Cannabinoids activate p38 mitogen-activated protein kinases through CB1 receptors in hippocampus

Cannabinoid receptors (CBI-R) are the target of a novel class of neuromodul ators, the endocannabinoids. Yet, their signalling mechanisms in adult brai n are poorly understood. We report that, in rat and mouse hippocampal slice s, anandamide and 2-arachidonoylglycerol, synthetic cannabinoids, and Delta (9)-tetrahydrocannabinol activated p38 mitogen-activated protein kinases ( MAPK), but not c-Jun N-terminal kinase (JNK). In contrast, lysophosphatidic acid (LPA), a lipid messenger acting on different receptors, increased bot h p38-MAPK and JNK phosphorylation. The effects of cannabinoids on p38-MAPK were mediated through activation of CB1-R because they were blocked in the presence of SR 141716 A and absent in CB1-R knockout mice, two conditions that did not alter the effects of LPA. The activation of p38-MAPK by cannab inoids was insensitive to inhibitors of Src. These results provide new insi ghts into the cellular mechanisms by which cannabinoids exert their effects in hippocampus.