Editors' ChoicePain

You May Feel Some Discomfort—or Not!

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Science Translational Medicine  16 May 2012:
Vol. 4, Issue 134, pp. 134ec86
DOI: 10.1126/scitranslmed.3004287

During regular checkups, our pediatrician usually takes a quick look at the shins of my son, who just turned five. They are covered in playground bruises reflecting colors of every state of hemoglobin breakdown, and she says “Good!” From the bruises, she knows that he behaves like his peers: running, climbing, and biking, with occasional trips and falls. My son hardly ever complains, reminding me how variably pain is perceived.

Mood, anticipation, and social upbringing are among the strong determinants of what kind of pain response an individual has to noxious stimuli—making an effective analgesic treatment too often a mystery to both patient and physician. Now, Sorge and his colleagues have identified genetic factors contributing to the variability in chronic pain responses. These results are the first step in finding new drug targets and also demonstrate how truly unfair it can be to expect someone in pain to just “get over it.”

The researchers used a nerve injury model in mouse strains with various genetic makeups and determined that touch elicited different degrees of abnormal hypersensitivity. Mapping this response pattern to the whole genome showed that a region within the P2rx7 gene had the strongest correlation with the abnormal response. Here, a unique coding mutation—P451L in the P2X7 receptor (P2X7R)—led the researchers to hypothesize that this mutation was protected from an atypically intense response to injury. Indeed, the authors confirmed that mouse strains carrying the Leu451 allele of P2X7R, in which an exchange in amino acids alters the makeup of the receptor protein, exhibit a decrease in their hypersensitive response. The researchers went on to demonstrate that the likely mechanism is a lack in P2X7R-mediated pore formation rather than a change in P2X7R’s alternate function as a cationic channel. Furthermore, and perhaps most important, in two groups of patients suffering either post-mastectomy or osteoarthritic pain, they found that carriers of a His270 allele of R270H, a loss-of-function mutation within human P2X7R, experienced less chronic pain than those without this allele.

With these findings, the researchers suggest that P2X7R pore formation plays an integral part of a patient’s pain response. How specific downstream effects contribute to this process, though, remains to be seen. Nevertheless, these data help to shed further light on the genetics of pain, moving us closer toward the goal of individualized pain management.

R. E. Sorge et al., Genetically determined P2X7 receptor pore formation regulates variability in chronic pain sensitivity. Nat. Med. 18, 595–599 (2012). [Abstract]

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