Cutaneous Biology Research Center, Department of Dermatology and MGH Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02129, USA.
Doctoral School of Clinical Medicine, University of Szeged, Szeged 6720, Hungary.
Sci Adv. 2021 Apr 2;7(14). doi: 10.1126/sciadv.abd1310. Print 2021 Apr.
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 ( ) 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.
人类和自然红发的老鼠具有较高的基础疼痛阈值和对阿片类镇痛药的敏感性增加。我们研究了导致红发老鼠疼痛阈值升高的机制，这是由于黑皮质素 1 受体 (MC1R) 功能丧失所致，结果发现，较高的阈值是黑素细胞依赖性的，而与黑色素无关。MC1R 功能丧失导致黑素细胞原促黑皮质素转录和血浆中黑素细胞刺激素 (MSH) 水平降低在红发（）老鼠中。外周 α-MSH 的减少解除了阿片受体 OPRM1 介导的中枢阿片紧张，导致疼痛阈值增加。我们确定 MC4R 是 MSH 反应性受体，它与 OPRM1 信号相反，中脑导水管周围灰质区是阿片/黑素皮质素拮抗的中枢区域。这项工作强调了黑素细胞 MC1R 和循环黑素皮质素在调节疼痛中的生理作用，并为红发个体中阿片信号改变和疼痛敏感性提供了机制框架。
