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Genetic insights toward improved management of chronic pain after mastectomy.

Chronic breast pain is a surgical complication in up to 50% of patients with cancer undergoing breast removal (mastectomy). This type of pain usually arises as a consequence of direct nerve (typically the intercostobrachial nerve) or soft tissue injury and is often accompanied by breast phantoms and other paraesthesias. Mechanistic insight on the pathophysiology of the condition is sketchy and existing treatments are largely inadequate. The burden of persistent pain is particularly debilitating for these patients, who also suffer the psychosocial and medical stress of cancer treatment. Importantly, disease prognosis is extremely problematic because the genetic and environmental factors that predispose to breast pain remain unknown. Both pain sensitivity and propensity for developing chronic pain are complex polygenic traits, with 30% to 60% of the variation in persistent pain phenotypes attributed to heritable factors. Modern neuroscience uses a plethora of DNA screening methodologies to dissect genes with predominant roles in maladaptive pain processing. Many studies focus on ion channels because these proteins fundamentally determine firing properties and excitability of pain-sensing neurons. Accumulating research has now established that certain potassium (K) channel subunits are vitally involved in pain signalling in both health and disease. In this issue of PAIN, Langford et al. use a candidate gene approach to link persistent pain after mastectomy with various SNPs in 5 K channel genes, namely KCNA1 (Kv1.1), KCND2 (Kv4.2), GIRK1, GIRK2, and TASK3. Although genetic screening cannot interpret the SNP effect on protein activity per se, experience with other K channels suggests that pharmacologically enhancing conduction of these channels may lead to decreased excitability and antinociception. Interestingly, some of the identified SNPs are located in noncoding regions, such as RNA-binding domains or methylation substrates. Unless in linkage disequilibrium with undetermined functional SNPs, this observation supports the emerging role of epigenetic modifications in pain. Earlier work by the group also uncovered SNPs in GIRK1, GIRK2, and TASK3 connected to the occurrence of breast pain before surgery. This reinforces the proposed involvement of these subunits in pain signalling and also provides a genetic correlate to the observation that preoperative breast pain is often a predictor of chronic pain after surgery. It is not clear whether this early pain was acute or chronic, but the symptoms reported by patients hint toward a nociceptive rather than neuropathic nature. The potential involvement of these 3 subunits in normal pain is a suboptimal quality from a pharmacotherapy perspective because drug modulation may compromise the usefulness of normal pain perception. How exactly might these subunits be involved in pain processing? Kv1.1 was recently characterized as a mechanoreceptor, and its function alone or in partnership with Kv1.2 may regulate excitability at nerve endings or juxtaparanodes of sensory neurons, but also in the central nervous system (CNS) through regulation of morphine antinociception. Kv4.2 most likely confers its effect spinally through ERK-dependent sensitization because peripheral expression seems to be very limited. GIRK channels are involved in postsynaptic inhibition and interact with the opioid pathway. Indeed, Ippolito et al. proposed GIRK1-mediated protective effects in the spinal cord, whereas GIRK2 polymorphisms are linked to chronic back pain. However, recent studies suggest that sensory neuron-expressed GIRK2 also contribute to opioid-mediated analgesia in the periphery. Deciphering the precise locus of function will be instrumental for drug design and treatment regime (eg, peripherally restricted vs blood-brain barrier-crossing compounds, systemic vs local administration, etc). In particular, the ubiquitous K channel expression raises the possibility of unwanted effects in the heart or CNS, necessitating additional mechanistic insight on the role of these proteins in vivo. Chronic breast pain is thought to also have an inflammatory component arising from tissue damage during surgery, although malignancy-related influences cannot be excluded. Supporting this, a separate study in the same cohort concluded that persistent breast pain is associated with genetic variation in inflammatory cytokines/receptors such as IL-1R and IL-10. Together, these data raise the possibility of unidentified interactions between these inflammatory components and K (or other ion) channels to establish a hyperexcitable phenotype, circumstantial evidence of which is already found in the literature. Since analysis was limited to a small selection of genes, it would be informative to interrogate the involvement of additional K channels, such as Kv7 channels that are known to be directly modulated by inflammatory agents. One caveat of population studies is that real effects can be missed because of inadequate power for the detection of multiple associations. For instance, although there was an association of KCNS1 SNPs in the initial analysis, statistical Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.