Anandamide excites central terminals of dorsal root ganglion neurons via vanilloid receptor-1 activation

Recently, the cannabinoid (CB) receptor agonist anandamide (AEA) has been s hown to excite perivascular terminals of primary sensory neurons via activa tion of the vanilloid receptor-1 (VR-1). To determine whether AEA stimulate s central terminals of these neurons, via VR-1 activation, we studied the r elease of calcitonin gene-related peptide (CGRP)- and substance P (SP)-like immunoreactivities (LI) from slices of rat dorsal spinal cord. Mobilizatio n of Ca2+ in rat dorsal root ganglion (DRG) neurons in culture was also stu died. AEA (0.1-10 muM) increased the outflow of CGRP-LI and SP-LI from slic es of the rat dorsal spinal cord in a Ca2+-dependent manner and increased [ Ca2+](i) in capsaicin-sensitive cultured DRG neurons. Both effects of AEA w ere abolished by capsaicin pretreatment and by the VR-1 antagonist capsazep ine but not affected by the CB receptor antagonists AM281 or AM630. Both ne uropeptide release and Ca2+ mobilization induced by electrical field stimul ation (EFS) were inhibited by a low concentration of AEA (10 nM). Inhibitio n by AEA of EFS-induced responses was reversed by AM281 and AM630, but was not affected by capsazepine. Results indicate that stimulation of VR-1 with high concentrations of AEA excites central terminals of capsaicin-sensitiv e DRG neurons, thus causing neuropeptide release in the dorsal spinal cord. This novel activity opposes the CB receptor-mediated inhibitory action of low concentrations AEA. However, only if large amounts of endogenous AEA co uld be produced at the level of the dorsal spinal cord, they may not inhibi t, but rather activate, nociceptive sensory neurons.