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NEUROREGULATION AND MOTILITY

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

¹Mucosal Inflammation, ²Gastrointestinal, and ³Neuroscience Research Groups, Department of Physiology and Biophysics, University of Calgary, Calgary, Alberta, T2N 4N1, Canada; and ⁴Departments of Anesthesiology and Physiology and Biophysics, University of Washington, Seattle, Washington 98195

Submitted 17 November 2003 ; accepted in final form 15 December 2003

We investigated the distribution and function of cannabinoid (CB)₁ receptors in the submucosal plexus of the guinea pig ileum. CB₁ 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 ± 12 and 30 ± 14%, respectively, by the CB₁ receptor agonist WIN 55,212–2. This inhibitory effect was blocked by the CB₁ 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

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