Sex-specific mediation of opioid-induced hyperalgesia by the melanocortin-1 receptor

Anesthesiology. 2010 Jan;112(1):181-8. doi: 10.1097/ALN.0b013e3181c53849.


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.

Publication types

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

MeSH terms

  • Analgesics, Opioid / toxicity*
  • Animals
  • Dizocilpine Maleate / pharmacology
  • Dose-Response Relationship, Drug
  • Excitatory Amino Acid Antagonists / pharmacology
  • Female
  • Hyperalgesia / chemically induced*
  • Hyperalgesia / psychology
  • Infusions, Intravenous
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Morphine / toxicity
  • Naltrexone / pharmacology
  • Narcotic Antagonists / pharmacology
  • Receptor, Melanocortin, Type 1 / antagonists & inhibitors
  • Receptor, Melanocortin, Type 1 / drug effects*
  • Receptor, Melanocortin, Type 1 / genetics
  • Receptors, N-Methyl-D-Aspartate / drug effects
  • Sex Characteristics


  • Analgesics, Opioid
  • Excitatory Amino Acid Antagonists
  • Narcotic Antagonists
  • Receptor, Melanocortin, Type 1
  • Receptors, N-Methyl-D-Aspartate
  • Naltrexone
  • Dizocilpine Maleate
  • Morphine