The stimulation of capsaicin-sensitive bronchopulmonary unmyelinated C-fibers is involved in elicitation of the cough reflex . Tachykinins, like substance P, which is contained in afferent C-fiber endings within the airway epithelium and smooth muscle layer, are released by the activation of afferent C-fibers. Bonham et al. reported that substance P stimulates rapidly adapting receptors in guinea pigs . This stimulation of rapidly adapting receptors by substance P is a potential link between the two airway defense systems, both of which elicit bronchoconstriction, mucus secretion and cough. Such a link, by which C-fiber-receptor stimulation leads to the release of substance P and the subsequent stimulation of rapidly adapting receptors with myelinated Aδ fibers, has been previously proposed to explain the overlap of stimuli and reflex effects of both afferent systems ; i.e., the activation of C-fibers by capsaicin causes the release of substance P and the subsequent stimulation of rapidly adapting receptors, which may enhance cough reflexes. In the present study, we demonstrated that pretreatment with fentanyl significantly increased the number of citric acid-induced coughs in mice and that this effect was antagonized by pretreatment with moguisteine, a rapidly adapting receptor antagonist. Furthermore, the fentanyl-induced enhancement of the number of citric acid-induced coughs was also observed in capsaicin-pretreated C-fiber desensitized mice. Based on these results, it is likely that fentanyl activates mainly rapidly adapting receptors, but not C-fibers, to enhance citric acid-induced coughs.
In the present study, we also demonstrated that fentanyl-induced enhancement of the number of citric acid-induced coughs was abolished by pretreatment with fexofenadine, a histamine H1 receptor antagonist. However, fexofenadine had no effect on the number of citric acid-induced coughs. Furthermore, in the present study, we also observed that fentanyl significantly increased the histamine levels in BALF. Previously, we demonstrated that pre-inhalation of histamine concentration-dependently and significantly increased the number of citric acid-induced coughs in guinea pigs, and this effect was antagonized by pretreatment with fexofenadine . These results suggest that histamine may enhance cough receptor sensitivity through the activation of histamine H1 receptors in the airways. We also observed that the histamine-induced increase in the number of citric acid-induced coughs was concentration-dependently reduced when animals were pretreated with TNP-ATP, P2X-type ionotropic purinergic receptor antagonist . Furthermore, we reported that the ATP-induced increase in the number of citric acid-induced coughs was concentration-dependently reduced when animals were pre-treated with TNP-ATP . We also demonstrated that the ATP-induced increase in the number of citric acid-induced coughs was not abolished in C-fiber-desensitized guinea pigs . On the other hand, inhaled ATP had no significant effect on the number of capsaicin-induced coughs in naive animals . These results suggested that ATP activates C-fiber-independent pathways, i.e., it directly activates rapidly adapting receptors, to enhance citric acid-induced coughs . Tamesue et al. reported that histamine induced the release of ATP from segments of vas deferens, and this effect was blocked by pyridamine and triprolidine, histamine H1 receptor antagonists, but not by ranitidine, an H2 receptor antagonist . Furthermore, histamine also increased the release of ATP from superfused cultured smooth muscle cells . The authors suggested that ATP might be released as an autacoid from smooth muscles in the presence of histamine . Taken together, these results suggest that although histamine, by itself, does not directly modulate the sensitivity of the cough reflex, it is likely to enhance the excitability of rapidly adapting receptors and/or cough receptors in response to tussive stimuli via the modulation of ATP release in the airways. Based on our previous and present results, it is possible that fentanyl enhances the release of histamine in bronchoalveolar tissue and this histamine first enhances the excitability of rapidly adapting receptors through the activation of histamine H1 receptors and then causes a cough reflex.
Narcotic analgesics can induce the release of histamine both in vitro and in vivo in animals as well as in human. However, plasma histamine levels after i.v. injection of fentanyl are much less than those after the injection of morphine [1, 2, 14]. Furthermore, incubation of human skin mast cells with fentanyl did not induce the release of histamine . However, in the present study, i.v. injection of fentanyl markedly increased the histamine levels in BALF. Although further studies are needed to determine the mechanisms that underlie these findings, it is possible that mast cell heterogeneity may play a role in the different effects of fentanyl on histamine release.
In conclusion, our present results suggest that fentanyl enhances the excitability of rapidly adapting receptors to cause cough. Furthermore, enhancement of histamine release in the airways might some how be related to fentanyl-induced enhancement of cough sensitivity. However, further studies are necessary before this possibility can be established with greater certainty.