British journal of pharmacology
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BACKGROUND AND PURPOSE We recently demonstrated that activation of the spinal sigma-1 receptor induces mechanical and thermal hypersensitivity via calcium-dependent second messenger cascades and phosphorylation of the spinal NMDA receptor GluN1 subunit (pGluN1). Here we examined the role of NO in this process, as it plays a critical role in PKC-mediated calcium signalling and the potentiation of NMDA receptor function. EXPERIMENTAL APPROACH The effects of intrathecal (i.t.) pretreatment with nNOS inhibitors on PRE084 (sigma-1 receptor agonist)-induced pain were assessed in mice by use of mechanical allodynia and thermal hyperalgesia tests. ⋯ PRE084 also time-dependently decreased the ratio of phosphorylated nNOS (pnNOS) to nNOS expression and the number of spinal pnNOS-ir cells. This decrease in pnNOS was prevented by BD1047, a sigma-1 receptor antagonist and cyclosporin A, a calcineurin inhibitor, but not by a sGC inhibitor. CONCLUSIONS AND IMPLICATIONS Spinal sigma-1 receptor-induced sensitization is mediated by an increase in nNOS activity, which is associated with an NO-induced increase in PKC-dependent pGluN1 expression.
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The endogenous cannabinoid system participates in oligodendrocyte progenitor differentiation in vitro. To determine the effect of synthetic cannabinoids on oligodendrocyte differentiation, we exposed differentiating cultures of oligodendrocytes with cannabinoid CB(1), CB(2) and CB(1)/CB(2) receptor agonists and antagonists. The response of the PI3K/Akt and the mammalian target of rapamycin (mTOR) signalling pathways were studied as effectors of cannabinoid activity. ⋯ Activation of cannabinoid CB(1) or CB(2) receptors with selective agonists accelerated oligodendrocyte differentiation through the mTOR and Akt signalling pathways.
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BACKGROUND AND PURPOSE The endocannabinoid 2-arachidonoylglycerol (2-AG) is degraded primarily by monoacylglycerol lipase (MGL). We compared peripheral antinociceptive effects of JZL184, a novel irreversible MGL inhibitor, with the reversible MGL-preferring inhibitor URB602 and exogenous 2-AG in rats. EXPERIMENTAL APPROACH Nociception in the formalin test was assessed in groups receiving dorsal paw injections of vehicle, JZL184 (0.001-300 µg), URB602 (0.001-600 µg), 2-AG (ED(50)), 2-AG + JZL184 (at their ED(50)), 2-AG + URB602 (at their ED(50)), AM251 (80 µg), AM251 + JZL184 (10 µg), AM630 (25 µg) or AM630 + JZL184 (10 µg). ⋯ CONCLUSIONS AND IMPLICATIONS MGL inhibitors suppressed formalin-induced pain through peripheral CB(1) and CB(2) receptor mechanisms. MGL inhibition increased paw skin 2-AG accumulation to mediate these effects. MGL represents a target for the treatment of inflammatory pain.