The international study, led by scientists in Israel, was published online August 5 in Genome Research.
Past research had used mouse models of phantom limb pain and anesthesia dolorosa, in which a denervated hind paw is scratched and bitten by the mouse — a behavioral response known as "autotomy" and construed as a response to "unpleasant phantom limb sensations." Response variations between mouse strains, and even among individual mice, were mapped to a region on chromosome 15. The new study used fine-mapping techniques to narrow the field of 155 candidate genes in this region, eventually pinpointing Cacng2.
"We applied a diversity of tools to prioritize the most likely candidate associated to a pain phenotype, which is a difficult phenotype to study (compared with straightforward endpoints)," said senior author Ariel Darvasi, PhD, head of the Life Sciences Program, Institute of Life Sciences, Hebrew University of Jerusalem, Israel, in his email to Medscape Medical News.
Analysis of gene expression in nerve-injured vs sham-operated mice found 21 genes of the 155 whose expression was significantly affected (P ~ .05 when corrected for multiple comparisons). Comparing animals with high vs low autotomy behavior identified 10 genes with significantly altered expression. Only Cacng2 was on both lists, downregulated 3.78-fold in animals with nerve injury (P = 3 × 10−31) and 2.00-fold in high-autotomy vs low-autotomy mice (P = 3 × 10−4).
"The prioritization process highlighted Cacng2 as the most likely candidate. Even then, we needed to apply yet another set of tools including functional assessment of mutant mice along with human studies to confidently establish the link between CACNG2 and pain," Dr. Darvasi explained.
Human studies enrolled 549 Israeli Jewish women with unilateral complete or partial surgical removal of a breast for cancer an average of 6.6 years after their surgery. Treatments included mastectomy (54.3%), lumpectomy (45.7%), chemotherapy (51.4%), radiotherapy (38.8%), and/or hormonal therapy (32.1%). All patients had dissection of axillary lymph nodes. Chronic pain was reported by 215 women, but not by the remaining 334. DNA for genomic analysis was obtained from 30-mL blood samples.
Interestingly, less pain was reported by patients at shorter times after their surgery in women who did not receive chemotherapy, who had complete mastectomy, or who were of Ashkenazi Jewish ancestry.
Of the 12 single nucleotide polymorphisms (SNPs) of CACNG2 analyzed, 5 demonstrated significant association with neuropathic pain (P values, .02, .02, .03, .04, and .05). Three of the CACNG2 SNPs constituted a "core" that could account for increased pain susceptibility (odds ratio [OR], 1.65; P = .001). Even when analysis was limited to the 319 Ashkenazi women, significance was maintained (OR, 1.51; P = .031).
The report enumerates several positive results of identifying CACNG2 as a pain susceptibility gene. First, it supports the role of genetic factors in chronic pain susceptibility after nerve injury, which may reduce the stigma attached to unwarranted suspicions of malingering or fraud. Second, the human results validate the existing mouse models for neuropathic pain studies. Third, increased knowledge of CACNG2's influence on neuropathic pain may enhance scientific understanding of pain physiology.
Environmental factors also influence chronic pain. For instance, mice housed in group caging exhibit higher levels of autotomy. "Increased levels of stress are the most likely explanation, although not proven yet," said Dr. Darvasi. "Stress is a well-known risk factor for chronic migraine, for example. Also...housing nerve-injured male rats with females reduced autotomy in the rats (reduce stress, reduce pain)."
"The social effects on autotomy are very interesting, but no one has ever figured them out," added Jeffrey S. Mogil, PhD, professor of pain studies, Department of Psychology, McGill University, Montreal, Quebec, Canada, in his email comments to Medscape Medical News.
However, Dr. Mogil urged caution: "CACNG2 is not the first gene to be associated with pain, and it won't be the last. Unfortunately, it's starting to appear like there might be scores, even hundreds of relevant genes, and to predict anything you'd have to know many/most of them. We're decades away from that," said Dr. Mogil. "However, every time someone identifies a new one, it either gives the drug companies a new target for drug development or helps prioritize this target over others."
Dr. Darvasi agreed that "further research is needed before this can be brought to the clinic...significant progress is still required before one will be able to predict predisposition to chronic pain following surgery." However, such considerations will be important in considering elective surgeries, or even the type of surgery. "Since neuropathic pain is induced by nerve injury, surgeons might take special care to spare nerves if the patient is known to be prone to developing nerve pain."
For the present, Dr. Darvasi suggests: "On the treatment front, our results may trigger further research, which has the potential of developing new therapies for this currently poorly treated condition."
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