Salvinorin A inhibits colonic transit and neurogenic ion transport in mice by activating κ-opioid and cannabinoid receptors

Abstract  The major active ingredient of the plant Salvia divinorum , salvinorin A (SA) has been used to treat gastrointestinal (GI) symptoms. As the action of SA on the regulation of colonic function is unknown, our aim was to examine the effects of SA on mouse colonic motility and secretion in vitro and in vivo . The effects of SA on GI motility were studied using isolated preparations of colon, which were compared with preparations from stomach and ileum. Colonic epithelial ion transport was evaluated using Ussing chambers. Additionally, we studied GI motility in vivo by measuring colonic propulsion, gastric emptying, and upper GI transit. Salvinorin A inhibited contractions of the mouse colon, stomach, and ileum in vitro , prolonged colonic propulsion and slowed upper GI transit in vivo . Salvinorin A had no effect on gastric emptying in vivo . Salvinorin A reduced veratridine-, but not forskolin-induced epithelial ion transport. The effects of SA on colonic motility in vitro were mediated by κ-opioid receptors (KORs) and cannabinoid (CB) receptors, as they were inhibited by the antagonists nor-binaltorphimine (KOR), AM 251 (CB₁ receptor) and AM 630 (CB₂ receptor). However, in the colon in vivo , the effects were largely mediated by KORs. The effects of SA on veratridine-mediated epithelial ion transport were inhibited by nor-binaltorphimine and AM 630. Salvinorin A slows colonic motility in vitro and in vivo and influences neurogenic ion transport. Due to its specific regional action, SA or its derivatives may be useful drugs in the treatment of lower GI disorders associated with increased GI transit and diarrhoea.     

TRPV1 in colitis: is it a good or a bad receptor? – a viewpoint

The role of the transient receptor potential vanilloid-1 (TRPV1) has been repeatedly investigated in animal models of inflammation. The present issue of Neurogastroenterology and Motility includes another report on this issue and, not unexpectedly, many questions on the precise role of TRPV1 receptors in inflammation remain unanswered. This Editorial Viewpoint discusses the present knowledge on TRPV1 receptor involvement in intestinal inflammation and discusses the question whether the TRPV1 has to be regarded as the good or the bad receptor in this context. Since TRPV1 activation turns out being a valuable approach, translation of this knowledge to human disease is highly recommended.     

The role of the endocannabinoid system in the pathophysiology and treatment of irritable bowel syndrome

Abstract  Irritable bowel syndrome (IBS) is a spectrum of disorders characterized by abdominal discomfort and pain, associated with altered bowel habits. Though gut motility, secretion and sensation may be altered in patients with IBS, the pathophysiology of this condition remains to be fully understood. The endocannabinoid system is involved in the regulation of numerous gastrointestinal functions including motility, sensation and secretion under both physiological and pathophysiological conditions. Activation of cannabinoid (CB)₁ and CB₂ receptors under various circumstances reduces motility, limits secretion and decreases hypersensitivity in the gut. Drugs that alter the levels of endocannabinoids in the gut also reduce motility and attenuate inflammation. In this review, we discuss the role of the endocannabinoid system in gastrointestinal physiology. We go on to consider the involvement of the endocannabinoid system in the context of symptoms associated with IBS and a possible role of this system in the pathophysiology and treatment of IBS.     

A novel herbal preparation desensitizes mesenteric afferents to bradykinin in the rat small intestine

Abstract Herbal preparations are evolving as promising agents for the treatment of functional gastrointestinal disorders which are considered to be secondary to visceral hypersensitivity. We aimed to determine whether a new combination of six herbal extracts reduces the sensitivity of intestinal afferents in rat. Male Wistar rats (250–350 g, n = 6 per group) were gavaged with either vehicle or 2.5, 5 or 10 mL kg^?1 of STW 5‐II, a herbal preparation which contains six extracts. Two hours later, animals were anaesthetized and extracellular multi‐unit mesenteric afferent nerve recordings were obtained in the proximal jejunum in vivo. Afferent discharge to 5‐hydroxy‐tryptamine (5‐HT) (5, 10, 20 and 40 μg kg^?1, i.v.), luminal distension (0–60 mmHg) and bradykinin (BK) (15, 30 and 60 μg kg^?1, i.v.) was recorded. At baseline, spontaneous afferent discharge was not different following pretreatment with the various doses of STW 5‐II compared with vehicle. The pressure‐dependent increase in afferent discharge to intraluminal ramp distension and the dose‐dependent increase in afferent firing following 5‐HT were also uninfluenced by STW 5‐II pretreatment. In contrast, the afferent nerve responses to 15, 30 and 60 μg kg^?1 of BK were reduced following 10 mL kg^?1 STW 5‐II with peaks at 106 ± 19, 153 ± 22 and 156 ± 25 imp s^?1 compared with 160 ± 15, 228 ± 14 and 220 ± 16 imp s^?1 following vehicle pretreatment (mean ± SEM, P < 0.05). Intestinal afferent sensitivity to BK which plays a prime role in nociception was reduced following STW 5‐II. Thus, STW 5‐II may be of therapeutic use for conditions that involve neuronal hypersensitivity and the release of BK in the intestine.     

Cannabinoid type 1 receptor modulates intestinal propulsion by an attenuation of intestinal motor responses within the myenteric part of the peristaltic reflex

Cannabinoid-1 (CB1) receptor activation affects gastrointestinal propulsion in vivo. It was our aim to further characterize the involved myenteric mechanisms in vivo and in vitro. In CB1(-/-) mice and wild-type littermates we performed in vivo transit experiments by charcoal feeding and in vitro electrophysiological recordings in mouse small intestinal smooth muscle. Ascending neuronal contraction (ANC) following electrical field stimulation was studied in rat ileum in a partitioned organ bath separating the aboral stimulation site from the oral recording site. The knockout animals displayed an accelerated upper gastrointestinal transit compared to control animals. The CB1 receptor antagonist AM251 stimulated the force of the ANC in a concentration dependent manner when added in the oral chamber. Anandamide significantly inhibited the ANC when added in the oral chamber. Neither AM251 nor anandamide had an influence on the contraction latency. No effects were observed when drugs were added in the aboral chamber, proving a CB1 mediated action on the neuromuscular junction. Resting membrane potentials and neuronal induced inhibitory junction potentials in CB1(-/-) mice were unchanged as compared to wild type. However, the electrophysiological slow waves were more sensitive to blockade of Ca(2+) channels in CB1(-/-) mice. Our data strongly suggest a physiological involvement of the CB-1 receptor in the regulation of small intestinal motility. Therefore, CB1 receptors are a promising target for the treatment of motility disorders.