MP1104, a mixed kappa-delta opioid receptor agonist has anti-cocaine properties with reduced side-effects in rats

Abstract

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.

Crosstalk Between Kappa Opioid and Dopamine Systems in Compulsive Behaviors

“…An ex vivo analysis also using voltammetry in disaggregated tissues, showed that a systemic injection of KOR agonist U-69593 increased dopamine uptake in the NAc (Thompson et al, 2000). A similar recent article shows that nor-BNI blocks the increase of dopamine uptake in the ventral and dorsal striatum, induced by an acute systemic injection of MP1104, a mixed Kappa/Delta opioid receptor agonist (Atigari et al, 2019). Nevertheless, the effect of KOR activation on dopamine uptake has yet not been not fully elucidated.…”

Strategies for DevelopingκOpioid Receptor Agonists for the Treatment of Pain with Fewer Side Effects

“…MP1104 produced potent antinociceptive effects in the radiant heat tail-withdrawal assay in male CD1 mice (Varadi et al, 2015) and reduced inflammatory pain in the intradermal formalin test in both male and female ICR mice (Ulker et al, 2020) (Table 2). Moreover, MP1104 has anti-cocaine effects in male Sprague-Dawley rats and showed no anxiogenic, pro-depressive, or aversive side-effects (Atigari et al, 2019).…”

Investigating the Role of G-protein Bias in the Anti-Nociceptive and Side Effect Profiles of Two Novel Mu Opioid Receptor Agonists Kurkinol and Kurkinorin

“…In vitro analysis revealed MP1104 had 3-and 13-fold higher selectivity for the κ receptor than the μ receptor and δ receptor respectively, with full agonism at all three receptors (Váradi et al, 2015). While in vivo it has been shown to induce potent, long acting anti-nociception in the tail-flick assay in both rats and mice and attenuates cocaine self-administration in rats (Atigari et al, 2019, Váradi et al, 2015. Furthermore, it does not induce anxiogenic or aversive effects as measured by elevated plus maze, forced swim test, and conditioned place aversion in rats (Atigari et al, 2019).…”

“…While in vivo it has been shown to induce potent, long acting anti-nociception in the tail-flick assay in both rats and mice and attenuates cocaine self-administration in rats (Atigari et al, 2019, Váradi et al, 2015. Furthermore, it does not induce anxiogenic or aversive effects as measured by elevated plus maze, forced swim test, and conditioned place aversion in rats (Atigari et al, 2019). Ultimately, these μ receptor/ κ receptor mixed agonists appear to show the same pre-clinical behavioural profile as what biased agonism is trying to achieve (Paton et al, 2020a.…”