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April 20, 2021
Study finds link between red hair and pain threshold
At a Glance
- A study in mice revealed the mechanisms that may link red hair with greater pain tolerance.
- Understanding these pathways could lead to new pain treatments.
Research has shown that people with red hair perceive pain differently than others. They may be more sensitive to certain types of pain and can require higher doses of some pain-killing medications. However, studies suggest that their general pain tolerance may be higher. People with red hair also respond more effectively to opioid pain medications, requiring lower doses.
People with red hair have a variant of the melanocortin-1 receptor (MC1R) gene. This gene controls the production of melanin, the pigment that gives skin, hair, and eyes their color. The cells that make melanin produce two forms—eumelanin and pheomelanin. People with red hair produce mostly pheomelanin, which is also linked to freckles and fair skin that tans poorly.
While red hair has been linked to differences in pain processing, the underlying reasons weren’t well understood. Researchers led by Dr. David E. Fisher of Massachusetts General Hospital examined the connection between MC1R and pain perception. The study was funded in part by NIH’s National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS). Results were published on April 2, 2021, in Science Advances.
The researchers conducted their experiments using a strain of red-haired mice that carry the MC1R variant also found in people with red hair. The mutation suppresses function of the melanocortin 1 receptor. These mice show higher tolerance to pain.
By crossing the red-haired mice with an albino strain to prevent melanin synthesis, the scientists were able to study the role of pigment. They found that mice carrying the MC1R red-hair variant had a higher pain threshold even without pigment synthesis. However, the number of melanocytes—melanin-producing cells—did affect pain thresholds. This showed that increased pain tolerance was caused by loss of MC1R function in melanocytes rather than other cell types.
The team then looked at how these melanocytes affected the pain threshold. They found that the melanocytes in red-haired mice secreted lower levels of a protein called proopiomelanocortin (POMC). POMC is cut into different hormones, including one that enhances pain perception (melanocyte stimulating hormone) and another that blocks pain (beta-endorphin). These hormones affect the balance between opioid receptors that inhibit pain (OPRM1) and melanocortin 4 receptors (MC4R) that increase pain sensitivity.
The presence of hormones that affect both these receptors would seem to maintain a balance. But the team found that the MCR1 red-hair variant altered the balance in favor of opioid receptors. The reason for this imbalance is that separate opioid receptor hormones are plentiful and were essentially unchanged, whereas separate MC4R hormones are not known to exist, thus tipping the balance in favor of anti-pain opioid signals. The end result was more opioid signals and a higher pain threshold.
“These findings describe the mechanistic basis behind earlier evidence suggesting varied pain thresholds in different pigmentation backgrounds,” Fisher says. “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.”
Uncovering the mechanisms that affect pain perception in people with red hair may also help others by informing new treatment strategies for pain.
—by Erin Bryant
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References: Reduced MC4R signaling alters nociceptive thresholds associated with red hair. Robinson KC, Kemény LV, Fell GL, Hermann AL, Allouche J, Ding W, Yekkirala A, Hsiao JJ, Su MY, Theodosakis N, Kozak G, Takeuchi Y, Shen S, Berenyi A, Mao J, Woolf CJ, Fisher DE. Sci Adv. 2021 Apr 2;7(14):eabd1310. doi: 10.1126/sciadv.abd1310. Print 2021 Apr. PMID: 33811065.
Funding: NIH’s National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS); Melanoma Research Alliance; US-Israel Binational Science Foundation; Dr. Miriam and Sheldon G. Adelson Medical Research Foundation; Rosztoczy Scholarship; Tempus Közalapítvány; Hungarian Academy of Sciences; Hungary’s National Research, Development and Innovation Office and Ministry of Human Capacities; EU Horizon 2020 Research and Innovation Program; KAKENHI.