Redheads May Experience Pain Differently Interview with:
David E. Fisher MD, PhD
Edward Wigglesworth Professor & Chairman
Dept of Dermatology
Director, Melanoma Program MGH Cancer Center
Director, Cutaneous Biology Research Center
Massachusetts General Hospital
Harvard Medical School

Dr. Fisher  What is the background for this study?

Response: This study followed up on prior published work from other investigators which demonstrated altered pain thresholds in humans and mice who had the redhair light-skin phenotypes.  The key focus of our current study was to firstly validate the overall findings, and then to  the mechanistic basis for the differences.  Of note, our laboratory does not primarily focus on the science of pain or nociceptive, but rather on skin and melanoma. For this reason we had accumulated a number of valuable genetic models of pigmentation (such as redhaired mice harboring alterations in the identical gene implicated in human red hair).  These mouse models served as the key resources for carrying out the current study.  What are the main findings? Does this finding make redheads more or less susceptible to pain?  Harder or easier to control pain?

Response: The study first examined the redhair genetic background after crossing it into albino (white) backgrounds (albinism is caused by a mutation affecting pigment synthesis that is downstream of the redhair gene). In this “blinded” study we confirmed the different nociceptive thresholds in redhaired mice.  For the nociceptive thresholds measured here (thermal and pressure) the redhaired background was associated with higher thresholds, meaning a stronger stimulus was required to elicit the behavioral response. That said, this study did not measure the analgesic responses to pain, and a variety of other descriptions have suggested that redhaired individuals require more analgesics to produce pain control.

The other main findings of this study involved the underlying mechanism responsible for the elevated nociceptive thresholds. This was seen to be caused by a change in the balance of mu opioid receptor ligands relative to melanocortin 4 receptor ligands. POMC is a pro-hormone precursor that encodes both beta-endorphin (a mu-opioid receptor ligand) and MSH (a MC4R ligand).  POMC and its derivative peptides are expressed at ~50% lower levels in the blood of redhaired mice. Whereas MSH is a pivotal ligand for MC4R, there are multiple additional ligands for mu opioid receptor which are not derived from POMC and do not change in the redhaired background. Therefore net mu opioid receptor ligands are less perturbed than MC4R ligands, and the analgesic effects of opioid signaling prevail, elevating the nociceptive thresholds. This mechanistic explanation was confirmed using a combination of genetic (knockout) and pharmacologic (agonist and antagonist) tools. What should readers take away from your report?

Response: Perhaps the most overarching takeaway is the authenticity of this nociceptive threshold difference in the red hair background.  The fact that this has been mechanistically dissected validates the behavioral effects of the pigment variation, and helps to justify individuals management of pain thresholds in such individuals. What recommendations do you have for future research as a result of this work?

Response: One implication of this research is that a tractable pathway modulating nociceptive thresholds is now apparent and can be studied in additional genetic contexts.  For example, individuals with light skin and dark hair might be valuable to study, since the production of POMC and its associated peptide hormones (endorphin and MSH) may contribute more broadly to pain thresholds in non-redhaired individuals. Another area of interest for future research is the finding of MC4R signaling as antagonistic to mu opioid receptor signaling, here shown in the endogenous genetic context.  This finding suggests that antagonists to MC4R may function similarly to agonists of mu opioid receptor—and thus might represent a novel and valuable class of new small molecules worthy of exploration for non-opioid analgesia.

Any disclosures? D.E.F. has a financial interest in Soltego, a company developing salt inducible kinase inhibitors for topical skin-darkening treatments that might be used for a broad set of human applications. The interests of D.E.F. were reviewed and are managed by Massachusetts General Hospital and Partners HealthCare in accordance with their conflict of interest policies.


Kathleen C. Robinson, Lajos V. Kemény, Gillian L. Fell, Andrea L. Hermann, Jennifer Allouche, Weihua Ding, Ajay Yekkirala, Jennifer J. Hsiao, Mack Y. Su, Nicholas Theodosakis, Gabor Kozak, Yuichi Takeuchi, Shiqian Shen, Antal Berenyi, Jianren Mao, Clifford J. Woolf, David E. Fisher. Reduced MC4R signaling alters nociceptive thresholds associated with red hair. Science Advances, 2021; 7 (14): eabd1310 DOI: 10.1126/sciadv.abd1310

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