortin-1 receptors in male and female mice, respectively, suggesting a broader relevance of this known sexual dimorphism. The data further indicate that the neural substrates contributing to hyperalgesia are morphine dose-dependent.
Juni
Aaron
A
Neuropsychology Doctoral Program, Queens College, City University of New York, Flushing, New York, USA.
Cai
Minying
M
Stankova
Magda
M
Waxman
Amanda R
AR
Arout
Caroline
C
Klein
Gad
G
Dahan
Albert
A
Hruby
Victor J
VJ
Mogil
Jeffrey S
JS
Kest
Benjamin
B
D000701:Analgesics, Opioid / Q000633:toxicity*; D000818:Animals; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005260:Female; D006930:Hyperalgesia / Q000139:chemically induced* / Q000523:psychology; D007262:Infusions, Intravenous; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009020:Morphine / Q000633:toxicity; D009271:Naltrexone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D044102:Receptor, Melanocortin, Type 1 / Q000037:antagonists & inhibitors / Q000187:drug effects* / Q000235:genetics; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects; D012727:Sex Characteristics
D000701:Analgesics, Opioid; D018691:Excitatory Amino Acid Antagonists; D009292:Narcotic Antagonists; D044102:Receptor, Melanocortin, Type 1; D016194:Receptors, N-Methyl-D-Aspartate; D009271:Naltrexone; D016291:Dizocilpine Maleate; D009020:Morphine