Transient receptor potential vanilloid subtype 1 channel mediated neuropeptide secretion and depressor effects: role of endoplasmic reticulum associated Ca2+ release receptors in rat dorsal root ganglion neurons

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Abstract
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 Ca2+ release receptors, leading to increased cytosolic Ca2+ in dorsal root ganglion neurons. Bolus injection of capsaicin (10 or 50 μg/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 μg/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 Ca2+-ATPase, thapsigargin (50 μg/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 μg/kg)-induced depressor effects. In vitro, capsaicin (0.3 μmol/l) increased intracellular Ca2+ concentrations and CGRP release from freshly isolated sensory neurons in dorsal root ganglion (P < 0.01), which were blocked by capsazepine (10 μmol/l) and attenuated by dantrolene but not thapsigargin or 2-aminoethoxydiphenyl borate. Our results indicate that transient receptor potential vanilloid subtype 1 channel activation triggers ryanodine receptor but not inositol (1,4,5)-trisphosphate receptor dependent Ca2+ release from endoplasmic reticulum in dorsal root ganglion neurons, leading to increased CGRP release and consequent depressor effects.