Redheads comprise around 1% of the world’s population, having the least common hair color found in humans. Redheads can most easily be spotted in Scotland, England and Ireland. In Scotland, were the highest proportion is found, only 13% of the population has red hair.

Red hair, as well as fair skin and freckles, is associated with genetic variations of the melanocortin-1 receptor (MC1R). Melanocortin receptors (there are 5) bind melanocortin peptides, a group of peptide hormones that are produced in the pituitary gland and that are all derived from the same precursor, proopiomelanocortin (POMC). POMC can be differentially cleaved to originate various peptides that include, for example, the adrenocorticotropic hormone (ACTH), melanocyte stimulating hormones (alpha-MSH, beta-MSH and gamma-MSH) and the endogenous opioid beta-endorphin.

MC1R, to which red hair is associated, is found primarily in melanocytes of the skin where, due to the action of alpha-MSH, it can regulate pigmentation of the skin and hair by stimulation of eumelanin synthesis. Hair color is determined by the quantity and proportion of eumelanin and pheomelanin. The latter colors the hair reddish and yellow, whereas eumelanin can be either black or brown. Varying concentrations of each originate different hair colors.

Red hair has high amounts of pheomelanin and, importantly, very low quantities of eumelanin. It is estimated that around 65-80% of natural redheads have variations in the MC1R gene that induce a loss of function of this receptor, thereby reducing the effect of alpha-MSH in the stimulation of eumelanin production, resulting in low eumelanin levels and, consequently, red hair.

So, what does this have to do with pain?

Studies in mice have demonstrated that MC1R is also expressed in the periaquedutal gray matter of the midbrain, an area that plays an important role in pain processing. It was also found that MC1R is associated with kappa-opioid analgesia, with this association being female-specific. This finding led to a study that aimed at evaluating the sex-specific involvement of MC1R in kappa-opioid analgesia in humans.

It was found that women with non-functional MC1Rs showed a higher effect of kappa-opioid analgesia, with all those women being redheads. Given the higher clinical relevance of mu-opiods, a new study was designed in order to assess a possible association between MC1R and mu-opiod analgesia. It was found that, in this case, there was no sex-specificity, but that the MC1R functional status did indeed affect mu-opiod analgesia, thereby establishing again a link between red hair and opioid analgesia.

A different sensitivity of redheads was also found for anesthesia, with studies showing that red-haired women require almost 20% more anesthetic in order to be fully anesthetized. This finding was, however, counterintuitive: given the higher opioid sensitivity of redheads, it would be expected that they should be more easily anesthetized. Posterior studies have actually shown that this effect is not that obvious and may depend on the anesthetic used.

Although a genetic association between red hair and analgesia is evident, it is still unclear whether redheads have a higher sensitivity to pain. There are studies showing that they may be more sensitive to thermal nociceptive stimuli, but others have also shown that this association is not that clear.

Regardless of the hair color, studies in mice showing a role for MC1R in acute noxious thermal responses and pain of inflammatory origin have made MC1R emerge has a potential new target in pain management.

References

Delaney A, Keighren M, Fleetwood-Walker SM, & Jackson IJ (2010). Involvement of the melanocortin-1 receptor in acute pain and pain of inflammatory but not neuropathic origin. PloS one, 5 (9) PMID: 20856883

Liem EB, Joiner TV, Tsueda K, & Sessler DI (2005). Increased sensitivity to thermal pain and reduced subcutaneous lidocaine efficacy in redheads. Anesthesiology, 102 (3), 509-14 PMID: 15731586

Mogil JS, Ritchie J, Smith SB, Strasburg K, Kaplan L, Wallace MR, Romberg RR, Bijl H, Sarton EY, Fillingim RB, & Dahan A (2005). Melanocortin-1 receptor gene variants affect pain and mu-opioid analgesia in mice and humans. Journal of medical genetics, 42 (7), 583-7 PMID: 15994880

Mogil JS, Wilson SG, Chesler EJ, Rankin AL, Nemmani KV, Lariviere WR, Groce MK, Wallace MR, Kaplan L, Staud R, Ness TJ, Glover TL, Stankova M, Mayorov A, Hruby VJ, Grisel JE, & Fillingim RB (2003). The melanocortin-1 receptor gene mediates female-specific mechanisms of analgesia in mice and humans. Proceedings of the National Academy of Sciences of the United States of America, 100 (8), 4867-72 PMID: 12663858

Myles PS, Buchanan FF, & Bain CR (2012). The effect of hair colour on anaesthetic requirements and recovery time after surgery. Anaesthesia and intensive care, 40 (4), 683-9 PMID: 22813497

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