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

Abstract

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.

Central N/OFQ-NOP Receptor System in Pain Modulation

“…Systemic GRT-TA2210 and Ro65-6570 attenuated CFA-induced inflammatory pain in rats without disrupting locomotor activity (Linz et al, 2013; Schiene et al, 2013). Moreover, a non-peptidic NOP receptor agonist, SCH 221510 (Varty et al, 2008), produced antihypersensitive effects on trinitrobenzene sulfonic acid-induced inflammatory pain (Sobczak et al, 2014; Sobczak, Salaga, Storr, & Fichna, 2013). These pharmacological findings agree with the functional studies from either ppN/OFQ or NOP receptor knockout mice that displayed normal sensitivity to acute pain, but showed increased inflammatory hyperalgesia (Depner, Reinscheid, Takeshima, Brune, & Zeilhofer, 2003).…”

Nociceptin Opioid Receptor (NOP) as a Therapeutic Target: Progress in Translation from Preclinical Research to Clinical Utility

“…114 Interestingly, only the i.p. and oral routes of administration were effective for the antinociceptive effects of 12 ; direct intracolonic administration did not have an effect on the intestinal swelling observed in these animals.…”

“…and oral routes of administration were effective for the antinociceptive effects of 12 ; direct intracolonic administration did not have an effect on the intestinal swelling observed in these animals. 114 It has been speculated that N/OFQ and therefore NOP agonists may play a role in neurogenic inflammation and pain, such as that in IBD. 115 These interesting findings, however, warrant further investigation before these applications can be translated to the clinic.…”

Measurement of Silver Nanolayer Absorption by the Body in an in Vivo Model of Inflammatory Gastrointestinal Diseases

“…Colonic inflammation was induced on Day 0 by intracolonic (i.c.) administering Trinitrobenzenesulfonic Acid (TNBS), as described previously in [27]. The mice from experimental group #3 were treated with silver-coated glass beads (5 beads/animal, i.c., twice daily) between Day 3 and Day 6.…”

“…The mice from experimental group #3 were treated with silver-coated glass beads (5 beads/animal, i.c., twice daily) between Day 3 and Day 6. On Day 7, all animals were euthanized and inflammation score was assessed, as described previously in [27]. Briefly, the colon was removed, opened longitudinally, rinsed with Phosphate Buffered Saline (PBS), and immediately examined.…”