Source: Photo by Colton Sturgeon on Unsplash

New research led by investigators at Massachusetts General Hospital (MGH) has offered up new insights into why people with red hair exhibit altered sensitivity to certain kinds of pain. The results of studies in mice with loss of melanocortin 1 receptor (MC1R) function could help point to new ways to manipulate the body’s natural mechanisms for controlling pain perception, for example, by designing new medications that inhibit receptors that are involved in sensing pain.

“Our ongoing work is focused on elucidating how additional skin-derived signals regulate pain and opioid signaling,” said Lajos V. Kemény, MD, PhD, a research fellow in Dermatology at MGH, who is co-senior author of the team’s paper, in Science Advances. “Understanding these pathways in depth may lead to the identification of novel pain-modulating strategies.” Kemény and team report on their findings in a paper titled, “Reduced MC4R signaling alters nociceptive thresholds associated with red hair.”

In people and mice with red hair (as in other species of animals with red fur), the skin’s pigment-producing melanocyte cells contain a variant form of MC1R. “Red hair in both species is caused by loss of-function variant alleles of the melanocortin 1 receptor (MC1R) …” the authors explained. This receptor sits on the cell surface and, if activated by circulating hormones called melanocortins, causes the melanocyte to switch from generating yellow/red melanin pigment to producing brown/black melanin pigment. Earlier work by David E. Fisher, MD, PhD, director of the Mass General Cancer Center’s Melanoma Program and director of MGH’s Cutaneous Biology Research Center, had demonstrated that the inability of red-haired individuals to tan or darken their skin pigment is traced to inactive variants of this receptor.

People and animals with natural red hair also have higher basal pain thresholds, and increased sensitivity to opioid pain analgesics, the team further pointed out. “Humans and mice with red hair exhibit altered pain thresholds, increased nonopioid analgesic requirements, and enhanced responses to opioid analgesics.” So, to investigate the mechanisms behind different pain thresholds in red-haired individuals, Fisher and his colleagues studied a strain of red-haired mice (Mc1re/e animals) that—as in humans— carries a dysfunctional MC1R variant, and also exhibits higher pain thresholds. This strain “ … recapitulates features of red-haired humans including synthesis of red/blond pheomelanin pigment, inability to tan following UV exposure, and increased ultraviolet (UV)–associated skin cancer risk,” the authors continued.

The team found that loss of melanocortin 1 receptor function in the red-haired mice caused the animals’ melanocytes to secrete lower levels of proopiomelanocortin (POMC), a molecule that is subsequently cut into different hormones, including one that sensitizes to pain and one that blocks pain. The presence of these hormones maintains a balance between opioid receptors that inhibit pain, and melanocortin 4 receptors (MC4R) that enhance perception of pain.

In red-haired mice (and therefore, possibly humans), having both hormones at low levels would seemingly cancel each other out. However, the body also produces additional, non-melanocyte-related factors that activate opioid receptors involved in blocking pain. Therefore, the net effect of lower levels of the melanocyte-related hormones is more opioid signals, which elevates the threshold for pain.

“MC1R loss of function decreases melanocytic proopiomelanocortin transcription and systemic melanocyte-stimulating hormone (MSH) levels in the plasma of red-haired (Mc1re/e),” the investigators wrote. “The data presented here suggest that elevated nociceptive thresholds found in the red-haired genetic background arise from a reduction in α-MSH levels caused by decreased POMC production in melanocytes, resulting in diminished MC4R signalling. Lower MC4R signaling, in turn, decreases its antagonism of opioid signaling within the CNS [central nervous system], which, despite diminished β-endorphin production, exhibits no discernible differences in other endogenous opioid ligands in the red hair background. Collectively, this produces a net melanocortin deficiency relative to opioid signaling, which alters the balance in favor of μ-opioid receptor–induced analgesia within the red hair background.”

“These findings describe the mechanistic basis behind earlier evidence suggesting varied pain thresholds in different pigmentation backgrounds,” said Fisher. “Understanding this mechanism provides validation of this earlier evidence and a valuable recognition for medical personnel when caring for patients whose pain sensitivities may vary.”

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