Mol Pain
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Paclitaxel is one of the most commonly used drugs to treat breast cancer. Its major dose-limiting toxicity is paclitaxel-induced peripheral neuropathy (PIPN). PIPN persists into survivorship and has a negative impact on patient's mood, functional status, and quality of life. No interventions are available to treat PIPN. A critical barrier to the development of efficacious interventions is the lack of understanding of the mechanisms that underlie PIPN. Mitochondrial dysfunction has been evaluated in preclinical studies as a hypothesized mechanism for PIPN, but clinical data to support this hypothesis are limited. The purpose of this pilot study was to evaluate for differential gene expression and perturbed pathways between breast cancer survivors with and without PIPN. ⋯ This study is the first to provide molecular evidence that a number of mitochondrial dysfunction mechanisms identified in preclinical models of various types of neuropathic pain including chemotherapy-induced peripheral neuropathy are found in breast cancer survivors with persistent PIPN and suggest genes for validation and as potential therapeutic targets.
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Expression of Nav1.8, encoded by SCN10A, can affect pain transmission and thus mediate the human pain phenotype. In the current study, we assessed whether the variant rs6801957, located in the SCN10A enhancer region, may have the potential to affect human pain. Through dual-luciferase reporter assays in 293T cells, we found that the SCN10A enhancer A (Enh-A) increased the activity of the SCN10A promoter ( P < 0.05). ⋯ We then found that mutant genotype A/A suppressed the increased effect of Enh-A compared with wild-type G/G ( P < 0.05). The association between rs6801957 and human experimental mechanical pain sensitivity was further validated in a larger cohort of 1005 women ( P < 0.05). In conclusion, these results demonstrated that the variant rs6801957 and Enh-A may affect SCN10A gene expression and play an important role in human mechanical pain sensitivity.
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Congenital insensitivity to pain with anhidrosis (CIPA) is a rare autosomal recessive disorder, characterized by loss of algesthesis and inability to sweat. CIPA is known to be caused by mutations in the neurotrophic tyrosine kinase receptor type 1 gene ( NTRK1). However, the details of NTRK1 mutations in Chinese CIPA patients remain unclear. ⋯ Interestingly, we discovered two forms of novel recurrent mutations: the first was a large intragenic deletion c.429-374_717 + 485del mediated by recombination between Alu elements, and the second was a deep intronic substitutions c.[851-798C > T;851-794C > G]. All probands were homozygotes or compound heterozygotes of these mutations. Current findings expand our knowledge about the mutation spectrum of NTRK1 in Chinese CIPA patients and provide more evidence for precise diagnosis of the clinically suspected patients with CIPA.
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Painful neuropathy is a frequent comorbidity in diabetes. Zucker diabetic fatty (fa/fa) rats develop type 2 diabetes spontaneously with aging and show nociceptive hypersensitivity at the age of 13 weeks. In preclinical and clinical studies, the treatment of diabetic neuropathy is challenging, but complementary medicine such as transcutaneous auricular vagus nerve stimulation (taVNS) appears beneficial to the relief of neuropathic pain. ⋯ We conclude that daily 30-min taVNS sessions lessen diabetic neuropathy development by enhancing serotonergic function in genetically diabetes prone individuals. Perspective This article presents taVNS as a new approach to inhibit the development of diabetic neuropathy in genetically prone individuals. This approach could potentially help clinicians who seek to avoid the complication of neuropathic pain in diabetic patient or to relieve the pain if there was one.
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Chronic pain induced by nerve damage due to trauma or invasion of cancer to the bone elicits severe ongoing pain as well as hyperalgesia and allodynia likely reflecting adaptive changes within central circuits that amplify nociceptive signals. The present study explored the possible contribution of the mesolimbic dopaminergic circuit in promoting allodynia related to neuropathic and cancer pain. Mice with ligation of the sciatic nerve or treated with intrafemoral osteosarcoma cells showed allodynia to a thermal stimulus applied to the paw on the injured side. ⋯ Optogenetic activation of these cells produced a significant but transient anti-allodynic effect in nerve injured or tumor-bearing mice without increasing response thresholds to thermal stimulation in sham-operated animals. Suppressed activity of mesolimbic dopaminergic neurons is likely to contribute to decreased inhibition of N. Acc. output neurons and to neuropathic or cancer pain-induced allodynia suggesting strategies for modulation of pathological pain states.