Opioid Pharmacology Research Articles

Opioid-induced Neurotoxicity in Patients with Cancer Pain.

Opioid-induced neurotoxicity (OINT) is a neuropsychiatric syndrome observed with opioid therapy. The mechanism of OINT is thought to be multifactorial, and many risk factors may facilitate its development. If symptoms of OINT are seen, the prescriber should consider hydration, discontinuation of the offending opioid drug, or switching of opioid medication, or the use of some adjuvants. Multiple factors like inter- and intraindividual differences in opioid pharmacology may influence the accuracy of dose calculations for opioid switching. Experience and clinical judgment in a specialistic palliative care setting should be used and individual patient characteristics considered when applying any conversion table.

Detection, chemical analysis, and pharmacological characterization of dipyanone and other new synthetic opioids related to prescription drugs.

The emergence of structurally diverse new synthetic opioids (NSOs) has caused the opioid crisis to spiral to new depths. Little information is available about the pharmacology of most novel opioids when they first emerge. Here, using a β-arrestin 2 recruitment assay, we investigated the in vitro μ-opioid receptor (MOR) activation potential of dipyanone, desmethylmoramide, and acetoxymethylketobemidone (O-AMKD) - recent NSOs that are structurally related to the prescription opioids methadone and ketobemidone. Our findings indicate that dipyanone (EC50=39.9 nM; Emax=155% vs. hydromorphone) is about equally active as methadone (EC50=50.3 nM; Emax=152%), whereas desmethylmoramide (EC50=1335 nM; Emax=126%) is considerably less active. A close structural analogue of ketobemidone (EC50=134 nM; Emax=156%) and methylketobemidone (EC50=335 nM; Emax=117%), O-AMKD showed a lower potency (EC50=1262 nM) and efficacy (Emax=109%). Evaluation of the opioid substitution product buprenorphine and its metabolite norbuprenorphine confirmed the increased in vitro efficacy of the latter. In addition to in vitro characterization, this report details the first identification and full chemical analysis of dipyanone in a seized powder, as well as a postmortem toxicology case from the USA involving the drug. Dipyanone was quantified in blood (370 ng/mL), in which it was detected alongside other NSOs (e.g., 2-methyl AP-237) and novel benzodiazepines (e.g., flualprazolam). While dipyanone is currently not commonly encountered in forensic samples worldwide, its emergence is worrisome and representative of the dynamic NSO market. Graphical Abstract.

Specific Pharmacology of Long-Acting, Extended-Release, and Sustained-Release Opioids for the Treatment of Chronic Nonmalignant Pain

Opioid products, specifically long-acting (LA), extended-release (ER), and sustained-release (SR) formulations, are used for the treatment of a subset of patients with chronic noncancer pain (CNCP). This article will review the specific pharmacology and risks associated with specific LA, ER, and SR opioid formulations that have been used in the treatment of chronic pain. This article will not address the indications for, evidence for and against, or general controversy regarding the use of any form of long-term opioid therapy for the treatment of chronic nonmalignant pain (CNMP), as this has been presented in other published works.

General pharmacology of long-acting, extended-release, and sustained-release opioids for the treatment of chronic nonmalignant pain.

Both short-acting (SA) opioids and long-acting (LA) opioids have been used for chronic pain (defined as pain lasting >3 months). SA opioids have a duration of action ranging between 2 and 4 hours, result in rapidly fluctuating drug levels and are suitable for acute, unstable, intermittent, breakthrough, and procedure-related pain.

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Final-semester nursing studentś knowledge and attitude regarding pain management in resources limited setting

BackgroundStudies suggest that pain assessment and management by appropriately trained and knowledgeable nurses significantly reduce patients suffering. This study aimed to investigate final-semester nursing students’ knowledge and attitudes toward pain management. MethodologyA descriptive cross-sectional study was conducted to examine the knowledge and attitudes of 190 final-semester nursing students regarding pain management. The Nurses’ Knowledge and Attitude Survey Regarding Pain (NKASRP) tool was used to collect data. We surveyed all final-semester nursing students from the Asmara College of Health Sciences. The collected data were entered into SPSS version 25. Both descriptive and inferential statistics were used to analyse the data, and a p value < 0.05 was considered significant throughout the analysis. ResultThe mean score for knowledge and attitude was 47.8 % (SD = 11.50). One-way ANOVA revealed that the influence of education and nursing specialisation was statistically significant, p < 0.001. Students in the bachelor’s programme [mean (M) = 52.72 %, standard deviation (SD) = 12.48] and master’s programme (M = 59.03 %, SD = 12.54) scored higher than those in the diploma programme (M = 43.67 %, SD = 8.40), p < 0.001. Similarly, nurse anaesthesia students (M = 61.60, SD = 11.46) and nurse midwifery students (M = 45.14, SD = 8.98) scored significantly higher than general nursing students (M = 58.01, SD = 16.37), p < 0.001. Finally, students’ average knowledge and attitude correlated significantly and positively with their Cumulative Grade Point Average (CGPA), r = 0.26, p < 0.001. ConclusionFinal semester nursing students had inadequate knowledge and attitudes towards pain management. Therefore, the current nursing curriculum should be revised to include courses that improve nursing students’ knowledge and attitudes about pain management. Courses related to pain focusing on pain physiology, opioid pharmacology, and pain assessment should be included in nursing curricula.

Development of a novel cell-based, In-Cell Western/ERK assay system for the high-throughput screening of agonists acting on the delta-opioid receptor.

Background: Extracellular signal-regulated kinases (ERKs) are important signaling mediators in mammalian cells and, as a result, one of the major areas of research focus. The detection and quantification of ERK phosphorylation as an index of activation is normally conducted using immunoblotting, which does not allow high-throughput drug screening. Plate-based immunocytochemical assays provide a cheaper and relatively high-throughput alternative method for quantifying ERK phosphorylation. Here, we present optimization steps aimed to increase assay sensitivity and reduce variance and cost using the LI-COR In-Cell Western (I-CW) system in a recombinant CHO-K1 cell line, over-expressing the human delta-opioid receptor (hDOPr) as a model. Methods: Cells cultured in 96-well microassay plates were stimulated with three standard/selective DOPr agonists (SNC80, ADL5859, and DADLE) and a novel selective DOPr agonist (PN6047) to elicit a phospho-ERK response as an index of activation. A number of experimental conditions were investigated during the assay development. Key results: Preliminary experiments revealed a clearly visible edge-effect which significantly increased assay variance across the plate and which was reduced by pre-incubation for 30 min at room temperature. ERK phosphorylation was detectable as early as 1 min after agonist addition, with a distinct peak at 3–5 min. Optimization of the cell seeding densities showed that 25,000 cells per well have the lowest basal phospho-ERK response and an optimal agonist ERK1/2 signal. Pre-incubation with apyrase (an ATPase) did not reduce the basal or agonist responses. All agonists produced concentration-dependent increases in phospho-ERK activation, and pertussis toxin was able to attenuate these ERK responses. Naltrindole, which is a selective DOPr antagonist, was able to antagonize the DOPr-mediated ERK activation of the ligands. Conclusion: We have developed an optimization protocol and highlighted a number of considerations when performing this high-throughput fluorescence immunocytochemical (ICC) assay measuring ERK phosphorylation in the human DOPr. The optimized protocol was found to be a more conducive option for the screening of delta agonists. This provides a basis for additional assay development to investigate opioid pharmacology. This protocol should be widely applicable for measuring ERK phosphorylation in any cell line and investigating other protein targets in GPCR drug discovery.

Opioids alter paw placement during walking, confounding assessment of analgesic efficacy in a postsurgical pain model in mice.

Introduction:Hind paw–directed assays are commonly used to study the analgesic effects of opioids in mice. However, opioid-induced hyperlocomotion can obscure results of such assays.Objectives:We aimed to overcome this potential confound by using gait analysis to observe hind paw usage during walking in mice.Methods:We measured changes in the paw print area after induction of postsurgical pain (using the paw incision model) and treatment with oxycodone.Results:Paw incision surgery reduced the paw print area of the injured hind paw as mice avoided placing the incised section of the paw on the floor. Surprisingly, oxycodone caused a tiptoe-like gait in mice, reducing the paw print area of both hind paws. Further investigation of this opioid-induced phenotype revealed that analgesic doses of oxycodone or morphine dose-dependently reduced the hind paw print area in uninjured mice. The gait changes were not dependent on opioid-induced increases in the locomotor activity; speed and paw print area had no correlation in opioid-treated mice, and other analgesic compounds that alter locomotor activity did not affect the paw print area.Conclusion:Unfortunately, the opioid-induced “tiptoe” gait phenotype prevented gait analysis from being a viable metric for demonstrating opioid analgesia in injured mice. However, this work reveals an important, previously uncharacterized effect of treatment with analgesic doses of opioids on paw placement. Our characterization of how opioids affect gait has important implications for the use of mice to study opioid pharmacology and suggests that scientists should use caution when using hind paw–directed nociceptive assays to test opioid analgesia in mice.

A Critical Review on the Pharmacodynamics and Pharmacokinetics of Non-steroidal Anti-inflammatory Drugs and Opioid Drugs Used in Reptiles

Non-steroidal anti-inflammatory drugs (NSAIDs) and opioids are analgesics used for moderate to severe pain in many animals, including reptiles. However, reptilian dosing regimens are often extrapolated from other animal species. This is not ideal as inter- and intra-species variability in physiology may result in varied drug disposition. Therefore, this critical review aims to collate data from pharmacological studies of selected NSAIDs and opioids performed in reptile and provide an analysis and discussion on the existing pharmacodynamic knowledge and pharmacokinetic data of NSAIDs and opioids use in reptiles. Additionally, key pharmacokinetic trends that may aid dosing of NSAIDs and opioids in reptiles will also be highlighted. Most of the existing reports of NSAID used in reptiles did not observe any adverse effects directly associated to the respective NSAID used, with meloxicam being the most well-studied. Despite the current absence of analgesic efficacy studies for NSAIDs in reptiles, most reports observed behavioural improvements in reptiles after NSAID treatment. Fentanyl and morphine were studied in the greatest number of reptile species with analgesic effects observed with the doses used, while adverse effects such as sedation were observed most with butorphanol use. While pharmacokinetic trends were drug- and species-specific, it was observed that clearance (CL) of drugs tended to be higher in squamates compared to chelonians. The half-life (t1/2) of meloxicam also appeared to be longer when dosed orally compared to other routes of drug administration. This could have been due to absorption-rate limited disposition. Although current data provided beneficial information, there is an urgent need for future research on NSAID and opioid pharmacology to ensure the safe and effective use of opioids in reptiles.

Positive Allosteric Modulation of the Mu Opioid Receptor

Opioid therapeutics, such as morphine, that act at the mu‐opioid receptor (MOR) are the clinical standard for patients struggling to manage symptoms associated with pain. It is widely understood that although opioids are effective at treating pain, their use leads to the development of severe adverse effects, such as constipation, addiction, and respiratory depression. Thus, there is a clear need for a safer alternative to manage pain. One such alternative is to enhance the effects of the body’s endogenous opioid system by positive allosteric modulation (PAM) of MOR. A known PAM, BMS‐986122, enhances MOR agonist potency in cellular models and MOR agonist mediated antinociception in vivo. In addition, this PAM is active alone in a variety of mouse pain assays by promoting the activity of endogenous opioid peptides. Moreover, at an effective antinociceptive dose, BMS‐986122 alone produces less severe adverse effects than morphine as determined by measures of constipation, respiratory depression, and conditioned place preference. However, we do not yet know how the overall pharmacology of opioids is affected by PAMs or if all opioid drugs are equally sensitive to PAM modulation. Here we compare the ability of BMS‐986122 to enhance the action of three structurally diverse opioid drugs, morphine, methadone, and fentanyl, in an acute pain assay and in an assay examining respiratory depression using CD‐1 male and female mice. We show that BMS‐986122 increases the antinociceptive effects of the opioid therapeutics in the warm water tail withdrawal assay without promoting the ability of the drugs to lower blood oxygen levels or heart rate. Future work will assess the effects of BMS‐986122 in additional acute and chronic pain models and with a more diverse group of opioids. If additional experiments support the concept that BMS‐986122 enhances MOR‐mediated antinociception but not MOR‐mediated respiratory depression, this will validate the development of MOR‐PAMs as standalone pain medications and support the use of PAMs as opioid‐sparing drugs for the effective management of pain.

Opioids for acute pain management in children.

Opioids are integral to multimodal analgesic regimens in children with moderate to severe acute pain. Throughout normal childhood there are marked changes in physiology, and social and psychological development that influence the perception and expression of pain, the pharmacology of opioids, and how they are used. A multidimensional pain assessment is key to guiding appropriate opioid prescribing. Most of the commonly used opioids in adults are used in children, with the increasing exception of codeine (as a result of regulatory change), and are generally well tolerated. Patient groups at increased risk of ventilatory impairment include neonates and those with obstructive sleep apnoea, severe neurodevelopmental conditions, trisomy 21, and severe epilepsy. Slow-release opioids are not recommended for general use, but may be used in select populations, for example, following scoliosis surgery, major trauma or burns. Prescribing and administration errors are a major issue in paediatrics generally; the potential consequences of opioid prescribing or administration errors are serious, particularly following hospital discharge. Opioids prescribed at discharge are frequently in excess of a child's analgesic requirements; three to five days supply appears sufficient for the majority of common paediatric operations. Discharge opioid prescriptions have been linked to long-term opioid use in adolescents with risk factors. Misuse of prescription opioids by adolescents is also concerning, with prevalence estimates ranging from 1.1% to 20%. Caregivers have a tendency to underdose opioids in their children; caregiver education may improve appropriate administration. Caregivers must also be provided with instructions on safe storage and disposal of unused opioids.

Increased heroin intake and relapse vulnerability in intermittent relative to continuous self-administration: Sex differences in rats.

Studies using intermittent-access drug self-administration show increased motivation to take and seek cocaine and fentanyl, relative to continuous access. In this study, we examined the effects of intermittent- and continuous-access self-administration on heroin intake, patterns of self-administration and cue-induced heroin-seeking, after forced or voluntary abstinence, in male and female rats. We also modelled brain levels of heroin and its active metabolites. Rats were trained to self-administer a palatable solution and then heroin (0.075 mg·kg-1 per inf) either continuously (6 h·day-1 ; 10 days) or intermittently (6 h·day-1 ; 5-min access every 30-min; 10 days). Brain levels of heroin and its metabolites were modelled using a pharmacokinetic software. Next, heroin-seeking was assessed after 1 or 21 abstinence days. Between tests, rats underwent either forced or voluntary abstinence. The oestrous cycle was measured using a vaginal smear test. Intermittent access exacerbated heroin self-administration and was characterized by a burst-like intake, yielding higher brain peaks of heroin and 6-monoacetylmorphine concentrations. Moreover, intermittent access increased cue-induced heroin-seeking during early, but not late abstinence. Heroin-seeking was higher in females after intermittent, but not continuous access, and this effect was independent of the oestrous cycle. Intermittent heroin access in rats resembles critical features of heroin use disorder: a self-administration pattern characterized by repeated large doses of heroin and higher relapse vulnerability during early abstinence. This has significant implications for refining animal models of substance use disorder and for better understanding of the neuroadaptations responsible for this disorder. This article is part of a themed issue on Advances in Opioid Pharmacology at the Time of the Opioid Epidemic. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v180.7/issuetoc.

Central metabolism as a potential origin of sex differences in morphine antinociception but not induction of antinociceptive tolerance in mice.

In rodents, morphine antinociception is influenced by sex. However, conflicting results have been reported regarding the interaction between sex and morphine antinociceptive tolerance. Morphine is metabolised in the liver and brain into morphine-3-glucuronide (M3G). Sex differences in morphine metabolism and differential metabolic adaptations during tolerance development might contribute to behavioural discrepancies. This article investigates the differences in peripheral and central morphine metabolism after acute and chronic morphine treatment in male and female mice. Sex differences in morphine antinociception and tolerance were assessed using the tail-immersion test. After acute and chronic morphine treatment, morphine and M3G metabolic kinetics in the blood were evaluated using LC-MS/MS. They were also quantified in several CNS regions. Finally, the blood-brain barrier (BBB) permeability of M3G was assessed in male and female mice. This study demonstrated that female mice showed weaker morphine antinociception and faster induction of tolerance than males. Additionally, female mice showed higher levels of M3G in the blood and in several pain-related CNS regions than male mice, whereas lower levels of morphine were observed in these regions. M3G brain/blood ratios after injection of M3G indicated no sex differences in M3G BBB permeability, and these ratios were lower than those obtained after injection of morphine. These differences are attributable mainly to morphine central metabolism, which differed between males and females in pain-related CNS regions, consistent with weaker morphine antinociceptive effects in females. However, the role of morphine metabolism in antinociceptive tolerance seemed limited. This article is part of a themed issue on Advances in Opioid Pharmacology at the Time of the Opioid Epidemic. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v180.7/issuetoc.

New pharmacological perspectives and therapeutic options for opioids: Differences matter.

Opioids remain the major drug class for the treatment of acute, chronic and cancer pain, but have major harmful effects such as dependence and opioid-induced ventilatory impairment. Although no new typical opioids have come onto the market in the past almost 50 years, a plethora of new innovative formulations has been developed to meet the clinical need. This review is intended to shed light on new understanding of the molecular pharmacology of opioids, which has arisen largely due to the genomic revolution, and what new drugs may become available in the coming years. Atypical opioids have and are being developed which not only target the mu opioid receptor but other targets in the pain pathway. Biased mu agonists have been developed but remain 'unbiased' clinically. The contribution of drugs targeting non-mu opioid receptors either alone or as heterodimers shows potential promise but remains understudied. That gene splice variants of the mu opioid receptor produce multiple receptor isoforms in different brain regions, and may change with pain chronicity and phenotype, presents new challenges but also opportunities for precision pain medicine. Finally, that opioids also have pro-inflammatory effects not aligned with mu opioid receptor binding affinity implicates a fresh understanding of their role in chronic pain, whether cancer or non-cancer. Hopefully, a new understanding of opioid analgesic drug action may lead to new drug development and better precision medicine in acute and chronic pain relief with less patient harm.

Opioids and pituitary function: expert opinion.

Opioids are highly addictive potent analgesics and anti-allodynics whose use has dramatically increased in recent decades. The precipitous rise in opioid dependency and opioid use disorder is an important public health challenge given the risks for severely adverse health outcomes. The long-term opioid impact on hypothalamic-pituitary axes is particularly underappreciated among both endocrinologists and primary care physicians. We review the effects of opioids on hypothalamic-pituitary-target gland function and their implications for clinical practice. Experts in hypothalamic-pituitary disorders and opioid pharmacology reviewed recently published literature and considered strategies for diagnosing and managing these opioid-induced endocrine effects. Opioid suppression of hypothalamic-pituitary axes can lead to hypogonadotropic hypogonadism, central adrenal insufficiency, and hyperprolactinemia. These important clinical manifestations are often under-estimated, poorly evaluated, and typically either untreated or not optimally managed. Data on biochemical testing for diagnosis and on the effect of hormone replacement in these patients is limited and prospective randomized controlled studies for guiding clinical practice are lacking. Patients should be informed about risks for hypogonadism, adrenal insufficiency, and hyperprolactinemia, and encouraged to report associated symptoms. Based on currently available evidence, we recommend clinical and biochemical evaluation for potential central adrenal insufficiency, central hypogonadism, and/or hyperprolactinemia in patients chronically treated with opioids as well as the use of current expert guidelines for the diagnosis and treatment of these conditions.

Metabolic interactions of benzodiazepines with oxycodone ex vivo and toxicity depending on usage patterns in an animal model.

Opioids and benzodiazepines are frequently combined in medical as well as in non-medical contexts. At high doses, such combinations often result in serious health complications attributed to pharmacodynamics interactions. Here, we investigate the contribution of the metabolic interactions between oxycodone, diazepam and diclazepam (a designer benzodiazepine) in abuse/overdose conditions through ex vivo, in vivo and in silico approaches. A preparation of pooled human liver microsomes was used to study oxycodone metabolism in the presence or absence of diazepam or diclazepam. In mice, diazepam or diclazepam was concomitantly administered with oxycodone to mimic acute intoxication. Diclazepam was introduced on Day 10 in mice continuously infused with oxycodone for 15 days to mimic chronic intoxication. In silico modelling was used to study the molecular interactions of the three drugs with CYP3A4 and 2D6. In mice, in acute conditions, both diazepam and diclazepam inhibited the metabolism of oxycodone. In chronic conditions and at pharmacologically equivalent doses, diclazepam drastically enhanced the production of oxymorphone. In silico, the affinity of benzodiazepines was higher than oxycodone for CYP3A4, inhibiting oxycodone metabolism through CYP3A4. Oxycodone metabolism is likely to be diverted towards CYP2D6. Acute doses of diazepam or diclazepam result in the accumulation of oxycodone, whereas chronic administration induces the accumulation of oxymorphone, the toxic metabolite. This suggests that overdoses of opioids in the presence of benzodiazepines are partly due to metabolic interactions, which in turn explain the patterns of toxicity dependent on usage. This article is part of a themed issue on Advances in Opioid Pharmacology at the Time of the Opioid Epidemic. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v180.7/issuetoc.

Therapeutic potential of opioid receptor heteromers in chronic pain and associated comorbidities.

Chronic pain affects 20% to 45% of the global population and is often associated with the development of anxio-depressive disorders. Treatment of this debilitating condition remains particularly challenging with opioids prescribed to alleviate moderate to severe pain. However, despite strong antinociceptive properties, numerous adverse effects limit opioid use in the clinic. Moreover, opioid misuse and abuse have become a major health concern worldwide. This prompted efforts to design original strategies that would efficiently and safely relieve pain. Targeting of opioid receptor heteromers is one of these. This review summarizes our current knowledge on the role of heteromers involving opioid receptors in the context of chronic pain and anxio-depressive comorbidities. It also examines how heteromerization in native tissue affects ligand binding, receptor signalling and trafficking properties. Finally, the therapeutic potential of ligands designed to specifically target opioid receptor heteromers is considered. LINKED ARTICLES: This article is part of a themed issue on Advances in Opioid Pharmacology at the Time of the Opioid Epidemic. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v180.7/issuetoc.

Alternative pain management via endocannabinoids in the time of the opioid epidemic: Peripheral neuromodulation and pharmacological interventions.

The use of opioids in pain management is hampered by the emergence of analgesic tolerance, which leads to increased dosing and side effects, both of which have contributed to the opioid epidemic. One promising potential approach to limit opioid analgesic tolerance is activating the endocannabinoid system in the CNS, via activation of CB1 receptors in the descending pain inhibitory pathway. In this review, we first discuss preclinical and clinical evidence revealing the potential of pharmacological activation of CB1 receptors in modulating opioid tolerance, including activation by phytocannabinoids, synthetic CB1 receptor agonists, endocannabinoid degradation enzyme inhibitors, and recently discovered positive allosteric modulators of CB1 receptors. On the other hand, as non-pharmacological pain relief is advocated by the US-NIH to combat the opioid epidemic, we also discuss contributions of peripheral neuromodulation, involving the electrostimulation of peripheral nerves, in addressing chronic pain and opioid tolerance. The involvement of supraspinal endocannabinoid systems in peripheral neuromodulation-induced analgesia is also discussed. LINKED ARTICLES: This article is part of a themed issue on Advances in Opioid Pharmacology at the Time of the Opioid Epidemic. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v180.7/issuetoc.

Strategies towards safer opioid analgesics-A review of old and upcoming targets.

Opioids continue to be of use for the treatment of pain. Most clinically used analgesics target the μ opioid receptor whose activation results in adverse effects like respiratory depression, addiction and abuse liability. Various approaches have been used by the field to separate receptor-mediated analgesic actions from adverse effects. These include biased agonism, opioids targeting multiple receptors, allosteric modulators, heteromers and splice variants of the μ receptor. This review will focus on the current status of the field and some upcoming targets of interest that may lead to a safer next generation of analgesics. LINKED ARTICLES: This article is part of a themed issue on Advances in Opioid Pharmacology at the Time of the Opioid Epidemic. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v180.7/issuetoc.

Regulator of G-Protein Signalling 4 (RGS4) negatively modulates nociceptin/orphanin FQ opioid receptor signalling: Implication for l-Dopa-induced dyskinesia.

Regulator of G-protein signalling 4 (RGS4) is a signal transduction protein that accelerates intrinsic GTPase activity of Gαi/o and Gαq subunits, suppressing GPCR signalling. Here, we investigate whether RGS4 modulates nociceptin/orphanin FQ (N/OFQ) opioid (NOP) receptor signalling and if this modulation has relevance for l-Dopa-induced dyskinesia. HEK293T cells transfected with NOP, NOP/RGS4 or NOP/RGS19 were challenged with N/OFQ and the small-molecule NOP agonist AT-403, using D1-stimulated cAMP levels as a readout. Primary rat striatal neurons and adult mouse striatal slices were challenged with either N/OFQ or AT-403 in the presence of the experimental RGS4 chemical probe, CCG-203920, and D1-stimulated cAMP or phosphorylated extracellular signal regulated kinase 1/2 (pERK) responses were monitored. In vivo, CCG-203920 was co-administered with AT-403 and l-Dopa to 6-hydroxydopamine hemilesioned rats, and dyskinetic movements, striatal biochemical correlates of dyskinesia (pERK and pGluR1 levels) and striatal RGS4 levels were measured. RGS4 expression reduced NOFQ and AT-403 potency and efficacy in HEK293T cells. CCG-203920 increased N/OFQ potency in primary rat striatal neurons and potentiated AT-403 response in mouse striatal slices. CCG-203920 enhanced AT-403-mediated inhibition of dyskinesia and its biochemical correlates, without compromising its motor-improving effects. Unilateral dopamine depletion caused bilateral reduction of RGS4 levels, which was reversed by l-Dopa. l-Dopa acutely up-regulated RGS4 in the lesioned striatum. RGS4 physiologically inhibits NOP receptor signalling. CCG-203920 enhanced NOP responses and improved the antidyskinetic potential of NOP receptor agonists, mitigating the effects of striatal RGS4 up-regulation occurring during dyskinesia expression. This article is part of a themed issue on Advances in Opioid Pharmacology at the Time of the Opioid Epidemic. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v180.7/issuetoc.