Role of agonist efficacy in exposure-induced enhancement of mu opioid reward in rats

Abstract

The abuse potential of opioid analgesics in humans appears to increase rapidly during initial regimens of opioid exposure. Previous work using intracranial self-stimulation (ICSS), a preclinical procedure useful for studying rewarding drug effects in drug-naïve animals, has similarly shown that rewarding effects of mu opioid receptor (MOR) agonists increase rapidly in rats during initial regimens of opioid administration. The goal of the present study was to evaluate the role of MOR agonist efficacy as a determinant in eliciting this trajectory of increased rewarding effects during initial opioid exposure in opioid-naïve rats. Separate groups of adult, male Sprague-Dawley rats responded for electrical brain stimulation using a frequency-rate ICSS procedure and received repeated daily treatment with vehicle or one of five MOR agonists that ranged from low to high efficacy (NAQ, nalbuphine, buprenorphine, fentanyl, methadone). Two additional groups were used to evaluate effects of repeated treatment with non-opioids (the cannabinoid CP55940 or the monoamine releaser amphetamine). Morphine was tested after each repeated treatment. In opioid-naïve rats tested before repeated dosing, MOR agonists produced primarily dose-and efficacy-dependent decreases in ICSS. Following repeated treatment, all MOR agonists except NAQ produced tolerance to opioid-induced rate-decreasing effects and enhanced expression of ICSS facilitation (indicative of opioid reward) by both the repeatedly administered drug and morphine. Repeated treatment with CP55940 and amphetamine produced different effects. Collectively, these results provide evidence to suggest that enhanced expression of opioid reward after initial regimens of opioid exposure has a low requirement for MOR agonist efficacy and is pharmacologically selective.

Antinociceptive and Abuse Potential Effects of Cannabinoid/Opioid Combinations in a Chronic Pain Model in Rats

“…The current study showed that CP55940 produced dose-dependent depression of ICSS in rats. Similar results have been previously reported in mice and rats [44,45]. In addition, other CB1 agonists produced similar effects in ICSS such as Δ9-tetrahydrocannabinol and WIN55,212-2 ((R)-(+)-[2,3-Dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone mesylate) [31,46].…”

Preclinical assessment of tramadol abuse potential: Effects of acute and repeated tramadol on intracranial self-stimulation in rats

“…This study evaluated the abuse-related effects of tramadol in rats using an ICSS procedure that has been used to evaluate a range of other opioid analgesics (Altarifi et al, 2017; Altarifi et al, 2012; Altarifi and Negus, 2011; Altarifi et al, 2015; Moerke and Negus, 2019; Wiebelhaus et al, 2016). We have shown previously that many MOR agonists produce little or no evidence of abuse-related ICSS facilitation in opioid-naïve adult male Sprague–Dawley rats, and instead produce primarily only an efficacy-dependent ICSS depression.…”

“…Rats were trained under a fixed-ratio 1 (FR 1) schedule of brain stimulation using procedures similar to those described previously (Altarifi et al, 2017; Altarifi et al, 2013; Altarifi et al, 2015; Moerke and Negus, 2019). Each lever press resulted in the delivery of a 0.5-second train of square-wave cathodal pulses (0.1 ms pulse duration), and stimulation was accompanied by illumination of the stimulus lights above the lever.…”

“…This study examined the effects of tramadol in rats using an assay of intracranial self-stimulation (ICSS) that has been used extensively in preclinical research to determine abuse potential of opioids and other classes of new medications (Moerke and Negus, 2019; Negus and Miller, 2014). In ICSS procedures, subjects equipped with a microelectrode targeting a brain reward area are trained to respond for pulses of electrical brain stimulation, and many drugs of abuse increase (or ‘facilitate’) ICSS responding.…”

“…In ICSS procedures, subjects equipped with a microelectrode targeting a brain reward area are trained to respond for pulses of electrical brain stimulation, and many drugs of abuse increase (or ‘facilitate’) ICSS responding. Previously, we showed that MOR agonists such as morphine can either facilitate or depress ICSS, depending on variables that include dose, pretreatment time and history of opioid exposure (Altarifi et al, 2012; Altarifi and Negus, 2011; Altarifi et al, 2013; Moerke and Negus, 2019). Specifically, MOR agonists often produce primarily ICSS depression upon initial exposure to opioid-naïve subjects, but repeated administration of morphine or other MOR agonists produces tolerance to these ICSS rate-decreasing effects and emergence of abuse-related ICSS rate-increasing effects (i.e.…”