Effects of stimulation of mu opioid and nociceptin/orphanin FQ peptide (NOP) receptors on alcohol drinking in rhesus monkeys

Abstract

Alcohol use disorder (AUD) persists as a devastating public health problem; widely effective pharmacological treatments are needed. Evidence from rodent models suggests that stimulating brain receptors for the neuropeptide nociceptin/orphanin FQ (NOP) can decrease ethanol drinking. We characterized the effects of the mu opioid peptide (MOP) receptor agonist buprenorphine and the buprenorphine analog (2S)-2-[(5R,6R,7R,14S)-N-cyclopropylmethyl-4,5-epoxy-6,14-ethano-3-hydroxy-6 methoxymorphinan-7-yl]-3,3-dimethylpentan-2-ol (BU08028), which stimulates MOP and NOP receptors, in a translational nonhuman primate model of AUD. Rhesus monkeys drank a 4% ethanol solution 6 h per day, 5 days per week via an operant behavioral panel in their home cages. To assess behavioral selectivity, monkeys responded via a photo-optic switch to earn food pellets. After characterizing the acute effects of BU08028 (0.001-0.01 mg/kg, i.m.) and buprenorphine (0.003-0.056 mg/kg, i.m.), the drugs were administered chronically using a model of pharmacotherapy assessment that incorporates clinical aspects of AUD and treatment. Acutely, both drugs decreased ethanol drinking at doses that did not affect food-maintained responding. During chronic treatment, effects of BU08028 and buprenorphine were maintained for several weeks without development of tolerance or emergence of adverse effects. BU08028 was~0.5 and 1.0 log units more potent in acute and chronic studies, respectively. The selective NOP receptor agonist SCH 221510 also selectively decreased ethanol intakes when given acutely (0.03-1.0 mg/kg, i.m.), whereas the MOP antagonist naltrexone (1.7-5.6 mg/kg, i.m.) decreased both ethanol intake and food pellets delivered. These data demonstrate that bifunctional MOP/NOP agonists, which may have therapeutic advantages to MOP-selective drugs, can decrease alcohol drinking in nonhuman primates.

PET Imaging of [11C]MPC-6827, a Microtubule-Based Radiotracer in Non-Human Primate Brains

“…Importantly, high SUV values in selective brain areas including putamen, globus pallidus, cortex, and hippocampus warrants additional studies to investigate microtubule regulation in models of diseases such as AUD and AD. Further studies will include [ 11 C]MPC-6827 PET imaging in NHP models of substance abuse disorder, including alcohol and cocaine self-administration [39,40], and NHP model of AD [38]. We will also characterize the metabolite analyses, arterial input functions, and specificity studies, and correlate the data with PET images using sophisticated pharmacokinetic modeling [31].…”

Sex differences in the effect of chronic delivery of the buprenorphine analogue BU08028 on heroin relapse and choice in a rat model of opioid maintenance

“…However, unlike classical full μ receptor agonists, such as heroin, and fentanyl or partial agonists, such as buprenorphine, BU08028 is not self-administered by rhesus monkeys (Ding et al, 2016). A more recent study also showed that buprenorphine and BU08028 both acutely and chronically decrease alcohol drinking in rhesus monkeys, with BU08028 showing higher potency than buprenorphine (Flynn et al, 2019). Together, these findings suggest that BU08028 can mimic the therapeutic effects of buprenorphine while carrying lower risk for abuse liability.…”

Therapeutic potentials of NOP and MOP receptor coactivation for the treatment of pain and opioid abuse

“…This is the first evidence demonstrating the identification of a novel bifunctional NOP/MOP agonist that inhibits abuse liability of prescription opioid oxycodone with behavioral selectivity. Moreover, a recent report demonstrated that BU08028 selectively attenuate alcohol intake without affecting food-maintained operant behaviors in NHPs (Flynn et al, 2019). Acute systemic administration of BU08028 decreased ethanol drinking, and the effective doses of BU08028 were lower than that of buprenorphine.…”

“…Acute systemic administration of BU08028 decreased ethanol drinking, and the effective doses of BU08028 were lower than that of buprenorphine. In addition, chronic dosing of BU08028 also attenuated ethanol drinking, with the effects maintained for several weeks without inducing tolerance and adverse effects (Flynn et al, 2019). Given that AT-121 and BU08028 alone did not produce reinforcing effects (i.e., abuse liability) in NHPs, bifunctional NOP/MOP partial agonists may have great therapeutic potential for treating not only pain but also substance use disorders with fewer side effects.…”