Sex-specific Mediation of Opioid-induced Hyperalgesia by the Melanocortin-1 Receptor

Abstract

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 κ-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-Mc1re/e (e/e) mice, spontaneous mutants of the B6 background lacking functional melanocortin-1 receptors, during continuous morphine infusion (1.6 and 40.0 mg kg−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 highdose 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.

Targeting Opioid-Induced Hyperalgesia in Clinical Treatment: Neurobiological Considerations

“…Thus far, a host of animal studies have found that OIH is reversible by the NMDA receptor antagonists MK-801 [31,42,[160][161][162][163][164][165], ketamine, or traxoprodil [93]. Human studies have found similar results by adding adjuvant ketamine [46,54,88,166], as well as gabapentinoids such as pregabalin [49,55] or gabapentin [23], or the cyclooxygenase-2 inhibitor parecoxib [48,167], as reviewed in the subsequent sections.…”

Sex differences in pain and pain inhibition: multiple explanations of a controversial phenomenon

“…The distinction between the latter two types can be considered the difference between 'quantitative' and 'qualitative' sex differences. Although attention has mostly been paid to documenting quantitative sex differences in pain, a growing number of examples of qualitative differences in pain have been reported 31,39,43,[53][54][55][56][57][58][59][60][61][62][63][64] , and these promise to be far more important in the long run. As a practical matter, analgesics are routinely titrated according to their effect, which will effectively mitigate any sex differences along with other sources of inter-individual variability.…”

“…Nature Reviews | Neuroscience qualitative sex differences in the midbrain, spinal cord and the primary afferent -are currently more comprehensively documented than the others. Multiple laboratories have observed that the midbrain-brain stem neural circuit subserving stress-induced analgesia, κ-opioid (and possibly μ-opioid) analgesia, morphine tolerance and morphine hyperalgesia in mice contains NMDAtype glutamate receptors (NMDARs) in males 49,56,57,[88][89][90] but not females; in many cases, females seem to use melanocortin 1 receptors (MC1Rs) instead 39,54,91 . In these studies, pharmacological antagonism with non-competitive NMDAR antagonists (for example, MK-801) blocks the phenomena in male but not female mice at any dose.…”

Red hair and anesthetic requirement

“…7 Au cours d'études ultérieures, les mêmes chercheurs ont trouvé que les mutations MC1R chez les souris et les humains réduisent la sensibilité à la douleur et augmentent la réponse analgésique aux récepteurs l des opiacés, 8 et aussi que l'effet de ces mutations est dépendante du sexe chez les souris. 9 En revanche, les cheveux roux n'influencent pas la pharmacodynamique du propofol. 10 Bien que des récepteurs de la mélanocortine-1 aient été identifiés dans le tissu hypophysaire humain, dans les cellules gliales et dans les cellules de la substance grise périaqueducale 11,12 le système nerveux central n'est pas le principal site de l'expression de MC1R.…”

“…8 They also observed that the effect of this mutation is sex-specific in mice. 9 In contrast, red hair does not influence propofol pharmacodynamics. 10 Although melanocortin-1 receptors have been identified in human pituitary tissue, glial cells, and cells of the human periaqueductal gray matter, 11,12 the central nervous system is not a major site of MC1R expression.…”