Articles: hyperalgesia.
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Connexin43 (Cx43), involved in intercellular signaling, is expressed in spinal dorsal horn astrocytes and crucial in the maintenance of neuropathic pain. Downregulation of spinal astrocytic Cx43 in mice enhances glutamatergic neurotransmission by decreasing glutamate transporter GLT-1 expression, resulting in cutaneous hypersensitivity. Decreased expression of astrocytic Cx43 could lead to altered expression of other nociceptive molecules. ⋯ Suppression of glycogen synthase kinase-3β (GSK-3β), a serine/threonine protein kinase, prevented upregulation of IL-6 and COX-2 expression induced by Cx43 downregulation in both cultured astrocytes and in mouse spinal dorsal horn. Inhibition of spinal GSK-3β also ameliorated Cx43 siRNA-induced mechanical hypersensitivity. The current findings indicate that downregulation of spinal astrocytic Cx43 leads to changes in spinal expression of pronociceptive molecules underlying the maintenance of pain following nerve injury.
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Neuroscience bulletin · Feb 2018
Involvement of NF-κB and the CX3CR1 Signaling Network in Mechanical Allodynia Induced by Tetanic Sciatic Stimulation.
Tetanic stimulation of the sciatic nerve (TSS) triggers long-term potentiation in the dorsal horn of the spinal cord and long-lasting pain hypersensitivity. CX3CL1-CX3CR1 signaling is an important pathway in neuronal-microglial activation. Nuclear factor κB (NF-κB) is a key signal transduction molecule that regulates neuroinflammation and neuropathic pain. ⋯ In addition, blockade of NF-κB down-regulated the expression of CX3CL1-CX3CR1 signaling, and conversely the CX3CR1-neutralizing antibody also down-regulated pNF-κB. These findings suggest an involvement of NF-κB and the CX3CR1 signaling network in the development and maintenance of TSS-induced mechanical allodynia. Our work suggests the potential clinical application of NF-κB inhibitors or CX3CR1-neutralizing antibodies in treating pathological pain.
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Br J Clin Pharmacol · Feb 2018
Randomized Controlled TrialDemonstration of an anti-hyperalgesic effect of a novel pan-Trk inhibitor PF-06273340 in a battery of human evoked pain models.
Inhibitors of nerve growth factor (NGF) reduce pain in several chronic pain indications. NGF signals through tyrosine kinase receptors of the tropomyosin-related kinase (Trk) family and the unrelated p75 receptor. PF-06273340 is a small molecule inhibitor of Trks A, B and C that reduces pain in nonclinical models, and the present study aimed to investigate the pharmacodynamics of this first-in-class molecule in humans. ⋯ The study demonstrated, for the first time, the translation of nonclinical effects into man in an inflammatory pain analgesic pharmacodynamic endpoint using a pan-Trk inhibitor.
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Human experimental pain models provide an important translational link between pre-clinical models and clinical pain. Using topical capsaicin and continuous heat application, the novel capsaicin/heat ongoing pain (CHOP) model induces long-lasting experimental pain of which the perceived intensity can be individually adjusted. ⋯ Here we demonstrate a novel pain model that can be applied for up to an hour without tissue damage. The CHOP model allows for investigation of primary and secondary hyperalgesia as well as top-down influences on sensitization, thereby providing an experimental model that can be used to assess clinically-oriented questions.
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Objective To investigate the association between trigger points (TrPs) and widespread pressure pain sensitivity in people with tension-type headache (TTH) and to determine if this association is different between frequent episodic (FETTH) or chronic (CTTH) headache. Design A cross-sectional study. Methods One hundred and fifty-seven individuals (29% male) with TTH participated. ⋯ The number of active and latent TrPs was significantly and negatively associated with PPTs: The higher the number of active or latent TrPs, the lower the widespread PPT, and the more generalized sensitization. This association was stronger within the FETTH group than the CTTH group. Conclusions This study found that the number of TrPs in head and neck/shoulder muscles was associated with widespread pressure hypersensitivity independently of the frequency of headache.