Lack of evidence for functional TRPV1 vanilloid receptors in rat hippocampal nerve terminals

Although TRPV1 vanilloid receptors (TRPV1Rs) have been assumed to be present in the brain, their role is not well-defined. Here, we tested the widely used TRPV1R agonists (E)-capsaicin (0.1–100 μM) and resiniferatoxin (RTX, 0.1 μM) on resting and K+-evoked Ca2+ entry and radiolabelled GABA release in rat hippocampal nerve terminals. (E)-capsaicin and RTX failed to evoke Ca2+ transients or to trigger [3H]GABA outflow. Both (E)-capsaicin (EC50, 40.4 μM) and its enantiomer (Z)-capsaicin (EC50, 22.9 μM), which is inactive at the TRPV1R, inhibited the K+-evoked Ca2+ entry, and to similar extent, the Ca2+-dependent K+-evoked [3H]GABA release. The TRPV1R enhancer/partial agonist 2-aminoethoxydiphenyl borate (1–300 μM) induced rapid Ca2+ entry. None of the above-mentioned findings proved to be sensitive to the TRPV1R antagonists iodoresiniferatoxin (I-RTX; 3 μM) and SB366791 (3 μM). The CB1 cannabinoid receptor antagonist AM251 (EC50, 1.1 μM) and I-RTX (EC50, 4.6 μM) also diminished the K+-evoked Ca2+ entry per se. We observed competitive antagonism between I-RTX and AM251, indicating that the two molecules may act at the same site. In conclusion, there is a need to examine the discrepancy between ex vivo and in vitro data to understand the neurochemical and physiological functions of brain TRPV1Rs.