Characterization of the anandamide induced depolarization of guinea‐pig isolated vagus nerve

There is considerable interest in elucidating potential endogenously derived agonists of the vanilloid receptor and the role of anandamide in this regard has received considerable attention. In the present study, we have used an electrophysiological technique to investigate the mechanism of activation of vanilloid receptors in an isolated vagal preparation. Both capsaicin and anandamide depolarized de‐sheathed whole vagal nerve preparations that was antagonized by the VR1 antagonist, capsazepine ( P <0.05) whilst this response was unaltered by the cannabinoid (CB1) selective antagonist SR141716A or the CB2 selective antagonist, SR144528, thereby ruling out a role for cannabinoid receptors in this response. The PKC activator, phorbol‐12‐myristate‐13‐acetate (PMA) augmented depolarization to both anandamide and capsaicin and this response was significantly inhibited with the PKC inhibitor, bisindolylmaleimide (BIM) ( P <0.05). The role of lipoxygenase products in the depolarization to anandamide was investigated in the presence of the lipoxygenase inhibitor, 5,8,11‐Eicosatriynoic acid (ETI). Depolarization to anandamide and arachidonic acid was significantly inhibited in the presence of ET1 ( P <0.05). However, in the absence of calcium depolarization to anandamide was not inhibited by ETI. Using confocal microscopy we have demonstrated the presence of vanilloid receptors on both neuropeptide containing nerves and nerves that did not stain for sensory neuropeptides. These results demonstrate that anandamide evokes depolarization of guinea‐pig vagus nerve, following activation of vanilloid receptors, a component of which involves the generation of lipoxygenase products. Furthermore, these receptors are distributed in both neuropeptide and non‐neuropeptide containing nerves.British Journal of Pharmacology (2002) 137 , 39–48. doi: 10.1038/sj.bjp.0704840