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The Journal of Neuroscience, February 15, 2001, 21(4):1104-1109

Anandamide Excites Central Terminals of Dorsal Root Ganglion Neurons via Vanilloid Receptor-1 Activation

Michele Tognetto^{1, 3}, Silvia Amadesi¹, Selena Harrison¹, Christophe Creminon², Marcello Trevisani¹, Mirko Carreras¹, Mario Matera³, Pierangelo Geppetti¹, and Alfredo Bianchi³

¹ Headache Center, Departments of Experimental and Clinical Medicine and Neuroscience, University of Ferrara and Sant'Anna Hospital, 44100 Ferrara, Italy ² Le Commissariat à l'Énergie Atomique (CEA), Service de Pharmacologie et d'Immunologie, Département de Recherche Médicale, CEA-Saclay, 91191 Gif sur Yvette, France, and ³ Department of Pharmacology, University of Catania, 95123 Catania, Italy

Recently, the cannabinoid (CB) receptor agonist anandamide (AEA) has been shown to excite perivascular terminals of primary sensory neurons via activation of the vanilloid receptor-1 (VR-1). To determine whether AEA stimulates central terminals of these neurons, via VR-1 activation, we studied the release of calcitonin gene-related peptide (CGRP)- and substance P (SP)-like immunoreactivities (LI) from slices of rat dorsal spinal cord. Mobilization of Ca²⁺ in rat dorsal root ganglion (DRG) neurons in culture was also studied. AEA (0.1-10 µM) increased the outflow of CGRP-LI and SP-LI from slices 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 were abolished by capsaicin pretreatment and by the VR-1 antagonist capsazepine but not affected by the CB receptor antagonists AM281 or AM630. Both neuropeptide release and Ca²⁺ mobilization induced by electrical field stimulation (EFS) were inhibited by a low concentration of AEA (10 nM). Inhibition 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-sensitive 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 could be produced at the level of the dorsal spinal cord, they may not inhibit, but rather activate, nociceptive sensory neurons.

Key words: anandamide (AEA); calcium; calcitonin gene-related peptide (CGRP); capsaicin; sensory neurons; substance P; vanilloid receptor-1 (VR-1)

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Copyright © 2001 Society for Neuroscience  0270-6474/01/2141104-06$05.00/0

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