Journal
NEUROPHARMACOLOGY
Volume 55, Issue 8, Pages 1274-1279Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.neuropharm.2008.01.010
Keywords
TRPV1; CB1; Anandamide; 2-Arachidonoylglycerol; Cannabinoid; Signalling; Vanilloid; Channel; Metabotropic
Categories
Funding
- Italian Ministero Istruzione Universita e Ricerca [2004-057339]
- Fondazione Cassa di Risparmio di Modena and Fondazione Cassa di Risparmio di Carpi
- BBSRC [BB/F003072/1] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/C003217/1, BB/F003072/1] Funding Source: researchfish
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N-arachidonoylethanolamine (anandamide, AEA), is a full agonist at both cannabinoid CB, receptors and transient receptor potential vanilloid type I (TRPV1) channels, and N-palmitoylethanolamine (PEA) potentiates these effects. In neurons of the rat dorsal root ganglia (DRG), TRPV1 is activated and/or sensitised by AEA as well as upon activation of protein kinases C (PKC) and A (PKA). We investigated here the effect on AEA levels of PKC and PKA activators in DRG neurons. AEA levels were significantly enhanced by both phorbol-miristoyl-acetate (PMA), a typical PKC activator, and forskolin (FSK), an adenylate cyclase stimulant, as well as by thrombin, which also activates PKC by stimulating protease-activated receptors (PARs). The levels of the other endocannabinoid and TRPV1-inactive compound, 2-arachidonoylglycerol (2-AG), were enhanced only by thrombin and to a lesser extent than AEA, whereas PEA was not affected by any of the treatments. Importantly, FSK- and PMA-induced elevation of AEA levels was not sensitive to intracellular Ca2+ chelation with BAPTA-acetoxymethyl (AM) ester. In human embryonic kidney (HEK-293) cells, which constitutively express PARs, thrombin, PMA and FSK elevated AEA levels, and the effects of the two former compounds were counteracted by the PKC inhibitor, RO318220, whereas the effect of FSK was reduced by the PKA inhibitor RpcAMPs. In conclusion, we report that AEA levels are stimulated by both PKC, either directly or after thrombin receptor activation, and PKA, possibly in a way independent from intracellular calcium. Since AEA activates TRPV1, these findings may suggest the existence of an amplificatory cascades on this receptor in sensory neurons. (C) 2008 Elsevier Ltd. All rights reserved.
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