Mol Pain
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Background Chronic visceral pain is a defining symptom of many gastrointestinal disorders. The KV7 family (KV7.1-KV7.5) of voltage-gated potassium channels mediates the M current that regulates excitability in peripheral sensory nociceptors and central pain pathways. Here, we use a combination of immunohistochemistry, gut-nerve electrophysiological recordings in both mouse and human tissues, and single-cell qualitative real-time polymerase chain reaction of gut-projecting sensory neurons, to investigate the contribution of peripheral KV7 channels to visceral nociception. ⋯ In human bowel tissues, KV7.3 and KV7.5 were expressed in neuronal varicosities co-labelled with synaptophysin and CGRP, and retigabine inhibited bradykinin-induced afferent activation in afferent recordings from human colon. Conclusions We show that KV7 channels contribute to the sensitivity of visceral sensory neurons to noxious chemical and mechanical stimuli in both mouse and human gut tissues. As such, peripherally restricted KV7 openers may represent a viable therapeutic modality for the treatment of gastrointestinal pathologies.
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Pain vulnerability and DNA methyltransferase 3a involved in the affective dimension of chronic pain.
Chronic pain with comorbid emotional disorders is a prevalent neurological disease in patients under various pathological conditions, yet patients show considerable difference in their vulnerability to developing chronic pain. Understanding the neurobiological basis underlying this pain vulnerability is essential to develop targeted therapies of higher efficiency in pain treatment of precision medicine. However, this pain vulnerability has not been addressed in preclinical pain research in animals to date. ⋯ In addition, social stress also revealed significant individual variance in anxiety behavior in mice. These findings suggest that individual pain vulnerability may be inherent mostly in the emotional/affective component of chronic pain and remain consistent in different aspects of negative emotion, in which adaptive changes in the function of DNA methyltransferase 3a for DNA methylation in central amygdala may play an important role. This may open a new avenue of basic research into the neurobiological mechanisms underlying pain vulnerability.
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Background Curcumin has been reported to have anti-inflammatory and anti-nociceptive effects. The present study was designed to explore the potential therapeutic effects of curcumin on visceral hyperalgesia and inflammation in a rat model of ulcerative colitis. We observed the effects of orally administered curcumin on the disease activity index, histological change in colon, colorectal distension-induced abdominal withdrawal reflex, the expression of transient receptor potential vanilloid 1 (TRPV1) and phosphorylated TRPV1 in dextran sulfate sodium-induced colitis rats. ⋯ In the HEK293 cell line stably expressing hTRPV1, curcumin (1, 3 µm) inhibited phorbol myristate acetate-induced upregulation of membrane TRPV1. Conclusion Oral administration of curcumin alleviates visceral hyperalgesia in dextran sulfate sodium-induced colitis rats. The anti-hyperalgesic effect is partially through downregulating the colonic expression and phosphorylation of TRPV1 on the afferent fibers projected from peptidergic and non-peptidergic nociceptive neurons of dorsal root ganglion.
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Painful peripheral neuropathy is a severe side effect in oxaliplatin therapy that compromises cancer patients' quality of life. However, its underlying pathogenic mechanisms remain largely unknown. Here, we found that intraperitoneal consecutive administration of oxaliplatin significantly increased excitability of small diameter dorsal root ganglion neurons and induced thermal hyperalgesia in rats. ⋯ Importantly, the upregulated CX3CL1 is mediated by the NF-κB signaling pathway, as inhibition of NF-κB p65 activation with pyrrolidine dithiocarbamate or p65 siRNA inhibited the upregulation of CX3CL1, the enhanced excitability of dorsal root ganglion neurons, and thermal hyperalgesia induced by oxaliplatin. Further studies with chromatin immunoprecipitation found that oxaliplatin treatment increased the recruitment of NF-κB p65 to the CX3Cl1 promoter region. Our results suggest that upregulation of CX3CL1 in dorsal root ganglion mediated by NF-κB activation contributes to the peripheral sensitization and chronic pain induced by oxaliplatin administration.
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Cobra neurotoxin, a short-chain peptide isolated from snake venom of Naja naja atra, showed both a central analgesic effect and a hyperalgesic effect in mice tests. In order to explore mechanisms, a hypothesis is put forward that cobra neurotoxin takes effect through adenosine receptor pathway. The central effects of cobra neurotoxin were evaluated using the hot plate test (a model of acute pain) and the spinal cord injury (a model of central pain) in mice and using A1 receptor antagonist (DPCPX) and A2A receptor antagonist (ZM241385); behaviors were scored and signal molecules such as reactive oxygen species and adenosine triphosphate levels and mitogen-activated protein kinases/extracellular signal-regulated protein kinase expression were measured. ⋯ Cobra neurotoxin may take effect through mitogen-activated protein kinases/extracellular signal-regulated protein kinase pathway inhibition by activating adenosine A1Rs and cause changes of reactive oxygen species and adenosine triphosphate through feedback mechanisms. Overdose cobra neurotoxin further activates the adenosine A2ARs to generate pain sensitization. This research proposes a new central analgesic mechanism of cobra neurotoxin and discloses dual regulation of pain.