Articles: hyperalgesia.
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Protease-activated receptor 2 (PAR2) is expressed on nociceptive neurons, and can sensitize transient receptor potential (TRP) ion channels to amplify neurogenic inflammation and pain. The mechanisms by which this occurs are not fully understood. PAR2 causes receptor-operated activation of TRPV4 channels and TRPV4 null mice have attenuated PAR2-stimulated neurogenic inflammation and mechanical hyperalgesia. Here we investigate the intracellular signalling mechanisms underlying PAR2-induced TRPV4 channel activation and pain. ⋯ This study supports a role for tyrosine kinases in PAR2-mediated receptor-operated gating of TRPV4 channels, independent of Gαq stimulation. The ability of a tyrosine kinase inhibitor to diminish PAR2-induced activation of TRPV4 channels and consequent mechanical hyperalgesia identifies bafetinib (which is in development in oncology) as a potential novel analgesic therapy.
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This study evaluated the involvement of tumour necrosis factor α (TNF-α) in orofacial thermal and mechanical hyperalgesia induced by an inflammatory stimulus or by chronic constriction of the infraorbital nerve (CION) using etanercept (Eta), a TNF-receptor fusion protein that inhibits TNF-α action. ⋯ These results suggest that TNF-α has an important role in cold, heat and mechanical hyperalgesia induced by inflammation or neuropathy in the orofacial region and this may contribute for the establishment of new therapeutic strategies to treat orofacial pain.
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In a recent study, we found that baicalin exhibited a potent analgesic effect on carrageenan-evoked thermal hyperalgesia. The underlining mechanisms may be associated with inhibition of inflammatory mediator overproduction, including proinflammatory cytokines, nitric oxide (NO), and prostaglandin E2 (PGE2). In the present study, we examined the effect of baicalin on the antinociceptive effect of morphine and histone deacetylase 1 (HDAC1) expression in the spinal cord dorsal horn in neuropathic pain rats. ⋯ The present findings suggest that baicalin can ameliorate neuropathic pain by suppressing HDAC1 expression and preventing histone-H3 acetylation in the spinal cord dorsal horn of SNL rats.
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Accumulating evidence suggests that spinal cord astrocytes play an important role in neuropathic pain sensitization by releasing astrocytic mediators (e.g. cytokines, chemokines and growth factors). However, it remains unclear how astrocytes control the release of astrocytic mediators and sustain late-phase neuropathic pain. Astrocytic connexin-43 (now known as GJ1) has been implicated in gap junction and hemichannel communication of cytosolic contents through the glial syncytia and to the extracellular space, respectively. ⋯ Spinal injection of TNF-α-activated astrocytes was sufficient to induce persistent mechanical allodynia, and this allodynia was suppressed by CXCL1 neutralization, CXCL1 receptor (CXCR2) antagonist, and pretreatment of astrocytes with connexin-43 small interfering RNA. Furthermore, nerve injury persistently increased excitatory synaptic transmission (spontaneous excitatory postsynaptic currents) in spinal lamina IIo nociceptive synapses in the late phase, and this increase was suppressed by carbenoxolone and Gap27, and recapitulated by CXCL1. Together, our findings demonstrate a novel mechanism of astrocytic connexin-43 to enhance spinal cord synaptic transmission and maintain neuropathic pain in the late-phase via releasing chemokines.
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Aspirin-triggered Lipoxin A4 (ATL), as a Lipoxin A4 (LXA4) epimer, is endogenously produced by aspirin-acetylated cycloxygenase-2 (COX-2) and plays a vital role in endogenous anti-inflammation via the LXA4 receptor (ALX). Recent investigations have indicated that spinal neuroinflammation and the activation of the Janus Kinase 2 (JAK2)/Signal Transducers and Transcription Activators 3 (STAT3) signaling pathway are involved in neuropathic pain states. However, the effect of ATL on neuroinflammation and JAK2/STAT3 signaling in chronic constriction injury (CCI)-induced neuropathic pain in rats has not been well-studied. ⋯ Blockade of JAK2-STAT3 signaling with intrathecal administration of the JAK2 inhibitor AG490 or the STAT3 inhibitor S3I-201 clearly reduced mechanical allodynia and the upregulation of pro-inflammatory cytokines in CCI rats. Interestingly, inhibition of JAK2/STAT3 signaling via ATL or the specific signaling inhibitor (AG49, S3I-201) further promoted the increased expression of suppressor of cytokine signaling 3 (SOCS3) mRNA in the spinal cord induced by CCI surgery. Taken together, our results suggested that the analgesic effect of ATL was mediated by inhibiting spinal JAK2/STAT3 signaling and hence the spinal neuroinflammation in CCI rats.