British journal of pharmacology
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CR4056 is a novel imidazoline-2 (I2 ) ligand exhibiting potent analgesic activity in animal models of pain. In this study, we investigated the effects of CR4056 in a well-established model of postoperative pain where rats develop hyperalgesia in the injured hind paw. ⋯ CR4056 is a novel pharmacological agent under development for postoperative pain both as stand-alone treatment and in association with morphine. CR4056 has successfully completed Phase I studies for tolerability and pharmacokinetics in healthy volunteers, and is currently entering the first proof-of-concept study in patients.
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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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The endocannabinoid anandamide (N-arachidonoyl ethanolamide; AEA) exerts negative inotropic and antiarrhythmic effects in ventricular myocytes. ⋯ Results indicate that AEA inhibited the function of voltage-dependent Na(+) and L-type Ca(2+) channels in rat ventricular myocytes, independent of CB1 and CB2 receptor activation.
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Acute lung injury (ALI) is a severe illness with a high rate of mortality. Maresin 1 (MaR1) was recently reported to regulate inflammatory responses. We used a LPS-induced ALI model to determine whether MaR1 can mitigate lung injury. ⋯ High-dose MaR1 mitigated LPS-induced lung injury in mice by inhibiting neutrophil adhesions and decreasing the levels of pro-inflammatory cytokines.
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Infection with Gram-negative bacteria has been recognized as an initiator of rheumatoid arthritis, which is characterized by chronic inflammation and infiltration of immune cells. Carbon monoxide (CO) exhibits anti-inflammatory properties. Here we have investigated the detailed mechanisms of vascular cell adhesion molecule-1 (VCAM-1) expression induced by LPS and if CO inhibited LPS-induced leukocyte adhesion to synovial fibroblasts by suppressing VCAM-1 expression. ⋯ LPS-mediated formation of the TLR4/MyD88/TRAF6/c-Src complex regulated NF-κB and MAPKs/AP-1 activation leading to VCAM-1 expression and leukocyte adhesion. CORM-2, which liberates CO to elicit direct biological activities, attenuated LPS-induced VCAM-1 expression by interfering with NF-κB and AP-1 activation, and significantly reduced LPS-induced immune cell infiltration of the synovium.