Respiratory actions of vanilloid receptor agonists in the nucleus of the solitary tract: comparison of resiniferatoxin with non-pungent agents and anandamide
Geraghty, DP and Mazzone, SB, Respiratory actions of vanilloid receptor agonists in the nucleus of the solitary tract: comparison of resiniferatoxin with non-pungent agents and anandamide, British Journal of Pharmacology, 137, (6) pp. 919-927. ISSN 0007-1188 (2002) [Refereed Article]
1 Activation of vanilloid receptors on sensory nerve terminals in the commissural nucleus of the solitary tract (cNTS) of rats with capsaicin, produces respiratory slowing. In this study, we used microinjection techniques employing pungent and non-pungent vanilloids to further characterize vanilloid receptors in the cNTS. 2 Microinjection of the pungent vanilloid, resiniferatoxin (RTX), into the cNTS of urethane-anaesthetized rats, dose-dependently reduced respiratory rate without affecting tidal volume. RTX was 20 fold more potent at slowing respiration (∼ED 50, 100 pmol) than capsaicin (∼ED 50, 2 nmol). Doses of RTX greater than 100 pmol caused either irregular (dyspnoeic) breathing or terminal apnoea (>250 pmol). The respiratory slowing response to RTX (75 pmol), was dose-dependently attenuated by injecting RTX (but not vehicle) into the same site 60 min earlier. 3 The non-pungent phorbol derivative of RTX, phorbol 12-phenylacetete 13-acetate 20-homovanillate (PPAHV, 0.1-1 nmol), also slowed respiration (ED 50, ∼1 nmol) and almost abolished response to RTX (75 pmol) injected into the same site 60 min later. 4 In contrast to RTX, PPAHV and capsaicin, the putative endogenous vanilloid receptor agonist, arachidonyl ethanolamide (AEA), and non-pungent capsaicin derivative, olvanil, had no direct effect on respiration. However, both AEA and olvanil dose-dependently reduced the respiratory response to injection of RTX (75 pmol) 60 min later into the same site (EC 50s, for AEA and olvanil, ∼2 and 0.2 nmol, respectively). 5 These studies suggest that both pungent and non-pungent vanilloids interact with vanilloid receptors in the cNTS. However, whereas RTX and PPAHV activate and subsequently desensitize vanilloid receptors on sensory nerve terminals in the cNTS, olvanil and AEA fail to activate despite readily desensitizing responses to RTX in this region.