4.4 Article

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

Journal

PHARMACOLOGICAL REPORTS
Volume 75, Issue 3, Pages 634-646

Publisher

SPRINGER HEIDELBERG
DOI: 10.1007/s43440-023-00446-8

Keywords

CYX-5; Intracerebroventricular (icv); Warm water tail flick test; Gastrointestinal motility; Charcoal meal; Castor oil-induced diarrhoea; Whole body plethysmography; Hypercapnia; Minute ventilation

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CYX-5 is a novel opioid peptide that acts as a G-protein biassed MOP receptor agonist, DOP receptor antagonist, and KOP receptor agonist. It provides pain relief, reduces stool output, and does not cause respiratory depression. The mechanism underlying its constipation effect may involve factors other than beta-arrestin2 recruitment.
BackgroundStrong 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 beta-arrestin2 recruitment at the mu-opioid (MOP) receptor and this stimulated research on discovery of G-protein biassed opioid analgesics. In other efforts, opioids with MOP agonist and delta-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.MethodsMale 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).ResultsCYX-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.ConclusionDespite its lack of recruitment of beta-arrestin2 at MOP, DOP and KOP receptors, CYX-5 evoked constipation, implicating a mechanism other than beta-arrestin2 recruitment at MOP, DOP and KOP receptors, mediating constipation evoked by CYX-5 and potentially other opioid ligands.

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