Nociceptin attenuates the escalation of oxycodone self-administration by normalizing CeA–GABA transmission in highly addicted rats

Abstract

Approximately 25% of patients who are prescribed opioids for chronic pain misuse them, and 5 to 10% develop an opioid use disorder. Although the neurobiological target of opioids is well known, the molecular mechanisms that are responsible for the development of addiction-like behaviors in some but not all individuals are poorly known. To address this issue, we used a unique outbred rat population (heterogeneous stock) that better models the behavioral and genetic diversity that is found in humans. We characterized individual differences in addiction-like behaviors using an addiction index that incorporates the key criteria of opioid use disorder: escalated intake, highly motivated responding, and hyperalgesia. Using in vitro electrophysiological recordings in the central nucleus of the amygdala (CeA), we found that rats with high addiction-like behaviors (HA) exhibited a significant increase in γ-aminobutyric acid (GABA) transmission compared with rats with low addiction-like behaviors (LA) and naive rats. The superfusion of CeA slices with nociceptin/orphanin FQ peptide (N/OFQ; 500 nM), an endogenous opioid-like peptide, normalized GABA transmission in HA rats. Intra-CeA levels of N/OFQ were lower in HA rats than in LA rats. Intra-CeA infusions of N/OFQ (1 μg per site) reversed the escalation of oxycodone self-administration in HA rats but not in LA rats. These results demonstrate that the downregulation of N/OFQ levels in the CeA may be responsible for hyper-GABAergic tone in the CeA that is observed in individuals who develop addiction-like behaviors. Based on these results, we hypothesize that small molecules that target the N/OFQ system might be useful for the treatment of opioid use disorder.

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

“…This latter finding was consistent with the ∼week-long recovery of ICSS thresholds observed following cessation of methamphetamine LgA IVSA (Jang, Whitfield, Schulteis, Koob & Wee, 2013). Relatedly, a period of 23.5 h abstinence following chronic morphine injections reduced ICSS reward (Altarifi & Negus, 2011) and somatic and behavioral signs of withdrawal were reported 12 h after the last LgA oxycodone (0.15 mg/kg/infusion, 12 h) self-administration session in recent studies (de Guglielmo, Kallupi, Sedighim, Newman & George, 2020; Kallupi et al, 2020; Kimbrough et al, 2020). The failure of 1 h of oxycodone IVSA to alter brain reward on the first session after 60 h discontinuation ( Figure 5A , also see Figure S2 ) is an important clue.…”

The Cocaine and Oxycodone Biobanks, Two Repositories from Genetically Diverse and Behaviorally Characterized Rats for the Study of Addiction

“…An application example was recently published ( Kallupi et al, 2020 ). Kallupi and colleagues were interested in investigating nociceptin/orphanin FQ peptide (N/OFQ, nociceptin) levels in the CeA of rats with high versus low addiction profiles for oxycodone to confirm a preliminary hypothesis.…”

“…C , Correlation between AI and the Z-score of nociceptin levels in the CeA; * p < 0.02 pearson correlation. Partial figure reproduced from Kallupi et al (2020) .…”

“…The behavioral measures include hyperalgesia using the von Frey test (for oxycodone), irritability-like behavior using the bottlebrush test (for cocaine) at LgA compared to BSL, opioidinduced analgesia and tolerance using the tail immersion test (for oxycodone) before ShA and after LgA with oxycodone on board relatively compared to BSL and BSL with oxycodone, motivation with progressive ratio (PR) test (for both oxycodone and cocaine) after ShA and LgA, compulsivity with fixed ratio (FR1) using contingent footshocks (for cocaine) and the effect of FDA approved treatments after LgA on PR tests (for oxycodone). Kallupi et al (Kallupi et al, 2020). 2.…”

Individual differences in members of Actinobacteria, Bacteroidetes, and Firmicutes is associated with resistance or vulnerability to addiction-like behaviors in heterogeneous stock rats

“…Both preclinical and clinical investigation of the microbiome report differences in the microbiome related to sex and genetics (Kim et al, 2020;Goodrich et al, 2014), and fluctuations to the microbiome occur as we age (Jasarevic et al, 2016) and with hormone status (Valeri and Endres, 2021). To address these questions, we analyzed the microbiome differences between HS rats by addiction index (Kallupi et al, 2020), a multifaceted measure of cocaine use and by sex to identify microbial constituents that may contribute to resistance/vulnerability to escalation of cocaine use.…”