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. 2020 Mar 15:871:172918.
doi: 10.1016/j.ejphar.2020.172918. Epub 2020 Jan 17.

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

Mohammad Zafar Imam  1 , Andy Kuo  1 , Sussan Ghassabian  1 , Yunxin Cai  2 , Yajuan Qin  2 , Tingyou Li  2 , Maree T Smith  3
Affiliations

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

Mohammad Zafar Imam et al. Eur J Pharmacol. .

Abstract

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.

Keywords: Antinociception; Constipation; Endomorphin-2 analogue; Gut motility; Intracerebroventricular; Respiratory depression.

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Conflict of interest statement

Declaration of competing interest None.

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