Effects of the novel, selective and low-efficacy mu opioid receptor ligand NAQ on intracranial self-stimulation in rats

Abstract

Rationale Low-efficacy mu opioid receptor agonists may be useful for some clinical indications, but clinically available low-efficacy mu agonists also have low selectivity for mu vs. kappa opioid receptors. NAQ is a novel opioid receptor ligand with low-efficacy at mu receptors and greater mu-receptor selectivity than existing low-efficacy agonists. Objectives This study examined behavioral effects of NAQ in rats using an intracranial self-stimulation (ICSS) procedure that has been used previously to examine other opioids. NAQ effects were examined before, during and after chronic morphine treatment, and effects of NAQ were compared to effects of nalbuphine and naltrexone. Methods Adult male Sprague-Dawley rats were trained to respond for electrical brain stimulation delivered via electrodes implanted in the medial forebrain bundle. A range of brain stimulation frequencies maintained a wide range of baseline ICSS rates. Effects of NAQ (0.32-10 mg/kg), nalbuphine (1.0 mg/kg) and naltrexone (0.1 mg/kg) were determined before morphine treatment and during treatment with 3.2 and 18 mg/kg/day morphine. NAQ effects were also redetermined beginning two weeks after termination of morphine treatment. Results NAQ produced weak ICSS facilitation in morphine-naïve rats but more robust ICSS facilitation during and after morphine treatment and also reversed morphine withdrawal-associated depression of ICSS. These effects were similar to effects of nalbuphine. Conclusions These results agree with the in vitro characterization of NAQ as a low-efficacy mu agonist. Opioid exposure may enhance abuse-related effects of NAQ, but NAQ may also serve as a low-efficacy and relatively safe option for treatment of opioid withdrawal or dependence.

Design, syntheses, and pharmacological characterization of 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6α-(isoquinoline-3′-carboxamido)morphinan analogues as opioid receptor ligands

“…These effects of NAQ were similar to that of nalbuphine. 24 The ICSS results thus agree with the in vitro characterization of NAQ as a low-efficacy MOR partial agonist and indicate that NAQ may serve as a relatively safe option for treatment of opioid withdrawal or dependence.…”

Nalbuphine: some aspects of the research and applications

“…Note that the therapeutic range for a rat determined by the authors using the formula based on the LD0 actually matches the ranges in physiological experiments on rats indicated in other sources [66,67,[69][70][71][72] and, therefore, can be considered one of the most valid. In addition, the 7-day interval in collection of material is the most appropriate to study the impact of nalbuphine in possible non-medical use, because such a given term is indicated as minimal for the formation of dependency on nalbuphine [30], while the medical use mostly continues for seven days.…”

“…Altarifi et al 2012 [69], 2013 [70], 2015 [71] used nalbuphine in experimental works studying the effects on opioid receptors and the efficiency of m-agonists and antagonists, using intracranial self-stimulation in rats (ICSS). The range of doses of nalbuphine amounted to 0.032-10 mg/kg (in recent works 0.1-10 mg/kg), while the authors noted a different reaction to nalbuphine in the rats that previously had opioids administered and the rats without previous opioid experience.…”

Antinociceptive Interactions between the Imidazoline I2 Receptor Agonist 2-BFI and Opioids in Rats: Role of Efficacy at the -Opioid Receptor

“…These promising findings have not been tested in controlled clinical trials, which reflects the reality that preclinical findings are way ahead of relevant clinical studies and highlights the necessity of expedited translational studies to eventually introduce these potentially valuable pain adjuvants into clinical practice. Interestingly, a recent study demonstrated that NAQ has sufficient efficacy to produce weak facilitation of intracranial self-stimulation in morphine-naive rats (Altarifi et al, 2015), suggesting the possibility of its abuse potential. Abuse potential of opioids is one important factor that limits its adequate clinical use.…”