Determinants of opioid abuse potential: Insights using intracranial self-stimulation

Negus, S. Stevens; Moerke, Megan J.

doi:10.1016/j.peptides.2018.10.007

Cited by 22 publications

(15 citation statements)

References 105 publications

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“…Results of the present study agree with previous findings that MOR agonists produce little or no ICSS facilitation in opioid-naïve male Sprague-Dawley rats, and instead produce primarily an efficacy-dependent ICSS depression (Altarifi et al, 2017;Altarifi et al, 2012;Altarifi et al, 2013;Altarifi et al, 2015;Miller et al, 2015;Negus and Moerke, 2019;Reid, 1987;Wiebelhaus et al, 2016). Thus, morphine administration in rats treated with repeated saline produced only a dose-dependent depression of ICSS.…”

Section: Effects Of Opioids In Drug-naïve Ratssupporting

confidence: 92%

“…Second, nalbuphine produced neither ICSS facilitation nor depression in opioid-naïve rats, but repeated treatment nonetheless enabled ICSS facilitation by nalbuphine itself and by morphine. This suggests that opioid-induced ICSS facilitation after repeated opioid treatment (a) has a lower efficacy requirement than ICSS depression in naïve subjects, (b) does not require initial ICSS depression, and (c) may involve an agonist-induced sensitization to opioid reward in addition to an unmasking of reward initially obscured by rate-decreasing effects (Negus and Moerke, 2019).…”

Section: Effects Of Repeated Opioid Treatmentmentioning

confidence: 98%

“…Many drugs of abuse increase (or "facilitate") low rates of ICSS responding maintained by low frequencies or intensities of brain stimulation, and as a result, ICSS facilitation is often interpreted as an abuse-related drug effect (Negus and Miller, 2014). Morphine and other MOR agonists often fail to produce ICSS facilitation in opioid-naïve subjects, and instead produce primarily dose-dependent ICSS depression; however, repeated daily treatment over the course of several days can produce tolerance to opioid-induced ICSS depression and heightened expression of abuse-related ICSS facilitation (Altarifi et al, 2013;Legakis and Negus, 2018;Miller et al, 2015;Negus and Moerke, 2019;Reid, 1987). This trajectory of increasing opioid-induced ICSS facilitation in rats resembles the increase in opioid abuse potential that can occur during initial regimens of opioid exposure in humans.…”

Section: Introductionmentioning

confidence: 99%

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

Moerke

Negus

2019

Neuropharmacology

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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.

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Section: Effects Of Opioids In Drug-naïve Ratssupporting

confidence: 92%

Section: Effects Of Repeated Opioid Treatmentmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

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

Moerke

Negus

2019

Neuropharmacology

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“…This depression in ICSS can possibly be attributed to their sedative effect at high doses [7]. On the other hand, morphine’s effect on ICSS has been adequately studied and showed a variable action of increasing and decreasing ICSS at low doses and high doses, respectively [2,47,48]. However, this is the first study to report the effect of tramadol-induced depression of ICSS.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2019

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Chronic pain is a persistent and debilitating health problem. Although the use of analgesics such as opioids is useful in mitigating pain, their prolonged use is associated with unwanted effects including abuse liability. This study assesses the antinociceptive effect of combining subtherapeutic doses of two opioids (morphine or tramadol) with the synthetic cannabinoid CP55940 (2-[(1R,2R,5R)-5-hydroxy-2-(3-hydroxypropyl)cyclohexyl]-5-(2-methyloctan -2-yl)phenol). It also evaluates the associated adverse effects of these drugs and combinations. Adult male rats were injected with intraplantar complete Freund’s adjuvant (CFA) to produce mechanical allodyia. Antinociceptive effect of morphine, tramadol, the synthetic cannabinoid CP55940, or their combinations was evaluated three to nine days post-CFA injections. Intracranial self-stimulation (ICSS) was utilized to evaluate the abuse liability of these drugs or their combinations. All drugs alone produced a dose-dependent antinociceptive effect. Morphine produced minimal effect on ICSS, but both tramadol and CP55940 produced dose-dependent depression of ICSS. Morphine at a dose of 0.32 mg/kg enhanced the antinociceptive effects of CP55940, in that, CP55940 produced antinociception at a lower dose (0.1 mg/kg) when compared to the vehicle. The aforementioned combinations did not change CP55940-induced depression of ICSS. On the other hand, tramadol failed to enhance the antinociceptive effect of CP55940. Our data suggest that combining CP55940 with morphine, but not tramadol, shows a better antinociceptive profile with no additional risk of abuse liability, which represents a potential pain management approach.

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“…Increases persisted for at least 7-8 days post-escalation, with recovery over about 10 days in the methamphetamine study. Withdrawal from ethanol (Schulteis, Markou, Cole & Koob, 1995), nicotine (Epping-Jordan, Watkins, Koob & Markou, 1998), amphetamine (Lin, Koob & Markou, 1999; Lin, Koob & Markou, 2000) and several opioids (Altarifi & Negus, 2011; Negus & Moerke, 2019), including fentanyl (Bruijnzeel, Lewis, Bajpai, Morey, Dennis & Gold, 2006), also elevates reward thresholds in rats. Correspondingly, the somatic signs of withdrawal from heroin increase progressively from 12 to 48 h in adult rats (Doherty & Frantz, 2013).…”

Section: Introductionmentioning

confidence: 99%

Paradoxical changes in brain reward status during oxycodone self-administration in a novel test of the negative reinforcement hypothesis

Nguyen

Grant

Taffe

2018

Preprint

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Background and Purpose: The extra-medical use and addiction of prescription opioid analgesics is a growing health problem. To characterize how prescription opioid abuse develops, this study investigated the affective consequences of escalating prescription opioid use using intracranial self-stimulation (ICSS) reward and oxycodone intravenous self-administration (IVSA) models.Experimental Approach: Male Wistar rats were given access to oxycodone IVSA (0.15 mg/kg/infusion, i.v.) in Short Access (ShA; 1 h) or Long Access (LgA; 12 h) sessions for 5 sessions/week followed by intermittent 60 h discontinuations from drug access, a novel explicit test of the negative reinforcement hypothesis. A separate group was first trained in the ICSS procedure and then in oxycodone IVSA in 11 h LgA sessions.Key Results: Rats given LgA to oxycodone escalated their responding more than ShA rats, with significant increases following 60 h discontinuations. Pre-session brain reward thresholds increased with sequential daily LgA IVSA sessions, consistent with a growing negative affective state consequent to successive daily intoxication/abstinence cycles. A 1 h oxycodone IVSA interval was sufficient to normalize these elevated reward thresholds, as was, paradoxically, a 60 h weekend abstinence. The increase in ICSS thresholds was attenuated in a group administered the long-acting kappa opioid antagonist norBNI prior to IVSA training. Conclusions and Implications:Changes in brain reward function during escalation of oxycodone selfadministration is driven by an interplay between kappa opioid receptor-mediated negative affective state associated with escalated oxycodone intake and dynamic restoration of brain reward status during longer periods of abstinence.

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Determinants of opioid abuse potential: Insights using intracranial self-stimulation

Cited by 22 publications

References 105 publications

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

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

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

Paradoxical changes in brain reward status during oxycodone self-administration in a novel test of the negative reinforcement hypothesis

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