Highly-selective µ-opioid receptor antagonism does not block L-DOPA-induced dyskinesia in a rodent model

• Published in: BMC research notes Vol. 13; no. 1; pp. 149 - 6
• Main Authors: Bartlett, Mitchell J, So, Lisa Y, Szabò, Lajos, Skinner, David P, Parent, Kate L, Heien, Michael L, Vanderah, Todd W, Polt, Robin, Sherman, Scott J, Falk, Torsten
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 12.03.2020; BioMed Central; BMC
• Subjects: Animals; Basal ganglia; Brain; Complications and side effects; Delta-opioid receptors; Dihydroxyphenylalanine; Disease Models, Animal; Dopa; Dopamine; Drug therapy; Dyskinesia; Dyskinesia, Drug-Induced - drug therapy; Glycopeptides - pharmacology; Laboratory animals; Levodopa; Levodopa - adverse effects; Male; Morphine; Morphine - pharmacology; Movement disorders; Mu-opioid receptors; Narcotic Antagonists - therapeutic use; Narcotics; Nociception - drug effects; Opioid receptors; Opioids; Parkinson's disease; Peptides; Rats, Sprague-Dawley; Receptors; Receptors, Opioid, mu - antagonists & inhibitors; Receptors, Opioid, mu - metabolism; Research Note; Risk factors; Rodents; Software; United States; Basal ganglia; Delta-opioid receptors; Levodopa; Mu-opioid receptors; Parkinson’s disease
• ISSN: 1756-0500; 1756-0500
• DOI: 10.1186/s13104-020-04994-7

Dopamine-replacement utilizing L-DOPA is still the mainstay treatment for Parkinson's disease (PD), but often leads to development of L-DOPA-induced dyskinesia (LID), which can be as debilitating as the motor deficits. There is currently no satisfactory pharmacological adjunct therapy. The endogenous opioid peptides enkephalin and dynorphin are important co-transmitters in the direct and indirect striatofugal pathways and have been implicated in genesis and expression of LID. Opioid receptor antagonists and agonists with different selectivity profiles have been investigated for anti-dyskinetic potential in preclinical models. In this study we investigated effects of the highly-selective μ-opioid receptor antagonist CTAP (> 1200-fold selectivity for μ- over δ-opioid receptors) and a novel glycopeptide congener (gCTAP5) that was glycosylated to increase stability, in the standard rat LID model. Intraperitoneal administration (i.p.) of either 0.5 mg/kg or 1 mg/kg CTAP and gCTAP5 completely blocked morphine's antinociceptive effect (10 mg/kg; i.p.) in the warm water tail-flick test, showing in vivo activity in rats after systemic injection. Neither treatment with CTAP (10 mg/kg; i.p.), nor gCTAP5 (5 mg/kg; i.p.) had any effect on L-DOPA-induced limb, axial, orolingual, or locomotor abnormal involuntary movements. The data indicate that highly-selective μ-opioid receptor antagonism alone might not be sufficient to be anti-dyskinetic.