Why do people with red hair show impaired sensitivity to certain types of pain?

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

In people with red hair (as in numerous other species of animals with red fur), the pigment-producing cells of the skin – called melanocytes – contain a variant form of the melanocortin 1 receptor.

This receptor sits on the cell surface, and if it becomes activated by circulating hormones called melanocortins, it causes the melanocyte to switch from generating yellow/red melanin pigment to producing brown/black melanin pigment. Earlier work by David E. Fisher, MD, Ph.D., director of the Mass General Cancer Center’s Melanoma Program and director of MGH’s Cutaneous Biology Research Center, demonstrated that the inability of red-haired individuals to tan or darken their skin pigment is traced to inactive variants of this receptor.

To investigate the mechanisms behind different pain thresholds in red-haired individuals, Fisher and his colleagues studied a strain of red-haired mice that (as in humans) 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 (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.

“These findings describe the mechanistic basis behind earlier evidence suggesting varied pain thresholds in different pigmentation backgrounds,” says 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, MD, Ph.D., a research fellow in Dermatology at MGH. “Understanding these pathways in depth may lead to the identification of novel pain-modulating strategies.”


Proopiomelanocortin deficiency

Proopiomelanocortin (POMC) deficiency causes severe obesity that begins at an early age. In addition to obesity, people with this condition have low levels of a hormone known as adrenocorticotropic hormone (ACTH) and tend to have red hair and pale skin.

Affected infants are usually a normal weight at birth, but they are constantly hungry, which leads to excessive feeding (hyperphagia). The babies continuously gain weight and are severely obese by age 1. Affected individuals experience excessive hunger and remain obese for life. It is unclear if these individuals are prone to weight-related conditions like cardiovascular disease or type 2 diabetes.

Low levels of ACTH lead to a condition called adrenal insufficiency, which occurs when the pair of small glands on top of the kidneys (the adrenal glands) do not produce enough hormones. Adrenal insufficiency often results in periods of severely low blood sugar (hypoglycemia) in people with POMC deficiency, which can cause seizures, elevated levels of a toxic substance called bilirubin in the blood (hyperbilirubinemia), and a reduced ability to produce and release a digestive fluid called bile (cholestasis). Without early treatment, adrenal insufficiency can be fatal.

Pale skin that easily burns when exposed to the sun and red hair are common in POMC deficiency, although not everyone with the condition has these characteristics.

Causes

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POMC deficiency is caused by mutations in the POMC gene, which provides instructions for making the proopiomelanocortin protein. This protein is cut (cleaved) into smaller pieces called peptides that have different functions in the body. One of these peptides, ACTH, stimulates the release of another hormone called cortisol from the adrenal glands. Cortisol is involved in the maintenance of blood sugar levels. Another peptide, alpha-melanocyte stimulating hormone (α-MSH), plays a role in the production of the pigment that gives skin and hair their color. The α-MSH peptide and another peptide called beta-melanocyte stimulating hormone (β-MSH) act in the brain to help maintain the balance between energy from food taken into the body and energy spent by the body. The correct balance is important to control eating and weight.

POMC gene mutations that cause POMC deficiency result in production of an abnormally short version of the POMC protein or no protein at all. As a result, there is a shortage of the peptides made from POMC, including ACTH, α-MSH, and β-MSH. Without ACTH, there is a reduction in cortisol production, leading to adrenal insufficiency. Decreased α-MSH in the skin reduces pigment production, resulting in the red hair and pale skin often seen in people with POMC deficiency. Loss of α-MSH and β-MSH in the brain dysregulates the body’s energy balance, leading to overeating and severe obesity.

POMC deficiency is a rare cause of obesity; POMC gene mutations are not frequently associated with more common, complex forms of obesity. Researchers are studying other factors that are likely involved in these forms.

Both parents carry one copy of a mutated gene. In the next generation, one child is affected with the condition, two children are carriers, and one is unaffected and not a carrier.
Credit: U.S. National Library of Medicine

References

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  • Krude H, Biebermann H, Gruters A. Mutations in the human proopiomelanocortin gene. Ann N Y Acad Sci. 2003 Jun;994:233-9. Review. Citation on PubMed
  • Krude H, Biebermann H, Luck W, Horn R, Brabant G, Grüters A. Severe early-onset obesity, adrenal insufficiency and red hair pigmentation caused by POMC mutations in humans. Nat Genet. 1998 Jun;19(2):155-7. Citation on PubMed
  • Krude H, Biebermann H, Schnabel D, Tansek MZ, Theunissen P, Mullis PE, Grüters A. Obesity due to proopiomelanocortin deficiency: three new cases and treatment trials with thyroid hormone and ACTH4-10. J Clin Endocrinol Metab. 2003 Oct;88(10):4633-40. Citation on PubMed
  • Krude H, Grüters A. Implications of proopiomelanocortin (POMC) mutations in humans: the POMC deficiency syndrome. Trends Endocrinol Metab. 2000 Jan-Feb;11(1):15-22. Review. Citation on PubMed
  • Lee YS. The role of leptin-melanocortin system and human weight regulation: lessons from experiments of nature. Ann Acad Med Singap. 2009 Jan;38(1):34-11. Review. Citation on PubMed

More information: Kathleen C. Robinson et al, Reduced MC4R signaling alters nociceptive thresholds associated with red hair, Science Advances (2021). DOI: 10.1126/sciadv.abd1310

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