title: Painful neuropathy: Mechanisms.
abstract: Painful neuropathy, like the other complications of diabetes, is a growing healthcare concern. Unfortunately, current treatments are of variable efficacy and do not target underlying pathogenic mechanisms, in part because these mechanisms are not well defined. Rat and mouse models of type 1 diabetes are frequently used to study diabetic neuropathy, with rats in particular being consistently reported to show allodynia and hyperalgesia. Models of type 2 diabetes are being used with increasing frequency, but the current literature on the progression of indices of neuropathic pain is variable and relatively few therapeutics have yet been developed in these models. While evidence for spontaneous pain in rodent models is sparse, measures of evoked mechanical, thermal and chemical pain can provide insight into the pathogenesis of the condition. The stocking and glove distribution of pain tantalizingly suggests that the generator site of neuropathic pain is found within the peripheral nervous system. However, emerging evidence demonstrates that amplification in the spinal cord, via spinal disinhibition and neuroinflammation, and also in the brain, via enhanced thalamic activity or decreased cortical inhibition, likely contribute to the pathogenesis of painful diabetic neuropathy. Several potential therapeutic strategies have emerged from preclinical studies, including prophylactic treatments that intervene against underlying mechanisms of disease, treatments that prevent gains of nociceptive function, treatments that suppress enhancements of nociceptive function, and treatments that impede normal nociceptive mechanisms. Ongoing challenges include unraveling the complexity of underlying pathogenic mechanisms, addressing the potential disconnect between the perceived location of pain and the actual pain generator and amplifier sites, and finding ways to identify which mechanisms operate in specific patients to allow rational and individualized choice of targeted therapies.
authors.affiliation: Graduate School of Biomedical Sciences, Sanford-Burnham Institute for Molecular Medicine, La Jolla, CA, USA; Department of Pathology, University of California San Diego, La Jolla, CA, USA.
authors.forename: Corinne A
authors.initials: CA
authors.lastname: Lee-Kubli
authors.affiliation: Department of Pathology, University of California San Diego, La Jolla, CA, USA. Electronic address: ncalcutt@ucsd.edu.
authors.forename: Nigel A
authors.initials: NA
authors.lastname: Calcutt
mesh_terms: D000700:Analgesics / Q000627:therapeutic use; D000818:Animals; D003920:Diabetes Mellitus / Q000175:diagnosis* / Q000453:epidemiology / Q000628:therapy; D003929:Diabetic Neuropathies / Q000175:diagnosis* / Q000453:epidemiology / Q000628:therapy; D006801:Humans; D009437:Neuralgia / Q000175:diagnosis* / Q000453:epidemiology / Q000628:therapy; D010146:Pain / Q000175:diagnosis / Q000453:epidemiology; D010147:Pain Measurement / Q000379:methods; D010523:Peripheral Nervous System Diseases / Q000175:diagnosis / Q000453:epidemiology / Q000628:therapy
chemical_list: D000700:Analgesics
keywords: Type 1; Type 2; allodynia; animal models; central; hyperalgesia; mechanisms; painful diabetic neuropathy; peripheral; streptozotocin; therapies