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

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Abstract
Cannabinoid receptors (CB1‐R) are the target of a novel class of neuromodulators, the endocannabinoids. Yet, their signalling mechanisms in adult brain are poorly understood. We report that, in rat and mouse hippocampal slices, anandamide and 2‐arachidonoylglycerol, synthetic cannabinoids, and Δ9‐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 both 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 cannabinoids was insensitive to inhibitors of Src. These results provide new insights into the cellular mechanisms by which cannabinoids exert their effects in hippocampus.