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 Ca 2ϩ in rat dorsal root ganglion (DRG) neurons in culture was also studied. AEA (0.1-10 M) increased the outflow of CGRP-LI and SP-LI from slices of the rat dorsal spinal cord in a Ca 2ϩ -dependent manner and increased [Ca 2ϩ ] 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 Ca 2ϩ 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.

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Our previous studies show that chronic administration of L-arginine decreases cyclosporin-A-induced bone loss. The present study was designed to investigate whether a soy diet could prevent cyclosporin A-induced osteopenia and eventually improve the protective effect of L-arginine. Rats on soy diet were treated with cyclosporin-A, L-arginine, cyclosporin-AπL-arginine or saline. Control groups received a normal diet and the same pharmacological treatment. Our results show that a soy diet prevents osteopenia only in the spinal cord (π30%) and confirm the protective effect of Larginine in cyclosporin-A-induced osteopenia in whole body, pelvis and spine of rats on a normal diet (π31%, π55%, π55%, respectively). Moreover these data show that the osteoprotective effect of L-arginine in the whole body, pelvis and spine improves in the case of soy diet (π60%, π72%, π89%, respectively). The results suggest that a soy diet exerts a positive effect in cyclosporin-A-induced osteopenia only in sites with high turn-over and improves the osteoprotective effect of L-arginine.