We May Now Know Why Redheads Exhibit Altered Pain Sensitivity

People with the MC1R mutation might have a higher pain tolerance due to increased opioid signaling involved with blocking pain. Image Credit: WAYHOME studio/Shutterstock.com

A new study published in the journal Science Advances explains why individuals with red hair (the rarest of the natural hair colors in humans) might exhibit altered pain tolerance.

The work, led by researchers from Massachusetts General Hospital (MGH) has validated a known phenomenon that links the pigmentation of one's hair to altered sensitivity to certain types of pain. 

"These findings describe the mechanistic basis behind earlier evidence suggesting varied pain thresholds in different pigmentation backgrounds," says David Fisher, MD, PhD, director of the Mass General Cancer Center's Melanoma Program in a statement. "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."

People with red hair have a distinct mutation in the melanocortin-1 receptor (MC1R), a receptor found on melanocytes (pigment-producing cells of the skin). The receptor normally responds as a signal transducer, where circulating hormones called melanocortins bind to it and then instruct the cell what to do downstream. By default, melanocytes produce yellow/reddish pigments, however, in response to circulating hormones that bind to MC1R, it can flip and instruct the melanocyte to start producing brown/black pigments instead.

Having a mutation in the MC1R could therefore cause the receptor not to function correctly, therefore losing the ability to signal melanocytes to produce the brown/black pigments – and hence by default, those with the mutation end up with red-colored hair. 

To study the mechanisms that lead to red hair individuals experiencing altered pain sensitivity, Fisher and colleagues investigated a specific strain of red-haired mice that has a higher pain tolerance due to a mutation in MC1R that causes the receptor not to function.

The researchers found that the mice that lacked MC1R activity, similar to humans with red hair, secreted lower levels of a molecule called proopiomelanocortin (POMC). This molecule is subsequently modified and sliced to form four different hormones. Out of the four, two are really important – one has a role in sensitizing to pain, and another involved in blocking it. Furthermore, the presence of these hormones regulates the balance of two other important receptors involved in pain signaling – the opioid receptors, which block pain, and the melanocortin 4 receptors that enhance pain perception.  

As the mice with MC1R mutation have lower levels of POMC, they end up with lower levels of these two hormones involved in sensitizing and blocking pain. Thus, they basically end up canceling each other out, so this alone can't describe the increased pain threshold in these mice. The lower levels of these hormones alter opioid signaling, and because the body also produces other non-melanocyte-related factors that can activate the opioid receptors, this overall results in more opioid signaling and an increased pain threshold in these mice.

It is worth considering that the current study only involved mice, so more research will need to be done to show if the same holds true in humans, but nevertheless, it could open up new pain-modulating strategies in the future.

"Our ongoing work is focused on elucidating how additional skin-derived signals regulate pain and opioid signaling," adds co-lead author Lajos V. Kemény, MD, PhD, a research fellow in Dermatology at MGH. "Understanding these pathways in depth may lead to the identification of novel pain-modulating strategies."

 


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