Reduced MC4R Signaling May Explain Why Redheads Have Different Pain Thresholds

New research led by investigators at Massachusetts General Hospital provides insights on why people with red hair exhibit altered sensitivity to certain kinds of pain. The findings are published in Science Advances.

To investigate the mechanisms behind different pain thresholds in red-haired individuals, the team studied a strain of red-haired mice that contains a variant that lacks melanocortin 1 receptor function and also exhibits higher pain thresholds. The team found that loss of melanocortin 1 receptor function in the red-haired mice caused the animals' melanocytes to secrete lower levels of a molecule called POMC (proopiomelanocortin) 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 that enhance perception of pain.

In red-haired mice, 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.

"These findings describe the mechanistic basis behind earlier evidence suggesting varied pain thresholds in different pigmentation backgrounds," says lead researcher David 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."

Fisher adds that the results suggest new ways to manipulate the body's natural processes that control pain perception—for example, by designing new medications that inhibit melanocortin 4 receptors involved in sensing pain. "Our ongoing work is focused on elucidating how additional skin-derived signals regulate pain and opioid signaling," adds co-lead author Lajos V. Kemény. "Understanding these pathways in depth may lead to the identification of novel pain-modulating strategies."