BACKGROUND AND PURPOSE: Cannabinoid (CB) receptor agonists have potential utility as anti-inflammatory drugs in chronic immune inflammatory diseases. In the present study, we characterized the signal transduction pathways affected by CB(2) receptors in quiescent and lipopolysaccharide (LPS)-stimulated murine microglia. EXPERIMENTAL APPROACH: We examined the effects of the synthetic CB(2) receptor ligand, JWH-015, on phosphorylation of MAPKs and NO production. KEY RESULTS: Stimulation of CB(2) receptors by JWH-015 activated JNK-1/2 and ERK-1/2 in quiescent murine microglial cells. Furthermore, CB(2) receptor activation increased p-ERK-1/2 at 15 min in LPS-stimulated microglia. Surprisingly, this was reduced after 30 min in the presence of both LPS and JWH-015. The NOS inhibitor L-NAME blocked the ability of JWH-015 to down-regulate the LPS-induced p-ERK increase, indicating that activation of CB(2) receptors reduced effects of LPS on ERK-1/2 phosphorylation through NO. JWH-015 increased LPS-induced NO release at 30 min, while at 4 h CB(2) receptor stimulation had an inhibitory effect. All the effects of JWH-015 were significantly blocked by the CB(2) receptor antagonist AM 630 and, as the inhibition of CB(2) receptor expression by siRNA abolished the effects of JWH-015, were shown to be mediated specifically by activation of CB(2) receptors. CONCLUSIONS AND IMPLICATIONS: Our results demonstrate that CB(2) receptor stimulation activated the MAPK pathway, but the presence of a second stimulus blocked MAPK signal transduction, inhibiting pro-inflammatory LPS-induced production of NO. Therefore, CB(2) receptor agonists may promote anti-inflammatory therapeutic responses in activated microglia.
Cannabinoid CB(2) receptors modulate ERK-1/2 kinase signalling and NO release in microglial cells stimulated with bacterial lipopolysaccharide / MERIGHI S.; GESSI S.; VARANI K.; SIMIONI C.; FAZZI D.; MIRANDOLA P.; BOREA PA.. - In: BRITISH JOURNAL OF PHARMACOLOGY. - ISSN 0007-1188. - 165(2012), pp. 1773-1788. [10.1111/j.1476-5381.2011.01673.x]