Distribution and function of the cannabinoid-1 receptor in the modulation of ion transport in the guinea pig ileum: relationship to capsaicin-sensitive nerves

Abstract

Distribution and function of the cannabinoid-1 receptor in the modulation of ion transport in the guinea pig ileum: relationship to capsaicin-sensitive nerves. Am J Physiol Gastrointest Liver Physiol 286: G863-G871, 2004. First published December 30, 2003 10.1152/ ajpgi.00482.2003.-We investigated the distribution and function of cannabinoid (CB)1 receptors in the submucosal plexus of the guinea pig ileum. CB 1 receptors were found on both types of submucosal secretomotor neurons, colocalizing with VIP and neuropeptide Y (NPY), the noncholinergic and cholinergic secretomotor neurons, respectively. CB1 receptors colocalized with transient receptor potential vanilloid-1 receptors on paravascular nerves and fibers in the submucosal plexus. In the submucosal ganglia, these nerves were preferentially localized at the periphery of the ganglia. In denervated ileal segments, CB1 receptor immunoreactivity in submucosal neurons was not modified, but paravascular and intraganglionic fiber staining was absent. Short-circuit current (I sc) was measured as an indicator of net electrogenic ion transport in Ussing chambers. In the ion-transport studies, I sc responses to capsaicin, which activates extrinsic primary afferents, and to electrical field stimulation (EFS) were reduced by pretreatment with the muscarinic antagonist atropine, abolished by tetrodotoxin, but were unaffected by VIP receptor desensitization, hexamethonium, ␣-amino-3-hydroxy-5-methlisoxazole-4-proprionic acid, or N-methyl-D-aspartate glutamate receptor antagonists. The responses to capsaicin and EFS were reduced by 47 Ϯ 12 and 30 Ϯ 14%, respectively, by the CB1 receptor agonist WIN 55,212-2. This inhibitory effect was blocked by the CB 1 receptor antagonist, SR 141716A. I sc responses to forskolin or carbachol, which act directly on the epithelium, were not affected by WIN 55,212-2. The inhibitory effect of WIN 55,212-2 on EFS-evoked secretion was not observed in extrinsically denervated segments of ileum. Taken together, these data show cannabinoids act at CB1 receptors on extrinsic primary afferent nerves, inhibiting the release of transmitters that act on cholinergic secretomotor pathways. submucosal plexus; vasoactive intestinal peptide; neuropeptide Y; transient receptor potential vanilloid-1 receptor THE ENTERIC NERVOUS SYSTEM exerts tight control over electrolyte and water transport by the intestinal epithelium (5, 7). Specifically, submucosal secretomotor neurons release vasoactive intestinal polypeptide and acetylcholine to activate cAMP-or Ca 2ϩ -dependent pathways, respectively, which control the gating of chloride transport through apically situated chloride transporters in enterocytes. The apically directed transport of chloride occurs predominantly via the cystic fibrosis transmembrane conductance regulator or a member of the calciumdependent chloride channel family (4). Whereas the intrinsic properties of these transporters have been, and continue to be, the subject of numerous studies, less well documented are the inputs that control the a...

Anandamide-Evoked Activation of Vanilloid Receptor 1 Contributes to the Development of Bladder Hyperreflexia and Nociceptive Transmission to Spinal Dorsal Horn Neurons in Cystitis

“…This assumption is supported by previous data that a significant proportion of TRPV1-expressing primary sensory neurons express the CB1 receptor and that anandamide evokes both TRPV1-mediated excitation and CB1 receptor-mediated inhibition in those cells (Ahluwalia et al, 2000(Ahluwalia et al, , 2003b. The recent data of MacNaughton et al (2004) that TRPV1 and the CB1 receptor are coexpressed by paravascular nerves and nerve fibers in submucosal ganglia in the ileum also support this assumption.…”

“…The effect of the CB1 receptor antagonist SR1411716A on the exogenous anandamide-evoked increase of reflex activity in naive bladders Previous data show that TRPV1 and the CB1 receptor are coexpressed in some primary sensory neurons and visceral afferents (Ahluwalia et al, 2000(Ahluwalia et al, , 2003bMacNaughton et al, 2004). To find out whether in addition to TRPV1 activation, anandamide also activated the CB1 receptor in bladder afferents, the CB1 receptor antagonist SR141716A (50 M) was applied onto the bladders for 10 min after determining the basal bladder reflex activity.…”

“…The CB1 receptor and TRPV1 are coexpressed by a significant proportion of nociceptive primary sensory neurons, which innervate both somatic and visceral tissues (Guo et al, 1999;Ahluwalia et al, 2000;Avelino et al, 2002;MacNaughton et al, 2004). The excitatory target of anandamide, TRPV1, is a nonselective cationic channel, which is responsive to various physical and chemical activators such as heat greater than ϳ43°C and vanilloids, including capsaicin, the pungent agent of the chili pepper (Caterina et al, 1997).…”

Mediation of neurogenic ion transport by acetylcholine, prostanoids and 5-hydroxytryptamine in porcine ileum

“…-Supporting this conclusion, a previous study using a specific VIP receptor antagonist in the porcine small intestine indicated that electrically-evoked I sc elevations were not altered; however, this receptor antagonist did inhibited the secretory action of exogenous VIP (Hildebrand and Brown, 1990). In the guinea pig small intestine, I sc responses to electrical stimulation were not altered in tissues desensitized to VIP (MacNaughton et al, 2004), but were inhibited by anti-VIP antiserum in tissues pretreated with atropine to abolish cholinergic influences (Cooke et al, 1987). Tachyphylaxis to substance P was not associated with a significant change in electricallyevoked responses in the porcine ileum.…”

Epithelial effects of proteinase-activated receptors in the gastrointestinal tract

“…We have evidence that capsaicin-sensitive extrinsic sensory afferent neurons can, through local axon reflexes, stimulate chloride secretion in guinea pig ileum in vitro (Vanner & MacNaughton 1995). More recent evidence implicates an interaction of the cannabinoid CB 1 receptor and the capsaicin receptor, TRPV1 (MacNaughton et al 2004). It is interesting to speculate that PAR-2 could modulate an interaction among the CB 1 receptor and capsaicin-sensitive afferents in the regulation of intestinal epithelial secretory function.…”