Participation of the endocannabinoid system in the effect of TNF-alpha on hypothalamic release of gonadotropin-releasing hormone (LHRH)

JAVIER FERNANDEZ-SOLARI; JUAN P PRESTIFILIPPO; STEFAN R BORNSTEIN; SAMUEL M MCCANN; VALERIA RETTORI

ANNALS OF THE NEW YORK ACADEMY OF SCIENCES.

New York Academy of Sciences

Año: 2006 vol. 1088 p. 238 - 250

0077-8923

It is known that delta9-tetrahydrocannabinol (THC), the major active ingredient of marijuana can suppress reproductive function. Also, we reported previously that the endocannabinoid, anandamide (AEA), inhibited LHRH release from medial basal hypothalamus (MBH) of male rats incubated in vitro as well as reduced plasma LH levels after AEA injections into the cerebral lateral ventricle (icv). On the other hand, it is known that during endotoxemia the hypothalamic gonadotropin axis is inhibited. Therefore, the aim of the present study was to determine if the effect of TNFa, a pro-inflammatory cytokine induced by LPS that inhibits LHRH release, is mediated by the activation of the endocannabinoid system. The intra peritoneal injection of LPS (5mg/Kg) as well as the icv injection of TNFa (100 ng/rat) increased significantly the AEA synthesis measured ex vivo in MBH´s removed 3 h after the treatments. In order to examine the possibility that TNFa also acted by increasing the synthesis of AEA that was released and activated the CB1-r followed by inhibition of LHRH release, we measured the effect of TNFa on the AEA synthase activity in MBH´s incubated in vitro. As expected, we found that TNFa (2.9x10-9M) increased the AEA synthesis. Secondly, we showed that TNFa reduced significantly the forskolin-stimulated LHRH release and that the CB1-r antagonist, AM251 (10-5M), blocked that inhibition supporting the hypothesis that TNFa inhibits LHRH release acting at least in part by activating the endocannabinoid system. Therefore, our data demonstrate a key role for the endocannabinoid system in the response of the reproductive system to inflammatory signals.