Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0423716 (Neuropathic pain)
 1,417 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Neuropathic pain is a major, intractable clinical problem and its pathophysiology is not well understood. Although recent gene expression profiling studies have enabled the identification of novel targets for pain therapy, classical study designs provide unclear results owing to the differential expression of hundreds of genes across sham and nerve-injured groups, which can be difficult to validate, particularly with respect to the specificity of pain modulation. To circumvent this, we used two outbred lines of rats, which are genetically similar except for being genetically segregated as a result of selective breeding for differences in neuropathic pain hypersensitivity. SerpinA3N, a serine protease inhibitor, was upregulated in the dorsal root ganglia (DRG) after nerve injury, which was further validated for its mouse homolog. Mice lacking SerpinA3N developed more neuropathic mechanical allodynia than wild-type (WT) mice, and exogenous delivery of SerpinA3N attenuated mechanical allodynia in WT mice. T lymphocytes infiltrate the DRG after nerve injury and release leukocyte elastase (LE), which was inhibited by SerpinA3N derived from DRG neurons. Genetic loss of LE or exogenous application of a LE inhibitor (Sivelastat) in WT mice attenuated neuropathic mechanical allodynia. Overall, we reveal a novel and clinically relevant role for a member of the serpin superfamily and a leukocyte elastase and crosstalk between neurons and T cells in the modulation of neuropathic pain.
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PMID:The serine protease inhibitor SerpinA3N attenuates neuropathic pain by inhibiting T cell-derived leukocyte elastase. 2595 29

Neuropathic pain is an integral component of several chronic pain conditions and poses a major health problem worldwide. Despite emerging understanding of mechanisms behind neuropathic pain, the available treatment options are still limited in efficacy or associated with side effects, therefore making it necessary to find viable alternatives. In a genetic screen, we recently identified SerpinA3N, a serine protease inhibitor secreted in response to nerve damage by the dorsal root ganglion neurons and we showed that SerpinA3N acts against induction of neuropathic pain by inhibiting the T-cell- and neutrophil-derived protease, leucocyte elastase (LE). In the current study, via detailed in vivo pharmacology combined with analyses of evoked- and spontaneous pain-related behaviors in mice, we report that on systemic delivery, a single dose of 3 independent LE inhibitors can block established nociceptive hypersensitivity in early and late phases in the spared nerve injury model of traumatic neuropathic pain in mice. We further report the strong efficacy of systemic LE inhibitors in reversing ongoing pain in 2 other clinically relevant mouse models-painful diabetic neuropathy and cancer pain. Detailed immunohistochemical analyses on the peripheral tissue samples revealed that both T-Lymphocytes and neutrophils are the sources of LE on peripheral nerve injury, whereas neutrophils are the primary source of LE in diabetic neuropathic conditions. In summary, our results provide compelling evidence for a strong therapeutic potential of generic LE inhibitors for the treatment of neuropathic pain and other chronic pain conditions harboring a neuropathic pain component.
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PMID:Therapeutic potential for leukocyte elastase in chronic pain states harboring a neuropathic component. 2883 3