Entourage effect of palmitoylethanolamide in the spinal cord of anesthetized rats

GARCÍA M.C.; ADLER-GRASCHINSKY E.; CELUCH S.M.

Buzios, Brasil

Congreso; I Congress IBRO/LARC of Neurosciences for Latin America, Caribbean and Iberian Peninsula; 2008

IBRO/LARC

ENTOURAGE EFFECT OF PALMITOYLETHANOLAMIDE IN THE SPINAL CORD OF ANESTHETIZED RATS García MC1,2, Adler-Graschinsky E1, Celuch SM1 1Inst. de Investig. Farmacol. (CONICET); 2Cát. Farmacología, FFyB (UBA). Junín 956, Buenos Aires. sceluch@ffyb.uba.ar The effects of arachidonoylethanolamide (anandamide; AEA) can be enhanced by structurally related, endogenous fatty acid derivatives termed entourage compounds. We have reported that intrathecal (it) injection of AEA to urethane-anesthetized rats induced a hypotensive effect due to the activation of both cannabinoid CB1 and vanilloid TRPV1 spinal receptors (García et al., Naunyn-Schmiedeberg’s Arch. Pharmacol. 368: 270, 2003). The aim of this study was to examine whether palmitoylethanolamide (PEA) behaves as an entourage compound for the hypotensive effects of endocannabinoids administered to the spinal cord. AEA (25, 50 and 100 nmol; it) induced a dose-dependent decrease in the mean blood pressure (∆ MBP: -1.2±2.4, -10.5±1.3 and -17.3±1.3 mmHg, respectively; n=4-6). PEA (100 nmol; it) did not modify per se the baseline MBP but increased the hypotensive response to AEA (25 and 50 nmol; it; p<0.05). Moreover, PEA enhanced the hypotensive effects of the endocannabinoid N-arachidonoyldopamine (25 nmol; it) and to the metabolically stable analog of AEA methanandamide (25 and 50 nmol). The hypotensive response induced by co-injection of PEA with 25 nmol AEA was prevented by pre-treatment with either the TRPV1 receptor antagonist capsazepine (20 nmol; it) or the CB1 receptor antagonist rimonabant (20 nmol; it) and the TRPV1 receptor agonist capsaicin (0.3 nmol; it). By contrast, a significant enhancement of PEA effect was observed after pretreatment with the URB602 (3.5 nmol; it), a putative inhibitor of PEA hydrolysis in microglia cells. It is suggested that PEA positively modulates the hypotensive responses to endocanabinoids in the spinal cord. This facilitatory effect involves the activation of both CB1 and TRPV1 spinal receptors and seems modulated by enzymatic hydrolysis. Supported by ANPCyT (PICT BID 1201/OC-AR- 5-14107) y CONICET (PIP 5695).