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Humans and mice with natural red hair have elevated basal pain thresholds and an increased sensitivity to opioid analgesics. We investigated the mechanisms responsible for higher nociceptive thresholds in red-haired mice resulting from a loss of melanocortin 1 receptor (MC1R) function and found that the increased thresholds are melanocyte dependent but melanin independent. MC1R loss of function decreases melanocytic proopiomelanocortin transcription and systemic melanocyte-stimulating hormone (MSH) levels in the plasma of red-haired (Mc1re/e ) mice. Decreased peripheral α-MSH derepresses the central opioid tone mediated by the opioid receptor OPRM1, resulting in increased nociceptive thresholds. We identified MC4R as the MSH-responsive receptor that opposes OPRM1 signaling and the periaqueductal gray area in the brainstem as a central area of opioid/melanocortin antagonism. This work highlights the physiologic role of melanocytic MC1R and circulating melanocortins in the regulation of nociception and provides a mechanistic framework for altered opioid signaling and pain sensitivity in red-haired individuals. Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).


Kathleen C Robinson, Lajos V Kemény, Gillian L Fell, Andrea L Hermann, Jennifer Allouche, Weihua Ding, Ajay Yekkirala, Jennifer J Hsiao, Mack Y Su, Nicholas Theodosakis, Gabor Kozak, Yuichi Takeuchi, Shiqian Shen, Antal Berenyi, Jianren Mao, Clifford J Woolf, David E Fisher. Reduced MC4R signaling alters nociceptive thresholds associated with red hair. Science advances. 2021 Apr;7(14)

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PMID: 33811065

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