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 kappa-opioid receptors (KORs) and cannabinoid (CB) receptors, as they were inhibited by the antagonists nor-binaltorphimine (KOR), AM 251 (CB(1) receptor) and AM 630 (CB(2) 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.

Novel Orally Available Salvinorin A Analog PR-38 Inhibits Gastrointestinal Motility and Reduces Abdominal Pain in Mouse Models Mimicking Irritable Bowel Syndrome

“…Among others, our group demonstrated in vitro that SA inhibited electrically evoked twitch contractions of mouse stomach, ileum, and colon in a concentration-dependent manner (Fichna et al, 2009a). In all tissues studied, the effect of SA was blocked by the universal opioid antagonist naloxone and a selective k-opioid receptor (KOR) antagonist, nor-binaltorphimine (nor-BNI), which was in good agreement with classic binding assays (Capasso et al, 2006).…”

“…Additionally, in the ileum and the colon, the inhibitory effect of SA was blocked by selective antagonists of cannabinoid type 1 (CB1) [N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide, AM 251] and cannabinoid type 2 (CB2) [6-iodo-2-methyl-1-[2-(4-morpholinyl)ethyl]-1H-indol-3-yl](4-methoxyphenyl)methanone (AM 630)] receptors. In the in vivo studies, it has been shown that SA slowed upper intestinal transit, as indicated by a lower geometric center (GC) of the upper GI tract (Fichna et al, 2009a) and colonic motility (Fichna et al, 2009a), and inhibited GI motility in croton oil-induced intestinal inflammation in mice (Capasso et al, 2008). Moreover, Guida et al (2012) have shown that SA reduces mechanical allodynia induced by peripheral formalin injection in mice.…”

“…Extracts from S. divinorum have been used for centuries by the Mazatec Indians for rituals and for alleviating symptoms of gastrointestinal (GI) disorders, such as abdominal pain and diarrhea (Fichna et al, 2009a). However, potential clinical application of S. divinorum derived natural compounds is strongly limited due to possible adverse effects in the central nervous system (CNS).…”

“…Opioid receptors, in particular m-opioid receptor (MOR) and KOR, and their ligands mediate several biologic functions and are attractive molecular targets in the development of therapeutics. In the CNS, opioid agonists regulate, among others, pain perception and antinociception, mood, cognitive function, and locomotor activity (Fichna et al, 2009a;Sobczak et al, 2014). In the periphery, opioid receptor agonists inhibit intestinal propulsive contractions and GI motility, mainly by decreasing pyloric tone and increasing absorption of fluids and electrolytes into the gut lumen, which results in their antidiarrheal and constipating effect (Fichna et al, 2009a;Sobczak et al, 2014).…”

“…In the CNS, opioid agonists regulate, among others, pain perception and antinociception, mood, cognitive function, and locomotor activity (Fichna et al, 2009a;Sobczak et al, 2014). In the periphery, opioid receptor agonists inhibit intestinal propulsive contractions and GI motility, mainly by decreasing pyloric tone and increasing absorption of fluids and electrolytes into the gut lumen, which results in their antidiarrheal and constipating effect (Fichna et al, 2009a;Sobczak et al, 2014). Recently, broader attention has been given to KORs and their ligands, which may become a target in the treatment of GI disorders, such as postoperative ileus, irritable bowel syndrome (IBS), and intestinal inflammation (Fichna et al, 2009a).…”