CYX-5, a G-protein biassed MOP receptor agonist, DOP receptor antagonist and KOP receptor agonist, evokes constipation but not respiratory depression relative to morphine in rats

• Published in: Pharmacological reports Vol. 75; no. 3; pp. 634 - 646
• Main Authors: Imam, Mohammad Zafar, Kuo, Andy, Ghassabian, Sussan, Cai, Yunxin, Qin, Yajuan, Li, Tingyou, Smith, Maree T.
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01.06.2023
• Subjects: Analgesics, Opioid - adverse effects; Animals; Castor Oil - adverse effects; Constipation - chemically induced; Constipation - drug therapy; Diarrhea - drug therapy; Drug Safety and Pharmacovigilance; GTP-Binding Proteins; Male; Medicine; Morphine - adverse effects; Narcotic Antagonists - pharmacology; Pharmacotherapy; Pharmacy; Rats; Rats, Sprague-Dawley; Receptors, Opioid, delta - agonists; Receptors, Opioid, mu - agonists; Respiratory Insufficiency - chemically induced; Hypercapnia; CYX-5; Warm water tail flick test; Minute ventilation; Intracerebroventricular; ); Gastrointestinal motility; Castor oil-induced diarrhoea; Whole body plethysmography; Charcoal meal; Intracerebroventricular (icv)
• ISSN: 1734-1140; 2299-5684
• DOI: 10.1007/s43440-023-00446-8

Background Strong opioid analgesics such as morphine alleviate moderate to severe acute nociceptive pain (e.g. post-surgical or post-trauma pain) as well as chronic cancer pain. However, they evoke many adverse effects and so there is an unmet need for opioid analgesics with improved tolerability. Recently, a prominent hypothesis has been that opioid-related adverse effects are mediated by β-arrestin2 recruitment at the µ-opioid (MOP) receptor and this stimulated research on discovery of G-protein biassed opioid analgesics. In other efforts, opioids with MOP agonist and δ-opioid (DOP) receptor antagonist profiles are promising for reducing side effects c.f. morphine. Herein, we report on the in vivo pharmacology of a novel opioid peptide (CYX-5) that is a G-protein biassed MOP receptor agonist, DOP receptor antagonist and kappa opioid (KOP) receptor agonist. Methods Male Sprague–Dawley received intracerebroventricular bolus doses of CYX-5 (3, 10, 20 nmol), morphine (100 nmol) or vehicle, and antinociception (tail flick) was assessed relative to constipation (charcoal meal and castor oil-induced diarrhoea tests) and respiratory depression (whole body plethysmography). Results CYX-5 evoked naloxone-sensitive, moderate antinociception, at the highest dose tested. Although CYX-5 did not inhibit gastrointestinal motility, it reduced stool output markedly in the castor oil-induced diarrhoea test. In contrast to morphine that evoked respiratory depression, CYX-5 increased tidal volume, thereby stimulating respiration. Conclusion Despite its lack of recruitment of β-arrestin2 at MOP, DOP and KOP receptors, CYX-5 evoked constipation, implicating a mechanism other than β-arrestin2 recruitment at MOP, DOP and KOP receptors, mediating constipation evoked by CYX-5 and potentially other opioid ligands.