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

Delta9-tetrahydrocannabinol (Δ9-THC) is an effective anti-emetic; however, other potential gastrointestinal therapeutic effects of Δ9-THC are less well-known. Here, we report a role of Δ9-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). Δ9-THC administered systemically (0.2 mg kg−1, I.V.) 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, I.V.). The effect of systemic Δ9-THC on gastric distention-evoked LOS relaxation was reversed by a selective cannabinoid1 (CB1) 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. CB1 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 CB1 receptors within their soma. Therefore, CB1 receptor staining in the NTS and DMN is not due to primary vagal afferents or preganglionic neurones. These novel findings suggest that Δ9-THC can modulate reflex LOS function and that the most likely site of action is via the CB1 receptor within the NTS. This effect of Δ9-THC may have implications in treatment of gastro-oesophageal reflux and other upper gut disorders

Roles of gastro-oesophageal afferents in the mechanisms and symptoms of reflux disease

Oesophageal pain is one of the most common reasons for physician consultation and/or seeking medication. It is most often caused by acid reflux from the stomach, but can also result from contractions of the oesophageal muscle. Different forms of pain are evoked by oesophageal acid, including heartburn and non-cardiac chest pain, but the basic mechanisms and pathways by which these are generated remain to be elucidated. Both vagal and spinal afferent pathways are implicated by basic research. The sensitivity of afferent fibres within these pathways may become altered after acid-induced inflammation and damage, but the severity of symptoms in humans does not necessarily correlate with the degree of inflammation. Gastro-oesophageal reflux disease (GORD) is caused by transient relaxations of the lower oesophageal sphincter, which are triggered by activation of gastric vagal mechanoreceptors. Vagal afferents are therefore an emerging therapeutic target for GORD. Pain in the absence of excess acid reflux remains a major challenge for treatment.Amanda J. Page and L. Ashley Blacksha