Objective: This study tests the hypothesis that the transient receptor potential vanilloid subtype 1 channel induced neuropeptide secretion and depressor response are mediated by, at least in part, activation of endoplasmic reticulum associated Ca release receptors, leading to increased cytosolic Ca in dorsal root ganglion neurons.
Methods/results: Bolus injection of capsaicin (10 or 50 microg/kg), a selective transient receptor potential vanilloid subtype 1 channel agonist, into anesthetized male Wistar rats caused a dose-dependent decrease in mean arterial pressure (P < 0.05). Capsaicin (50 microg/kg)-induced depressor effects and increase in plasma calcitonin gene related peptide (CGRP) levels (-29 +/- 2 mmHg, 82.2 +/- 5.0 pg/ml) were abolished by a selective transient receptor potential vanilloid subtype 1 channel antagonist, capsazepine (3 mg/kg, -4 +/- 1 mmHg, 41.8 +/- 4.4 pg/ml, P < 0.01), and attenuated by a selective ryanodine receptor antagonist, dantrolene (5 mg/kg, -12 +/- 1 mmHg, 57.2 +/- 2.6 pg/ml, P < 0.01), but unaffected by an inhibitor of endoplasmic reticulum Ca-ATPase, thapsigargin (50 microg/kg, -30 +/- 1 mmHg, 73.8 +/- 2.3 pg/ml, P > 0.05), or an antagonist of the inositol (1,4,5)-trisphosphate receptor, 2-aminoethoxydiphenyl borate (3 mg/kg, -34 +/- 5 mmHg, 69.0 +/- 3.7 pg/ml, P > 0.05). CGRP8-37 (1 mg/kg), a selective CGRP receptor antagonist, also blocked capsaicin-induced depressor effects. In contrast, dantrolene had no effect on CGRP (1 microg/kg)-induced depressor effects. In vitro, capsaicin (0.3 micromol/l) increased intracellular Ca concentrations and CGRP release from freshly isolated sensory neurons in dorsal root ganglion (P < 0.01), which were blocked by capsazepine (10 micromol/l) and attenuated by dantrolene but not thapsigargin or 2-aminoethoxydiphenyl borate.
Conclusion: Our results indicate that transient receptor potential vanilloid subtype 1 channel activation triggers ryanodine receptor but not inositol (1,4,5)-trisphosphate receptor dependent Ca release from endoplasmic reticulum in dorsal root ganglion neurons, leading to increased CGRP release and consequent depressor effects.