Is Diabetic Nerve Pain Caused by Dysregulated Ion Channels in Sensory Neurons?

Abstract

In diabetes, a common and debilitating chronic disease, peripheral diabetic neuropathy (PDN) is the most frequent complication, occurring in about two-thirds of the patients (1,2). At least one-third of patients with diabetes experience painful symptoms including hyperalgesia and/or allodynia as well as spontaneous pain in the form of burning or tingling, despite the degeneration of peripheral nerves (3). Eventually, these painful symptoms usually subside as the disabling pain is replaced by the complete loss of sensation. Both intractable pain and loss of sensation have significant adverse effects on quality-of-life measures. Unfortunately, current treatment options are unable to reverse these symptoms. Pain-sensing sensory neurons, or nociceptors, can be sensitized (become hyperexcitable) by various mechanisms in response to the pathological conditions or peripheral tissue injury associated with diabetes. Multiple pathogenic mechanisms, such as the formation of intracellular advanced glycation end products, inflammatory cytokines, increased aldose reductase activity, and oxidative stress, may contribute to the impaired function of sensory neurons in animals with PDN. However, multiple preclinical and clinical studies that aimed to target several of these mechanisms while simultaneously ensuring proper blood glucose control were unable to provide definite and complete pain relief (1,2). Importantly, currently available therapies are only partially effective and are often associated with serious side effects. For example, CaV2.2 channels (N-type) and their regulatory subunit α2δ are considered a major cellular target for the anticonvulsants gabapentin and pregabalin, which are commonly used to relieve diabetes-induced pain in humans …