No gain – no pain?
- 1Faculty of Medicine, Translational Neuroscience Facility, School of Medical Science, University of New South Wales, New South Wales, Sydney, Australia
- 2Sydney Children's Hospital and School of Women's and Children's Health, University of New South Wales, Sydney, New South Wales, Australia
- Correspondence to Dr Cindy Shin-Yi Lin, Faculty of Medicine, Translational Neuroscience Facility, School of Medical Science, University of New South Wales, NSW 2052 Sydney, Australia;
- Received 17 September 2012
- Revised 17 September 2012
- Accepted 17 September 2012
- Published Online First 21 November 2012
Pain is one of the most pervasive symptoms in clinical medicine and always presents a challenge, both in terms of diagnosis and management. Abnormal voltage gated sodium channels (VGSCs) are emerging as key determinants in painful neuropathies. Genetic, metabolic or immunological factors have independently been demonstrated to alter ion channel properties, providing insight into complex pathophysiological mechanisms in pain. Specifically, modification of the Nav 1.7 isoform, encoded by the SCN9A gene, can profoundly impact pain sensitivity.1 Nav 1.7 is expressed in the peripheral nervous system in sensory and sympathetic neurons. Activating mutations in SCN9A produce severe pain due to gain-of-function in primary erythromelalgia (EM)2 and Paroxysmal Extreme Pain Disorder.3 In contrast, loss-of-function SCN9A mutations attenuate channel activity and lead to congenital insensitivity-to-pain (CIP).4 Importantly, SCN9A has been recognised as a highly polymorphic gene and consequently ascribing pathogenicity to variants remains a ‘burning issue’ in understanding the role of VGSC mutations and painful neuropathies.
Klein and colleagues5 examined SCN9A in 19 patients across a range of painful neuropathies, including six with CIP and 13 with EM, and identified two novel SCN9A mutations: Q10>K in EM and a de novo splicing mutation IVS8-2A>G in CIP. Moreover, 17 patients lacked SCN9A mutations and frequent polymorphism variants were confirmed. These findings suggest that the mutation frequency of SCN9A remains low and the pathogenic basis for the majority of CIP and EM patients remains to be elucidated.6 Furthermore, this raises the point that many variants of SCN9A may modify pain perception, suggesting a more complicated phenotype–genotype correlation.
Klein and colleagues highlight the importance of the role of specific sodium (Na+) channel subtypes as key drivers of pain signalling. Despite SCN9A mutations being rare, acquired disruption of these channels play important roles in more common acquired painful neuropathies. In diabetes, metabolites target VGSCs7 and modify the sensitivity to pain, which explains why some diabetics suffer from pain and some do not.8 In addition, altered VGSCs kinetics9 are an important pathophysiological factor in the development of chemotherapy-induced neurotoxicity,10 for example, oxaliplatin11 which causes painful neuropathy. Further, pain in immune-mediated inflammatory neuropathy may arise as a consequence of axonal injury and reorganisation of VGSCs. Emerging evidence of the pivotal role of VGSCs in pain sensitivity is expected to provide further novel insights into various pain pathways and thereby future therapeutics.
Current clinically available treatment approaches in neuropathic pain include non-selective Na+ channel blockers, for example, valproate, carbamazepine, mexilitine and lidocaine, which have variable and limited success as underlying mechanisms remain unclear. The challenge for the next decade will be to effectively ‘translate’ recent developments put forward by research together with knowledge of genetic modifiers12 ,13 into new therapies. These will enable the development of more selective Na+ channel blockers directed at different isoforms and Na+ channel modulators that target specific patterns of Na+ channel activity to improve treatments in a variety of neuropathic pain conditions; simply, ‘no gain – no pain’.
Competing interests None.
Provenance and peer review Commissioned; externally peer reviewed.