Salvinorin A has antiinflammatory and antinociceptive effects in experimental models of colitis in mice mediated by KOR and CB1 receptors*

Fichna, Jakub; Dicay, Michael; Lewellyn, Kevin; Janecka, Anna; Zjawiony, Jordan K.; MacNaughton, Wallace K.; Storr, Martin

doi:10.1002/ibd.21873

Cited by 63 publications

(69 citation statements)

References 36 publications

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“…Originally, SA was identified as a potent KOR agonist, but recently it has also been shown to possess, unusual for plantderived opioids, the ability to activate CB receptors in in vitro and in vivo assays (Roth et al, 2002;Capasso et al, 2008;Fichna et al, 2009aFichna et al, , 2012Aviello et al, 2011). Here, we observed that the inhibitory effect of PR-38 on twitch contractions in mouse colon in vitro and on the GI motility in vivo was blocked by MOR and KOR antagonists.…”

Section: Discussionmentioning

confidence: 67%

“…This suggests that, among all the receptors targeted by PR-38, MOR is mostly responsible for its analgesic activity in abdominal pain models, and implicates the lack of the synergistic effect Novel Salvinorin A Analog PR-38 in IBS upon activation of opioid and CB receptors for the induction of analgesia. We have shown previously that the analgesic effect produced by SA in the same pain model was mediated by KOR and CB1 (Fichna et al, 2012). Our observations demonstrate that the modification of the SA molecule, which resulted in the increased affinity for MOR, changed the mechanism of the action of the compound and shifted the equilibrium toward MOR in production of the analgesic effect, which is crucial for further structure-activity relationship studies.…”

Section: Discussionmentioning

confidence: 79%

“…Moreover, Guida et al (2012) have shown that SA reduces mechanical allodynia induced by peripheral formalin injection in mice. It is noteworthy that SA also produced a potent antinociceptive effect in a mouse model of abdominal pain induced by mustard oil (MO) (Fichna et al, 2012). 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.…”

Section: Introductionmentioning

confidence: 99%

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

Sałaga

Polepally

Sobczak

et al. 2014

J Pharmacol Exp Ther

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The opioid and cannabinoid systems play a crucial role in multiple physiological processes in the central nervous system and in the periphery. Selective opioid as well as cannabinoid (CB) receptor agonists exert a potent inhibitory action on gastrointestinal (GI) motility and pain. In this study, we examined (in vitro and in vivo) whether PR-38 (2-O-cinnamoylsalvinorin B), a novel analog of salvinorin A, can interact with both systems and demonstrate therapeutic effects. We used mouse models of hypermotility, diarrhea, and abdominal pain. We also assessed the influence of PR-38 on the central nervous system by measurement of motoric parameters and exploratory behaviors in mice. Subsequently, we investigated the pharmacokinetics of PR-38 in mouse blood samples after intraperitoneal and oral administration. PR-38 significantly inhibited mouse colonic motility in vitro and in vivo. Administration of PR-38 significantly prolonged the whole GI transit time, and this effect was mediated by m-and k-opioid receptors and the CB1 receptor. PR-38 reversed hypermotility and reduced pain in mouse models mimicking functional GI disorders. These data expand our understanding of the interactions between opioid and cannabinoid systems and their functions in the GI tract. We also provide a novel framework for the development of future potential treatments of functional GI disorders.

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Section: Discussionmentioning

confidence: 67%

Section: Discussionmentioning

confidence: 79%

Section: Introductionmentioning

confidence: 99%

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

Sałaga

Polepally

Sobczak

et al. 2014

J Pharmacol Exp Ther

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“…The TNBS-induced mouse model of colitis is a wellestablished acute animal model of CD, as described earlier (Fichna et al, 2012a). On day 0, mice (5-8 per treatment group) were lightly anesthetized using 1% isoflurane (Aerrane; Baxter Healthcare Corp., Deerfield, IL), and TNBS (4 mg in 0.1 ml of 30% EtOH in 0.9% NaCl) was administered into the distal colon using a catheter (silicone pusher).…”

Section: Methodsmentioning

confidence: 99%

Anti-Inflammatory and Antinociceptive Action of an Orally Available Nociceptin Receptor Agonist SCH 221510 in a Mouse Model of Inflammatory Bowel Diseases

Sobczak

Mokrowiecka

Cygankiewicz

et al. 2013

J Pharmacol Exp Ther

Self Cite

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The nociceptin receptors (NOPs) are expressed in the gastrointestinal (GI) tract on muscle cell membranes and neurons, as well as the immune cells that infiltrate the mucosa. The involvement of NOPs in the pathophysiology of GI inflammation has been suggested, but due to the lack of selective NOP agonists, it never fully elucidated. Our aim was to characterize the anti-inflammatory and antinociceptive effect of the NOP agonist, SCH 221510 [3-endo-8-[bis(2-methylphenyl)methyl]-3-phenyl-8-azabicyclo [3.2.1]octan-3-ol], as a potential therapeutic strategy in the treatment of inflammatory bowel diseases (IBD). The anti-inflammatory action of SCH 221510 was determined after intraperitoneal, oral, and intracolonic administration of SCH 221510 (0.1-3.0 mg/kg once or twice daily) in mice treated with 2,4,6-trinitrobenzenesulfonic acid (TNBS). Antinociceptive action of SCH 221510 was evaluated in the mouse model of mustard oil (MO)-induced abdominal pain. Relative NOP mRNA expression was assessed in patients with IBD using real-time reverse transcriptase-polymerase chain reaction. We found that the expression of NOP mRNA was significantly decreased in patients with IBD. The administration (0.1 and 1.0 mg/kg i.p. twice daily and 3 mg/kg p.o. twice daily) of SCH 221510 attenuated TNBS colitis in mice. This effect was blocked by a selective NOP antagonist [J-113397 [(6. The intracolonic injections of SCH 221510 did not improve colitis in mice. The antinociceptive effect of SCH 221510 was observed after oral administration of SCH 221510 in MO-induced pain tests in mice with acute colitis. In conclusion, our results show a potent anti-inflammatory and antinociceptive effect upon selective activation of NOP receptors and suggest that the NOP agonist SCH 221510 is a promising drug candidate for future treatment of IBD.

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“…TNBS (Sigma-Aldrich; Merck KGaA, Darmstadt, Germany) was applied to induce colitis, as previously described (12,21,22). In brief, mice were fasted for 16 h, and anesthetized with 1% isoflurane.…”

Section: Animalsmentioning

confidence: 99%

Elevation of arachidonoylethanolamide levels by activation of the endocannabinoid system protects against colitis and ameliorates remote organ lesions in mice

et al. 2017

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Abstract. The endocannabinoid system (ECS) is a potential pharmaceutical target for the treatment of inflammatory bowel diseases (IBDs). The aim of this study was to explore the effects of activation of the ECS on IBD and the associated neural inflammation-induced disruption of the blood-brain barrier (BBB). In a mouse model of trinitrobenzene sulfonic acid-induced colitis, the inhibition of fatty acid amide hydrolase with URB597 elevated the arachidonoylethanolamide concentration of the colon. Macroscopic alterations of the colons were evaluated, and the 7-day survival rate of mice was analyzed. BBB integrity was assessed using a dye tracer method, and the cognitive function of mice was examined using a fear-conditioning test. URB597 treatment significantly reduced macroscopic alterations of the colon, decreased the mortality rate, and protected the integrity of the BBB in the mice (P<0.05). No significant changes were observed in the cognitive functions of the mice (P>0.05); therefore, the neuroprotective effect of ECS in this colitis model requires further investigation. Activation of the ECS was efficient in ameliorating colitis and increasing the survival rate of the mice, and reducing remote organ changes induced by colitis. The results suggest that modulation of the ECS is a potential therapeutic approach for IBDs and the associated remote organ lesions.

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Salvinorin A has antiinflammatory and antinociceptive effects in experimental models of colitis in mice mediated by KOR and CB1 receptors*

Abstract: Our results suggest that the drugs based on the structure of SA have the potential to become valuable antiinflammatory or analgesic therapeutics for the treatment of GI diseases.

Cited by 63 publications

References 36 publications

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

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

Anti-Inflammatory and Antinociceptive Action of an Orally Available Nociceptin Receptor Agonist SCH 221510 in a Mouse Model of Inflammatory Bowel Diseases

Elevation of arachidonoylethanolamide levels by activation of the endocannabinoid system protects against colitis and ameliorates remote organ lesions in mice

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