Role of CGRP and GABA in the hypotensive effect of intrathecally administered anandamide to anesthetized rats

In urethane-anesthetized rats the intrathecal (i.t.) injection of 100 nmol anandamide produced a hypotensive effect (−19.3±1.6 mm Hg; n=6) that was mimicked by i.t. administration of 0.25 nmol calcitonin gene-related peptide (CGRP; −26.2±1.8 mm Hg, n=4). Both effects were antagonized either by the CGRP receptor antagonist CGRP8–37 (5 nmol; i.t.) or by the γ-aminobutyric acid (GABA)A receptor antagonist bicuculline (8.8 nmol, i.t) or by the GABAB receptor antagonist 2-hydroxy saclofen (110 nmol; i.t.). On the contrary, blockade of spinal CGRP receptors by CGRP8–37 did not modify the hypotensive response to either the GABAA-receptor agonist muscimol (8.8 nmol; i.t.) or the GABAB-receptor agonist baclofen (100 nmol; i.t). This result suggests a unidirectional effect of CGRP on the GABAergic system. The response to anandamide remained unaltered after acute inhibition of nitric oxide (NO) synthase activity by either i.t. (1 μmol) or i.v. (10 mg/kg) injection of NG-nitro-l-arginine methyl ester (L-NAME), but increased significantly after long-term L-NAME administration (70 mg/kg/day; four weeks; p.o.), thus suggesting compensatory changes in cardiovascular homeostasis. It is proposed that the hypotensive effect of anandamide in urethane-anesthetized rats could involve the release of CGRP followed by the release of GABA in the spinal cord. NO does not appear to have a direct participation in the spinal mechanisms involved in the decrease of the blood pressure caused by anandamide.