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

Abstract

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.

FABP4 blocker attenuates colonic hypomotility and modulates white adipose tissue‐derived hormone levels in mouse models mimicking constipation‐predominant IBS

“…The behavioral responses to pain were determined as described previously. 23 In brief, BMS309403 or vehicle was administered acutely or chronically (for 13 consecutive days) 15 min before MO infusion. To avoid stimulation of somatic nociceptors, the perianal area was covered with vaseline.…”

Salvinorin A analogues PR‐37 and PR‐38 attenuate compound 48/80‐induced itch responses in mice

“…Locomotor activity was assessed as described previously by Salaga et al . (). Briefly, measurement was made automatically in a Digiscan actimeter (Omnitech Electronics Inc., Columbus, OH, USA).…”

“…The antagonists were used at the following doses: naltrindole (NLTR, 10 mg·kg −1 ), N‐(piperidin‐1‐yl)‐5‐(4‐iodophenyl)‐1‐(2,4‐dichlorophenyl)‐4‐methyl‐1H‐pyrazole‐3‐carboxamide (AM 251, 1 mg·kg −1 ), β‐funaltrexamine (β‐FNA, 1 mg·kg −1 ), norBNI (10 mg·kg −1 ) and NLX (1 mg·kg −1 ). Doses were selected based on the preliminary studies and published data (Chen et al ., ; Salaga et al ., 2014a,b; Taylor et al ., ). In experiments with oral administration, PR‐37 and PR‐38 were gavaged orally (p.o.)…”

“…In the in vitro studies, these two analogs displayed high affinity at KOR with K i values of 2.0 ± 0.9 and 9.6 ± 2.0 nM for PR‐37 and PR‐38, respectively (Polepally et al ., 2013; 2014), and potently inhibited adenylate cyclase in live HEK293 cells with EC 50 values of 137 ± 15 and 7 ± 1 nM respectively (Polepally et al ., 2013; 2014). Of note, recently we showed that PR‐38 has neither hallucinogenic nor anxiolytic or anxiogenic effects in mice (Salaga et al ., ). Here we performed similar behavioural tests to exclude the potential CNS‐related effects of PR‐37.…”

Why Do Plants Contain Biologically Active Compounds?

“…These compounds may serve as good leads for further development of non-hallucinogenic and non-addictive analgesic agents. As an example, preliminary in vivo and preclinical studies with 2-O-cinnamoylsalvinorin B (30) obtained in my laboratory show potential as a new agent for the treatment of irritable bowel syndrome (Fichna et al 2014;Salaga et al 2014). …”