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Highlights • After oxaliplatin treatment rats developed mechanical and cold hyperalgesia. • We observed intraepidermal nerve fiber degeneration, and mild spinal cord gliosis. • Co treatment with Metformin could prevent all these pathological outcomes. • This suggests metformin as a candidate drug to prevent oxaliplatin-induced neuropathy., Oxaliplatin is a commonly used drug to treat cancer, extending the rate of disease-free survival by 20% in colorectal cancer. However, oxaliplatin induces a disabling form of neuropathy resulting in more than 60% of patients having to reduce or discontinue oxaliplatin, negatively impacting their chance of survival. Oxaliplatin-induced neuropathies are accompanied by degeneration of sensory fibers in the epidermis and hyperexcitability of sensory neurons. These morphological and functional changes have been associated with sensory symptoms such as dysesthesia, paresthesia and mechanical and cold allodynia. Various strategies have been proposed to prevent or treat oxaliplatin-induced neuropathies without success. The anti-diabetic drug metformin has been recently shown to exert neuroprotection in other chemotherapy-induced neuropathies, so here we aimed to test if metformin can prevent the development of oxaliplatin-induced neuropathy in a rat model of this condition. Animals treated with oxaliplatin developed significant intraepidermal fiber degeneration, a mild gliosis in the spinal cord, and mechanical and cold hyperalgesia. The concomitant use of metformin prevented degeneration of intraepidermal fibers, gliosis, and the altered sensitivity. Our evidence further supports metformin as a new approach to prevent oxaliplatin-induced neuropathy with a potential important clinical impact.

Neuropathic pain (NeuP) arises due to injury of the somatosensory nervous system and is both common and disabling, rendering an urgent need for non-addictive, effective new therapies. Given the high evolutionary conservation of pain, investigative approaches from Drosophila mutagenesis to human Mendelian genetics have aided our understanding of the maladaptive plasticity underlying NeuP. Successes include the identification of ion channel variants causing hyper-excitability and the importance of neuro-immune signaling. Recent developments encompass improved sensory phenotyping in animal models and patients, brain imaging, and electrophysiology-based pain biomarkers, the collection of large well-phenotyped population cohorts, neurons derived from patient stem cells, and high-precision CRISPR generated genetic editing. We will discuss how to harness these resources to understand the pathophysiological drivers of NeuP, define its relationship with comorbidities such as anxiety, depression, and sleep disorders, and explore how to apply these findings to the prediction, diagnosis, and treatment of NeuP in the clinic., Calvo et al. discuss how applying genetic techniques, from model organisms to human populations, can help us understand the pathophysiology of neuropathic pain. These strategies could soon reveal novel analgesic drug targets and aid both personalized risk prediction and treatment.

HIV-associated sensory neuropathy (HIV-SN) is the most frequent manifestation of HIV disease. It often presents with significant neuropathic pain and is associated with previous exposure to neurotoxic nucleoside reverse transcriptase inhibitors. However, HIV-SN prevalence remains high even in resource-rich settings where these drugs are no longer used. Previous evidence suggests that exposure to indinavir, a protease inhibitor commonly used in antiretroviral therapy, may link to elevated HIV-SN risk. Here, we investigated whether indinavir treatment was associated with the development of a "dying back" axonal neuropathy and changes in pain-relevant limb withdrawal and thigmotactic behaviours. After 2 intravenous injections of indinavir (50 mg/kg, 4 days apart), adult rats developed hind paw mechanical hypersensitivity, which peaked around 2 weeks post first injection (44% reduction from baseline). At this time, animals also had (1) significantly changed thigmotactic behaviour (62% reduction in central zone entries) comparing with the controls and (2) a significant reduction (45%) in hind paw intraepidermal nerve fibre density. Treatment with gabapentin, but not amitriptyline, was associated with a complete attenuation of hind paw mechanical hypersensitivity observed with indinavir treatment. Furthermore, we found a small but significant increase in microglia with the effector morphology in the lumbar spinal dorsal horn in indinavir-treated animals, coupled with significantly increased expression of phospho-p38 in microglia. In summary, we have reported neuropathic pain-related sensory and behavioural changes accompanied by a significant loss of hind paw skin sensory innervation in a rat model of indinavir-induced peripheral neuropathy that is suitable for further pathophysiological investigation and preclinical evaluation of novel analgesics.

Neuropathic pain following peripheral nerve injury is associated with hyperexcitability in damaged myelinated sensory axons, which begins to normalise over time. We investigated the composition and distribution of shaker-type-potassium channels (Kv1 channels) within the nodal complex of myelinated axons following injury. At the neuroma that forms after damage, expression of Kv1.1 and 1.2 (normally localised to the juxtaparanode) was markedly decreased. In contrast Kv1.4 and 1.6, which were hardly detectable in the naïve state, showed increased expression within juxtaparanodes and paranodes following injury, both in rats and humans. Within the dorsal root (a site remote from injury) we noted a redistribution of Kv1-channels towards the paranode. Blockade of Kv1 channels with α-DTX after injury reinstated hyperexcitability of A-fibre axons and enhanced mechanosensitivity. Changes in the molecular composition and distribution of axonal Kv1 channels, therefore represents a protective mechanism to suppress the hyperexcitability of myelinated sensory axons that follows nerve injury. DOI: http://dx.doi.org/10.7554/eLife.12661.001, eLife digest Around 20% of the world’s population experiences long-lasting “chronic” pain, which often results in poor sleep, depression and anxiety. One of the most disabling forms of chronic pain is called neuropathic pain, which results from injuries to sensory nerves. Pain or discomfort is felt in response to touches that are not normally painful. Neuropathic pain is difficult to treat as we do not fully understand the molecular mechanisms that cause it. Stimulating a nerve causes it to produce action potentials. At a molecular level, these action potentials are generated by ions moving into and out of the neuron through proteins called ion channels. The movement of sodium ions into a neuron triggers an action potential, and the movement of potassium ions out of the neuron returns it to a resting state. After a sensory nerve is cut or otherwise damaged it becomes hyperactive and produces spontaneous electrical activity that the brain interprets as pain signals. However, it is not fully understood how cutting a nerve affects the ion channels in a way that generates this hyperactivity. Different types of ion channel are found in different regions of the nerve cell; for example, type 1 potassium channels are normally found in a region called the juxtaparanode at the axon of the neuron. Calvo et al. have now tracked what happens to type 1 potassium channels after nerve injury in rats. Soon after nerve damage occurred, nearly all of these ion channels disappeared from the juxtaparanode. At the same time, electrical activity in the cut nerve increased, and the recovering animals responded in ways that suggested they were hypersensitive to the nerve being touched. Three weeks after the injury, most rats lost their hypersensitivity and the electrical activity in the cut nerve returned to near-normal levels. Calvo et al. found that the recovering nerves contained new subtypes of type 1 potassium channels. These potassium channels did not just appear in the juxtaparanode: they also invaded the ‘fence’ region that normally separates potassium channels from sodium channels. The same was observed to happen in the nerves of patients that suffer from neuropathic pain due to a nerve injury. At this late time point after nerve injury, blocking the activity of potassium channels produced the same abnormal increase in the nerve’s electrical activity as seen immediately after the nerve had been cut. The rats’ hypersensitivity to touch also returned. This suggests that the appearance of the new potassium channel subtypes might be a protective mechanism that reduces the activity of a damaged nerve to decrease pain. These findings suggest new ways of treating neuropathic pain. Further studies are now needed to investigate whether drugs that can activate the new potassium channel subtypes could stop pain from an injured nerve becoming a long-term problem. DOI: http://dx.doi.org/10.7554/eLife.12661.002