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Running from pain: mechanisms of exercise-mediated prevention of neuropathic pain.

Neuropathic pain can be a highly debilitating condition. It is characterized by pathological pain sensations, such as spontaneous shooting or burning pain, hyperalgesia, and allodynia, as well as numbness, altered sensation, or other sensory disturbances. This disorder can arise from a wide variety of nerve-damaging stimuli, including lumbar radiculopathy, trauma, diabetes, HIV infection, shingles, cancer, and surgery. Given the diverse etiology of neuropathic pain, it is perhaps not surprising that this disorder remains a relatively common global problem, with an estimated 7% to 10% of adults in the general population having chronic pain with neuropathic characteristics. Neuropathic pain is also difficult to treat effectively. Standard analgesics are relatively ineffective in neuropathic pain. In their place, current guidelines recommend treatment with antiepileptic drugs and antidepressants. Evidence from the United States and Europe suggests that these standard treatments are not widely used, and many cases of neuropathic pain remain undertreated or even untreated. However, a lack of adequate treatment cannot fully explain the prevalence of neuropathic pain: even within clinical trials of standard treatments, less than half of patients with neuropathic pain experience satisfactory pain relief and often describe problematic side effects. This same lack of efficacy can be observed in a community setting, where patients with neuropathic pain have moderate pain intensity despite receiving the recommended treatment for their condition. These data highlight a clear deficiency in our ability to adequately treat neuropathic pain, even within best-case scenarios. Part of our inability to treat neuropathic pain arises from the complexity of physiological changes that induce and sustain neuropathic pain and our limited capacity to address these changes. A complex series of events affecting multiple levels of somatosensation contributes to neuropathic pain. At the periphery, nerve injury can increase the excitability of sensory afferents and induce spontaneous activity in both Aand Cfibers, as well as induce the sprouting of collateral afferents in the periphery within the sensory territory innervated by the injured afferents. Nerve injury also induces changes at the central level, withmisprocessing of sensory input to the spinal cord dorsal horn being a key mechanism by which hyperalgesia and allodynia can arise. In particular, it is thought that the activation of nociceptive networks in the dorsal horn by low-threshold Ab afferents is responsible for tactile allodynia commonly seen in neuropathic pain conditions. The loss of a neuronal inhibition in both peripheral and central neurons is a key process by which abnormal sensory processing can arise in neuropathic pain. Because intracellular chloride levels regulate both primary afferent depolarization and neuronal inhibition in the spinal cord dorsal horn, a loss of chloride homeostasis can dramatically reduce the effectiveness of neuronal inhibition to “gate” activity in nociceptive networks. After nerve injury, the activation of microglia in the dorsal horn and changes in the expression of neurotrophic factors lead to increased activity of NKCC1 in dorsal root ganglion neurons and a reduction in KCC2 activity in the dorsal horn, which disrupts chloride levels and neuronal inhibition in sensory afferents and dorsal horn neurons, respectively. The essential role of chloride homeostasis in neuropathic pain is revealed by the pronounced analgesic efficacy of a novel class of drugs that reverses chloride imbalance by restoring KCC2 activity without causing motor impairments. A complex interplay of peripheral and central changes therefore contributes to abnormal sensory processing, hyperalgesia, and allodynia seen in neuropathic pain. Yet, despite our increasing understanding of how neuropathic pain can develop, we only have a very superficial understanding of why some highrisk patients do not develop neuropathic pain and what innate mechanisms act to counter the development of this debilitating condition. A study by López-Álvarez et al. in this issue of PAIN highlights the potential for engaging endogenous processes that counter the development of neuropathic pain after nerve injury. In this work, the authors provide intriguing evidence that neuropathic pain and its underlying causes may be partially treatable with certain exercise regimes. The authors used a sciatic transection model of neuropathic pain in rats that produces collateral sprouting and innervation of sciatic nerve territory by afferents from the saphenous nerve, followed by gradual reinnervation of the sciatic nerve territory by the resected afferents. Both saphenous and sciatic nerve territories displayed hyperalgesia after resection and collateral sprouting and reinnervation. The authors demonstrated that subjecting the injured rats to an exercise regime of increasing intensity for 1 week after resection not only reduced the extent of collateral sprouting but also the development of hyperalgesia in both saphenous and sciatic nerve territories. Crucially, López-Álvarez et al. also demonstrate that this exercise regime prevented changes in the NKCC1 and KCC2 expression that normally occur after nerve injury and contribute to abnormal pain responses. Both of these effects were associated with the exercise-induced normalized expression of the neurotrophic factors nerve growth factor and brain-derived neurotrophic factor. Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.