Sensitizing effects of lafutidine on CGRP‐containing afferent nerves in the rat stomach

Abstract

1 Capsaicin sensitive a erent nerves play an important role in gastric mucosal defensive mechanisms. Capsaicin stimulates a erent nerves and enhances the release of calcitonin gene-related peptide (CGRP), which seems to be the predominant neurotransmitter of spinal a erents in the rat stomach, exerting many pharmacological e ects by a direct mechanism or indirectly through second messengers such as nitric oxide (NO). 2 Lafutidine is a new type of anti-ulcer drug, possessing both an antisecretory e ect, exerted via histamine H 2 receptor blockade, and gastroprotective activities. Studies with certain antagonists or chemical dea erentation techniques suggest the gastroprotective actions of lafutidine to be mediated by capsaicin sensitive a erent nerves, but this is an assumption based on indirect techniques. In order to explain the direct relation of lafutidine to a erent nerves, we conducted the following studies.3 We determined CGRP and NO release from rat stomach and speci®c [ 3 H]-resiniferatoxin (RTX) binding to gastric vanilloid receptor subtype 1 (VR1), which binds capsaicin, using EIA, a microdialysis system and a radioreceptor assay, respectively. 4 Lafutidine enhanced both CGRP and NO release from the rat stomach induced by a submaximal dose of capsaicin, but had no e ect on speci®c [ 3 H]-RTX and capsaicin binding to VR1. 5 In conclusion, our ®ndings demonstrate that lafutidine modulates the activity of capsaicin sensitive a erent nerves in the rat stomach, which may be a key mechanism involved in its gastroprotective action.

In vitro production of capsaicin through plant tissue culture

“…In high concentration, capsaicinoids damage these nerves thereby damaging the gastrointestinal systems [54; 49]. However, in lower concentration, capsaicinoids increase the blood flow in the mucosal lining thereby increasing the secretion of mucus in the gastrointestinal tract and promoting defence activity against microbes [54].…”

Protective Effects of Gastric Mucus

“…The action of CGRP is in part mediated by endogenous NO. The gastroprotective action of lafutidine has been reduced or abolished by treatment with tetrodotoxin, CGRP 8-37 , or chemical defunctionalisation of afferent nerves (Mimaki et al, 2002;Onodera et al, 1999a), indicating that capsaicin-sensitive nerves contribute significantly to the mechanisms underlying the actions of lafutidine (Nishihara et al, 2002). Moreover, lafutidine has been shown to significantly increase CGRP release in both experimental animal models and humans (Harada & Okajima, 2007;Nishihara et al, 2002;Ikawa et al, 2006;Shimatani et al, 2006).…”

“…The gastroprotective action of lafutidine has been reduced or abolished by treatment with tetrodotoxin, CGRP 8-37 , or chemical defunctionalisation of afferent nerves (Mimaki et al, 2002;Onodera et al, 1999a), indicating that capsaicin-sensitive nerves contribute significantly to the mechanisms underlying the actions of lafutidine (Nishihara et al, 2002). Moreover, lafutidine has been shown to significantly increase CGRP release in both experimental animal models and humans (Harada & Okajima, 2007;Nishihara et al, 2002;Ikawa et al, 2006;Shimatani et al, 2006). Several reports indicate that the VR1 of capsaicinsensitive afferent nerves may not contribute the CGRP release by lafutidine, suggesting the existence of yet unidentified sites for lafutidine other than VR1 on these nerves (Fukushima et al, 2006;Nishihara et al, 2002).…”

“…Moreover, lafutidine has been shown to significantly increase CGRP release in both experimental animal models and humans (Harada & Okajima, 2007;Nishihara et al, 2002;Ikawa et al, 2006;Shimatani et al, 2006). Several reports indicate that the VR1 of capsaicinsensitive afferent nerves may not contribute the CGRP release by lafutidine, suggesting the existence of yet unidentified sites for lafutidine other than VR1 on these nerves (Fukushima et al, 2006;Nishihara et al, 2002). The gastroprotective effects of lafutidine are decreased by treatment with NO synthase inhibitors or NO antidotes (Nishihara et al, 2002;, indicating the involvement of NO generation in lafutidine function.…”

“…Several reports indicate that the VR1 of capsaicinsensitive afferent nerves may not contribute the CGRP release by lafutidine, suggesting the existence of yet unidentified sites for lafutidine other than VR1 on these nerves (Fukushima et al, 2006;Nishihara et al, 2002). The gastroprotective effects of lafutidine are decreased by treatment with NO synthase inhibitors or NO antidotes (Nishihara et al, 2002;, indicating the involvement of NO generation in lafutidine function. Similar results have been obtained with another second-generation H 2 -receptor antagonist, roxatidine (Ichikawa et al, 1997(Ichikawa et al, , 1999.…”