Intracerebroventricular administration of CYX-6, a potent μ-opioid receptor agonist, a δ- and κ-opioid receptor antagonist and a biased ligand at μ, δ & κ-opioid receptors, evokes antinociception with minimal constipation and respiratory depression in rats in contrast to morphine

• Published in: European journal of pharmacology Vol. 871; p. 172918
• Main Authors: Imam, Mohammad Zafar, Kuo, Andy, Ghassabian, Sussan, Cai, Yunxin, Qin, Yajuan, Li, Tingyou, Smith, Maree T.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 15.03.2020
• Subjects: Analgesics, Opioid - administration & dosage; Analgesics, Opioid - adverse effects; Analgesics, Opioid - metabolism; Analgesics, Opioid - pharmacology; Animals; Antinociception; Constipation; Constipation - chemically induced; Endomorphin-2 analogue; Gut motility; Infusions, Intraventricular; Intracerebroventricular; Ligands; Male; Morphine - adverse effects; Morphine - pharmacology; Nociceptin; Opioid Peptides - drug effects; Rats; Rats, Sprague-Dawley; Receptors, Opioid, delta - antagonists & inhibitors; Receptors, Opioid, delta - metabolism; Receptors, Opioid, kappa - antagonists & inhibitors; Receptors, Opioid, kappa - metabolism; Receptors, Opioid, mu - agonists; Receptors, Opioid, mu - metabolism; Respiratory depression; Respiratory Insufficiency - chemically induced; Antinociception; Respiratory depression; Endomorphin-2 analogue; Intracerebroventricular; Gut motility; Constipation
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2020.172918

Mu opioid receptor (MOPr) agonists are thought to produce analgesia via modulation of G-protein-coupled intracellular signalling pathways whereas the β-arrestin2 pathway is proposed to mediate opioid-related adverse effects. Here, we report the antinociception, constipation and respiratory depressant profile of CYX-6, a potent MOPr agonist that is also a delta and a kappa opioid receptor (DOPr/KOPr) antagonist and that lacks β-arrestin2 recruitment at each of the MOPr, DOPr and the KOPr. In anaesthetised male Sprague Dawley rats, an intracerebroventricular (i.c.v.) guide cannula was stereotaxically implanted. After 5–7 days post-surgical recovery, rats received a single i.c.v. bolus dose of CYX-6 (3–30 nmol), morphine (100 nmol) or vehicle. Antinociception was assessed using the warm water tail flick test (52.5 ± 0.5 °C). Constipation was assessed using the charcoal meal gut motility test and the castor oil-induced diarrhoea test. Respiratory depression was measured by whole-body plethysmography in awake, freely moving animals, upon exposure to a hypercapnic gas mixture (8% CO2, 21% O2 and 71% N2). The intrinsic pharmacology of CYX-6 given by the i.c.v. route in rats showed that it produced dose-dependent antinociception. It also produced respiratory stimulation rather than depression and it had a minimal effect on intestinal motility in contrast to the positive control, morphine. CYX-6 is an endomorphin-2 analogue that dissociates antinociception from constipation and respiratory depression in rats. Our findings provide useful insight to inform the discovery and development of novel opioid analgesics with a superior tolerability profile compared with morphine.