Cannabinoid1 receptor in the dorsal vagal complex modulates lower oesophageal sphincter relaxation in ferrets

Delta9-tetrahydrocannabinol (delta9-THC) is an effective anti-emetic; however, other potential gastrointestinal therapeutic effects of delta9-THC are less well-known. Here, we report a role of delta9-THC in a vago-vagal reflex that can result in gastro-oesophageal reflux, that is, gastric distension-evoked lower oesophageal sphincter (LOS) relaxation. Oesophageal, LOS and gastric pressures were measured using a miniaturized, manometric assembly in decerebrate, unanaesthetized ferrets.Gastric distension (30 ml) evoked LOS relaxation (70 +/- 8% decrease from baseline). Delta9-THC administered systemically (0.2 mg kg-1, iv.) or directly to the dorsal hindbrain surface (0.002 mg),significantly attenuated the nadir of the gastric distention-evoked LOS relaxation, and time to reach maximal response. Similar increases to maximal effect were observed after treatment with the cannabinoid receptor agonist WIN 55,212-2 (0.2 mg kg-1 iv.). The effect of systemic delta9-THC on gastric distention-evoked LOS relaxation was reversed by a selective cannabinoid1 (CBI) receptor antagonist, SR141617A (1 mg kg-1 i.v.). Since this reflex is vagally mediated, we used a CB1 receptor antiserum and immunocytochemistry to determine its distribution in ferret vagal circuitry. CBI receptor staining was present in cell bodies within the area postrema, nucleus tractus solitarius (NTS) and nodose ganglion. Intense terminal-like staining was noted within the NTS and dorsal motor vagal nucleus (DMN). Neither nodose ganglionectomy nor vagotomy altered the CB1 receptor terminal-like staining in the dorsal vagal complex. Retrogradely labelled gastric- or LOS-projecting DMN neurones did not express CBI receptors within their soma. Therefore, CBI receptor staining in the NTS and DMN is not due to primary vagal afferents or preganglionic neurones. These novel findings suggest that delta9-THC can modulate reflex LOS function and that the most likely site of action is via the CBI receptor within the NTS. This effect of delta9-THC may have implications in treatment of gastro-oesophageal reflux and other upper gut disorders.