MP1104, a mixed kappa-delta opioid receptor agonist has anti-cocaine properties with reduced side-effects in rats
| Autor: | Bronwyn M. Kivell, Diana V. Atigari, Rajendra Uprety, Gavril W. Pasternak, Susruta Majumdar |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Agonist Male Elevated plus maze medicine.drug_class Drug-Seeking Behavior Self Administration Pharmacology Nucleus accumbens κ-opioid receptor Article δ-opioid receptor Rats Sprague-Dawley 03 medical and health sciences Cellular and Molecular Neuroscience 0302 clinical medicine Cocaine Dopamine Uptake Inhibitors Receptors Opioid delta medicine Animals Neuropharmacology business.industry Receptors Opioid kappa Rats Analgesics Opioid 030104 developmental biology Anxiogenic Opioid Morphinans business 030217 neurology & neurosurgery medicine.drug |
| Zdroj: | Neuropharmacology |
| ISSN: | 1873-7064 |
| Popis: | Kappa opioid receptor (KOPr) agonists have preclinical anti-cocaine and antinociceptive effects. However, adverse effects including dysphoria, aversion, sedation, anxiety and depression limit their clinical development. MP1104, an analogue of 3-iodobenzoyl naltrexamine, is a potent dual agonist at KOPr and delta opioid receptor (DOPr), with full agonist efficacy at both these receptors. In this study, we evaluate the ability of MP1104 to modulate cocaine-induced behaviors and side-effects preclinically. In male Sprague-Dawley rats trained to self-administer cocaine, MP1104 (0.3 and 1 mg/kg) reduced cocaine-primed reinstatement of drug-seeking behavior and caused significant downward shift of the dose-response curve in cocaine self-administration tests (0.3 and 0.6 mg/kg). The anti-cocaine effects exerted by MP1104 are in part due to increased dopamine (DA) uptake by the dopamine transporter (DAT) in the dorsal striatum (dStr) and nucleus accumbens (NAc). MP1104 (0.3 and 0.6 mg/kg) showed no significant anxiogenic effects in the elevated plus maze, pro-depressive effects in the forced swim test, or conditioned place aversion. Furthermore, pre-treatment with a DOPr antagonist, led to MP1104 producing aversive effects. This data suggests that the DOPr agonist actions of MP1104 attenuate the KOPr-mediated aversive effects of MP1104. The overall results from this study show that MP1104, modulates DA uptake in the dStr and NAc, and exerts potent anti-cocaine properties in self-administration tests with reduced side-effects compared to pure KOPr agonists. This data supports the therapeutic development of dual KOPr/DOPr agonists to reduce the side-effects of selective KOPr agonists. This article is part of the Special Issue entitled 'Opioid Neuropharmacology: Advances in treating pain and opioid addiction'. |
| Databáze: | OpenAIRE |
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