Reduced MC4R signaling alters nociceptive thresholds associated with red hair

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 (Mc1r(e/e)) mice. Decreased peripheral alpha-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.

Automated summary

Research has found that individuals with red hair have higher basal pain thresholds and increased sensitivity to opioid analgesics. The increased pain thresholds are attributed to a loss of MC1R function, which decreases melanocytic proopiomelanocortin transcription and systemic MSH levels. This leads to increased nociceptive thresholds by derepressing central opioid tone.