FQ Peptide Receptor Research Articles

Potent and selective NOP receptor activation reduces cocaine self-administration in rats by lowering hedonic set point.

Developing new medications for the treatment of cocaine dependence continues to be a research priority. Compelling evidence indicates that mixed opioid receptor agonists, particularly bifunctional compounds that target nociceptin/orphanin FQ peptide (NOP) and mu opioid receptors, may be useful for the treatment of cocaine addiction. Here, we verify that potent and selective pharmacological activation of NOP receptors is sufficient to reduce relevant facets of cocaine addiction in animal models. Accordingly, we determined whether systemic injections of the small molecule AT-312 (0, 1, 3 mg/kg) could reduce operant cocaine self-administration, motivation for cocaine, and vulnerability to cocaine relapse in rats. Results indicate that a potent and selective NOP receptor agonist was equally efficacious in reducing the number of cocaine infusions in short (1-hour), as well as long (6-hour) access sessions. When tested on an economic-demand reinforcement schedule, AT-312 reduced Q0 , the parameter that describes the amount of drug consumed at zero price, while leaving the parameter α, a measure of motivation for drug consumption, unaltered. Furthermore, AT-312 successfully reduced conditioned reinstatement of cocaine seeking. In contrast, the NOP receptor agonist did not modify food self-administration. Blockade of the NOP receptor with the antagonist SB-612111 prevented the effect of AT-312 in decreasing cocaine-reinforced responding under a 2-hour fixed ratio 1 schedule, suggesting a NOP receptor-mediated mechanism. This work demonstrates that potent and selective activation of NOP receptors is sufficient to decrease cocaine taking and seeking behaviors in rats.

Tetrabranched Hetero-Conjugated Peptides as Bifunctional Agonists of the NOP and Mu Opioid Receptors.

The general aim of the work was the validation of a new synthetic methodology designed for obtaining bifunctional heterotetrabranched peptide ligands. Applying an easily accessible synthetic route, we provided a small series of heteromultimeric peptide conjugates targeting the nociceptin/orphanin FQ (N/OFQ) peptide receptors (NOP) and mu opioid receptors. Among these, H-PWT1-N/OFQ-[Dmt1]dermorphin demonstrated a similar and high agonist potency at the NOP and mu receptors. The achieved results confirmed the robustness of the approach that is extremely versatile and virtually applicable to different peptide sequences whose pharmacological activity can be combined for generating dual acting multimeric compounds. These innovative pharmacological tools will be extremely helpful for investigating the consequences of the simultaneous activation and/or blockage of different peptidergic receptors.

BPR1M97, a dual mu opioid receptor/nociceptin-orphanin FQ peptide receptor agonist, produces potent antinociceptive effects with safer properties than morphine

There is unmet need to design an analgesic with fewer side effects for severe pain management. Although traditional opioids are the most effective painkillers, they are accompanied by severe adverse responses, such as respiratory depression, constipation symptoms, tolerance, withdrawal, and addiction. We indicated BPR1M97 as a dual mu opioid receptor (MOP)/nociceptin-orphanin FQ peptide (NOP) receptor full agonist and investigated the pharmacology of BPR1M97 in multiple animal models. In vitro studies on BPR1M97 were assessed using cyclic-adenosine monophosphate production, β-arrestin, internalization, and membrane potential assays. In vivo studies were characterized using the tail-flick, tail-clip, lung functional, heart functional, acetone drop, von Frey hair, charcoal meal, glass bead, locomotor activity, conditioned place preference (CPP) and naloxone precipitation tests. BPR1M97 elicited full agonist properties for all cell-based assays tested in MOP-expressing cells. However, it acted as a G protein-biased agonist for NOP. BPR1M97 initiated faster antinociceptive effects at 10 min after subcutaneous injection and elicited better analgesia in cancer-induced pain than morphine. Unlike morphine, BPR1M97 caused less respiratory, cardiovascular, and gastrointestinal dysfunction. In addition, BPR1M97 decreased global activity and induced less withdrawal jumping precipitated by naloxone. Thus, BPR1M97 could serve as a novel small molecule dual receptor agonist for antinociception with fewer side effects than morphine.This article is part of the Special Issue entitled ‘New Vistas in Opioid Pharmacology’.

Activation of Membrane Estrogen Receptors Attenuates NOP-Mediated Tactile Antihypersensitivity in a Rodent Model of Neuropathic Pain.

Women manifest a higher prevalence of several chronic pain disorders compared to men. We demonstrated earlier that estrogen rapidly attenuates nociceptin/orphanin FQ (N/OFQ) peptide receptor (NOP)-mediated thermal antinociception through the activation of membrane estrogen receptors (mERs). However, the effect of mER activation on NOP-mediated attenuation of tactile hypersensitivity in a neuropathic model of pain and the underlying mechanisms remain unknown. Following spared nerve injury (SNI), male and ovariectomized (OVX) female rats were intrathecally (i.t.) injected with a selective mER agonist and nociceptin/orphanin FQ (N/OFQ), the endogenous ligand for NOP, and their effects on paw withdrawal thresholds (PWTs) were tested. In addition, spinal cord tissue was used to measure changes in phosphorylated extracellular signal regulated kinase (ERK), protein kinase A (PKA), protein kinase C (PKC), and protein kinase B (Akt) levels. SNI significantly reduced PWTs in males and OVX females, indicating tactile hypersensitivity. N/OFQ restored PWTs, indicating an antihypersensitive effect. Selective mER activation attenuated the effect of N/OFQ in an antagonist-reversible manner. SNI led to a robust increase in the phosphorylation of ERK, PKA, PKC, and Akt. However, mER activation did not further affect it. Thus, we conclude that activation of mERs rapidly abolishes NOP-mediated tactile antihypersensitivity following SNI via an ERK-, PKA-, PKC-, and Akt-independent mechanism.

Cebranopadol, a Novel First-in-Class Analgesic Drug Candidate: First Experience With Cancer-Related Pain for up to 26 Weeks

ContextPain is one of the most prevalent symptoms associated with cancer. Strong opioids are commonly used in the analgesic management of the disease, but carry the risk of severe side effects. Cebranopadol is a first-in-class drug candidate, combining nociceptin/orphanin FQ peptide and opioid peptide receptor agonism. For cancer patients, frequently experiencing multimorbidities and often exposed to polypharmacy, cebranopadol is easy to handle given its once-daily dosing, the small tablet size that enables swallowing, and the option to flexibly titrate to an effective dose. ObjectivesWe assessed the safety and tolerability of prolonged treatment with oral cebranopadol for up to 26 weeks in patients suffering from chronic moderate-to-severe cancer-related pain. MethodsThis was a non-randomized, multi-site, open-label, single-arm clinical trial with patients who had completed a double-blind trial comparing morphine prolonged release with cebranopadol. In this extension trial, patients were treated with oral cebranopadol for up to 26 weeks. ResultsCebranopadol was safe and well tolerated in patients with chronic moderate-to-severe pain related to cancer in the dose range tested (200–1000 μg once daily). The median and mean pain levels remained in the range of mild pain during the treatment period. ConclusionOur data suggest that cebranopadol was safe and well tolerated when administered for up to 26 weeks in patients with chronic cancer-related pain who were previously treated with cebranopadol or morphine prolonged release.

Effects of stimulation of mu opioid and nociceptin/orphanin FQ peptide (NOP) receptors on alcohol drinking in rhesus monkeys.

Alcohol use disorder (AUD) persists as a devastating public health problem; widely effective pharmacological treatments are needed. Evidence from rodent models suggests that stimulating brain receptors for the neuropeptide nociceptin/orphanin FQ (NOP) can decrease ethanol drinking. We characterized the effects of the mu opioid peptide (MOP) receptor agonist buprenorphine and the buprenorphine analog (2S)-2-[(5R,6R,7R,14S)-N-cyclopropylmethyl-4,5-epoxy-6,14-ethano-3-hydroxy-6 methoxymorphinan-7-yl]-3,3-dimethylpentan-2-ol (BU08028), which stimulates MOP and NOP receptors, in a translational nonhuman primate model of AUD. Rhesus monkeys drank a 4% ethanol solution 6 h per day, 5 days per week via an operant behavioral panel in their home cages. To assess behavioral selectivity, monkeys responded via a photo-optic switch to earn food pellets. After characterizing the acute effects of BU08028 (0.001-0.01 mg/kg, i.m.) and buprenorphine (0.003-0.056 mg/kg, i.m.), the drugs were administered chronically using a model of pharmacotherapy assessment that incorporates clinical aspects of AUD and treatment. Acutely, both drugs decreased ethanol drinking at doses that did not affect food-maintained responding. During chronic treatment, effects of BU08028 and buprenorphine were maintained for several weeks without development of tolerance or emergence of adverse effects. BU08028 was ~0.5 and 1.0 log units more potent in acute and chronic studies, respectively. The selective NOP receptor agonist SCH 221510 also selectively decreased ethanol intakes when given acutely (0.03-1.0 mg/kg, i.m.), whereas the MOP antagonist naltrexone (1.7-5.6 mg/kg, i.m.) decreased both ethanol intake and food pellets delivered. These data demonstrate that bifunctional MOP/NOP agonists, which may have therapeutic advantages to MOP-selective drugs, can decrease alcohol drinking in nonhuman primates.

Comparison of Reinforcing and Antinociceptive Effects of Agonists with Mixed NOP and MOP Receptor Agonist Action in Nonhuman Primates

Agonists with mixed nociceptin/orphanin FQ peptide (NOP) and mu opioid peptide (MOP) receptor agonist activities have been demonstrated as effective analgesics with fewer side effects. However, these newly developed compounds with different efficacies at the NOP and MOP receptors have not been compared in terms of their reinforcing and antinociceptive effects. The aim of this study was to determine and compare effects of AT‐121 and BU08028 (NOP/MOP partial agonists), AT‐175 (NOP full/MOP partial agonist), and cebranopadol (mixed NOP and opioid full agonist) in a series of behavioral assays established in rhesus monkeys (Macaca mutatta). Following systemic administration, AT‐121 (3–30 ug/kg), BU08028 (1–10 ug/kg), AT‐175 (1–10 ug/kg), and cebranopadol (1–5.6 ug/kg) all dose‐dependently produced antinociceptive effects against an acute noxious stimulus and attenuated capsaicin‐induced hypersensitivity. In the intravenous drug self‐administration assay, the relative reinforcing strengths (i.e., abuse potential) of these compounds were compared in monkeys under a progressive‐ratio schedule of reinforcement over a wide dose range. Unlike oxycodone and heroin producing robust reinforcing effects, AT‐121, BU08028, and AT‐175 did not significantly produce reinforcing effects. However, cebranopadol produced moderate reinforcing effects as compared to oxycodone and heroin. Taken together, these pharmacological studies in primates indicate that agonists with mixed NOP and MOP receptor agonist activities exert opioid‐like analgesic effects. Although the NOP receptor activation could attenuate the reinforcing effects mediated MOP partial agonist action, the NOP full agonist activity may not be able to completely attenuate the reinforcing effects mediated by MOP full agonist activity in primates.Support or Funding InformationThe US. NIH/NIDA grants (DA023281, DA027811, DA032568, and DA035359) and US. Department of Defense (W81XWH‐13‐2‐0045).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

BU10038 as a safe opioid analgesic with fewer side-effects after systemic and intrathecal administration in primates

BackgroundThe marked increase in mis-use of prescription opioids has greatly affected our society. One potential solution is to develop improved analgesics which have agonist action at both mu opioid peptide (MOP) and nociceptin/orphanin FQ peptide (NOP) receptors. BU10038 is a recently identified bifunctional MOP/NOP partial agonist. The aim of this study was to determine the functional profile of systemic or spinal delivery of BU10038 in primates after acute and chronic administration. MethodsA series of behavioural and physiological assays have been established specifically to reflect the therapeutic (analgesia) and side-effects (abuse potential, respiratory depression, itch, physical dependence, and tolerance) of opioid analgesics in rhesus monkeys. ResultsAfter systemic administration, BU10038 (0.001–0.01 mg kg−1) dose-dependently produced long-lasting antinociceptive and antihypersensitive effects. Unlike the MOP agonist oxycodone, BU10038 lacked reinforcing effects (i.e. little or no abuse liability), and BU10038 did not compromise the physiological functions of primates including respiration, cardiovascular activities, and body temperature at antinociceptive doses and a 10–30-fold higher dose (0.01–0.1 mg kg−1). After intrathecal administration, BU10038 (3 μg) exerted morphine-comparable antinociception and antihypersensitivity without itch scratching responses. Unlike morphine, BU10038 did not cause the development of physical dependence and tolerance after repeated and chronic administration. ConclusionsThese in vivo findings demonstrate the translational potential of bifunctional MOP/NOP receptor agonists such as BU10038 as a safe, non-addictive analgesic with fewer side-effects in primates. This study strongly supports that bifunctional MOP/NOP agonists may provide improved analgesics and an alternative solution for the ongoing prescription opioid crisis.

Cancer-related chronic pain: Investigation of the novel analgesic drug candidate cebranopadol in a randomized, double-blind, noninferiority trial.

Cancer-related pain is a growing health problem given the increasing life expectancy of cancer patients. Opioids are commonly used to treat cancer-related pain, but carry the risk of severe side effects, limiting their use. Cebranopadol is a first-in-class drug candidate, combining nociceptin/orphanin FQ peptide and opioid peptide receptor agonism. This trial examined the analgesic efficacy of cebranopadol compared with morphine prolonged release (PR) in patients with moderate-to-severe cancer-related pain. This double-blind, parallel-group, multiple-dose trial was designed as noninferiority trial for efficacy of cebranopadol versus morphine PR. Planned with 524 patients, finally 126 patients were treated for up to 7weeks (low accrual). The primary efficacy endpoint was the average amount of daily rescue medication intake (morphine immediate release) over the last 2weeks of treatment. For the primary endpoint, noninferiority of cebranopadol with and superiority over morphine PR were demonstrated (Full Analysis Set: ∆[95%CI]=-7.48mg [-12.05, -2.92]; Per Protocol Set: ∆[95%CI]=-4.67mg [-9.25, -0.10]). The vast majority of patients (≥75%, either treatment) had clinically relevant pain reduction, and noninferiority on this secondary endpoint was not shown. Mostly used doses were ≤800μg cebranopadol or ≤120mg morphine PR daily. A total of 83.1% of patients on cebranopadol and 82.0% on morphine PR experienced treatment-emergent adverse events. Cebranopadol was effective, safe and well tolerated in the dose range tested (200-1,000μg) in patients suffering from chronic moderate-to-severe cancer-related pain and was superior to morphine PR on the primary endpoint. Cebranopadol presents a new approach to treat cancer pain. The drug candidate was easy to titrate, safe and well tolerated, and as effective as morphine PR in patients suffering from chronic moderate-to-severe cancer-related pain.

N/OFQ-NOP System in Food Intake.

While lifestyle modifications should be the first-line actions in preventing and treating obesity and eating disorders, pharmacotherapy also provides a necessary tool for the management of these diseases.However, given the limitations of current anti-obesity drugs, innovative treatments that improve efficacy and safety are needed.Since the discovery that the activation of the Nociceptin/Orphanin (N/OFQ) FQ peptide (NOP) receptor by N/OFQ induces an increase of food intake in laboratory animals, and the finding that this effect can be blocked by NOP antagonists, many NOP agonists and antagonists have been synthesized and tested in vitro and in vivo for their potential regulation of feeding behavior. Promising results seem to suggest that the N/OFQergic system may be a potential therapeutic target for the neural control of feeding behavior and related pathologies, especially in binge-like eating behavior.

Cebranopadol: A Novel First-in-Class Potent Analgesic Acting via NOP and Opioid Receptors.

Cebranopadol is a novel first-in-class analgesic with highly potent agonistic activity at nociceptin/orphanin FQ peptide (NOP) and opioid receptors. It is highly potent and efficacious across a broad range of preclinical pain models. Its side effect profile is better compared to typical opioids. Mechanistic studies have shown that cebranopadol's activity at NOP receptors contributes to its anti-hyperalgesic effects while ameliorating some of its opioid-type side effects, including respiratory depression and abuse potential. Phase II of clinical development has been completed, demonstrating efficacy and good tolerability in acute and chronic pain conditions.This article focusses on reviewing data on the preclinical in vitro and in vivo pharmacology, safety, and tolerability, as well as clinical trials with cebranopadol.

NOP Receptor Signaling Cascades.

The nociceptin/orphanin FQ (N/OFQ) peptide (NOP) receptor is a G protein-coupled receptor with wide distribution throughout the peripheral and central nervous system. Similar to other opioid receptors, NOP receptors couple to intracellular second messengers and regulatory proteins to affect biological systems. In this chapter, we review the current literature for NOP signaling cascades including their role as classic GPCRs, the investigation of their kinase and arrestin signaling pathways, and the importance of examining biased signaling to critically evaluate the therapeutic potential of novel NOP agonists.

Synthesis, Biological Evaluation, and SAR Studies of 14β-phenylacetyl Substituted 17-cyclopropylmethyl-7, 8-dihydronoroxymorphinones Derivatives: Ligands With Mixed NOP and Opioid Receptor Profile.

A series of 14β-acyl substituted 17-cyclopropylmethyl-7,8-dihydronoroxymorphinone compounds has been synthesized and evaluated for affinity and efficacy for mu (MOP), kappa (KOP), and delta (DOP) opioid receptors and nociceptin/orphanin FQ peptide (NOP) receptors. The majority of the new ligands displayed high binding affinities for the three opioid receptors, and moderate affinity for NOP receptors. The affinities for NOP receptors are of particular interest as most classical opioid ligands do not bind to NOP receptors. The predominant activity in the [35S]GTPγS assay was partial agonism at each receptor. The results are consistent with our prediction that an appropriate 14β side chain would access a binding site within the NOP receptor and result in substantially higher affinity than displayed by the parent compound naltrexone. Molecular modeling studies, utilizing the recently reported structure of the NOP receptor, are also consistent with this interpretation.

A dual-targeting painkiller

Pain Opioids are among the most effective treatments for severe pain. Their pain-relieving effects are mediated by activation of the mu opioid receptor (MOR). Unfortunately, selective MOR agonists induce diverse side effects, including respiratory depression, tolerance, hyperalgesia, and dependence. Recently, activation of the nociceptin/orphanin FQ peptide receptor (NOR) has been reported to enhance MOR agonist–induced analgesia without producing side effects. Ding et al. developed a bifunctional MOR/NOR agonist called AT-121, which showed potent analgesic effects in nonhuman primates without inducing hyperalgesia, respiratory depression, or dependence. Bifunctional MOR/NOR agonists might thus represent a safe and effective pharmacological tool for treating severe pain. Sci. Transl. Med. 10 , eaar3483 (2018).

A bifunctional nociceptin and mu opioid receptor agonist is analgesic without opioid side effects in nonhuman primates.

Misuse of prescription opioids, opioid addiction, and overdose underscore the urgent need for developing addiction-free effective medications for treating severe pain. Mu opioid peptide (MOP) receptor agonists provide very effective pain relief. However, severe side effects limit their use in the clinical setting. Agonists of the nociceptin/orphanin FQ peptide (NOP) receptor have been shown to modulate the antinociceptive and reinforcing effects of MOP agonists. We report the discovery and development of a bifunctional NOP/MOP receptor agonist, AT-121, which has partial agonist activity at both NOP and MOP receptors. AT-121 suppressed oxycodone's reinforcing effects and exerted morphine-like analgesic effects in nonhuman primates. AT-121 treatment did not induce side effects commonly associated with opioids, such as respiratory depression, abuse potential, opioid-induced hyperalgesia, and physical dependence. Our results in nonhuman primates suggest that bifunctional NOP/MOP agonists with the appropriate balance of NOP and MOP agonist activity may provide a dual therapeutic action for safe and effective pain relief and treating prescription opioid abuse.

Cebranopadol: A Novel, First-in-Class, Strong Analgesic: Results from a Randomized Phase IIa Clinical Trial in Postoperative Acute Pain

Cebranopadol is a potent, first-in-class analgesic with a novel mechanistic approach combining nociceptin/orphanin FQ peptide (NOP) and opioid peptide receptor agonism. We aim to evaluate, for the first time, the analgesic efficacy, safety, and tolerability of cebranopadol in patients suffering from moderate to severe acute pain following bunionectomy. We conducted a phase IIa, randomized, multi-center, double-blind, double-dummy, placebo- and active-controlled, parallel group clinical trial. A total of 258 patients who underwent a primary bunionectomy were randomly assigned to receive a single oral administration of cebranopadol 200 µg, 400 µg, or 600 µg, morphine controlled-release (CR) 60 mg, or placebo. The primary efficacy end-point was the sum of pain intensity (SPI) 2 to 10 hours (SPI2-10) after the first investigational medicinal product (IMP) intake time-point. Cebranopadol doses of 400 µg and 600 µg were more effective in reducing postoperative acute pain compared to placebo, from 2 hours until approximately 22 hours after the first IMP intake time-point. No difference was observed between cebranopadol 200 µg and placebo. Per the subject global impression of the IMP assessment, patients who received cebranopadol 400 µg and 600 µg were more satisfied with the ability of the medication to treat their pain compared to those who received morphine CR 60 mg. On the primary end-point, the effect of morphine CR 60 mg was smaller than that of cebranopadol 400 µg and 600 µg. However, the analgesic effect of morphine CR 60 mg emerged later relative to IMP intake, as shown by the fact that similar SPI results as seen for cebranopadol 400 µg and 600 µg were obtained for later time windows. Cebranopadol treatment was safe, and single-dose administrations of 400 µg were better tolerated than morphine CR 60 mg. The relative frequency of patients with at least one treatment-emergent adverse event (TEAE) increased with increasing cebranopadol doses and was highest in the morphine CR 60 mg group. Although a double-dummy design was used to ensure blinding, a limitation of this trial was that cebranopadol and morphine CR were administered at 2 different time-points post-surgery, given the anticipated difference in the time to reach the maximum plasma concentration between the 2 treatments. Administration of single cebranopadol doses of 400 µg and 600 µg induced more effective analgesia following bunionectomy surgery compared to the traditional opioid morphine on the primary end-point (SPI2-10), while both cebranopadol doses and morphine ensured adequate 24-hour pain relief. Moreover, cebranopadol was better tolerated and received a better overall rating by the patients. Opioids, morphine, µ-opioid receptor, nociceptin/orphanin FQ peptide receptor, analgesic, bunionectomy, surgery, post-operative pain, single hallux valgus repair.

Pharmacological Assays for Investigating the NOP Receptor.

The nociceptin/orphanin FQ (N/OFQ) peptide receptor (NOP) is a G protein-coupled receptor involved in the regulation of several physiological functions and pathological conditions. Thus, researchers from academia and industry are pursuing NOP to discover and study novel pharmacological entities. In a multidisciplinary effort of pharmacologists, medicinal chemists, and molecular and structural biologists the mechanisms of NOP activation and inhibition have been, at least partially, disentangled. Here, we review the in vitro methodologies employed, which have contributed to our understanding of this target. We hope this chapter guides the reader through the mostly established assay platforms to investigate NOP pharmacology, and gives some hints taking advantage from what has already illuminated the function of other GPCRs. We analyzed the pharmacological results obtained with a large panel of NOP ligands investigated in several assays including receptor binding, stimulation of GTPγS binding, decrease of cAMP levels, calcium flux stimulation via chimeric G proteins, NOP/G protein and NOP/β-arrestin interaction, label-free assays such as dynamic mass redistribution, and bioassays such as the electrically stimulated mouse vas deferens.

Mu-opioid peptide (MOP) and nociceptin/orphanin FQ peptide (NOP) receptor activation both contribute to the discriminative stimulus properties of cebranopadol in the rat

The novel potent analgesic cebranopadol is an agonist at nociceptin/orphanin FQ peptide (NOP) and classical opioid receptors, with the highest in-vitro activity at NOP and mu-opioid peptide (MOP) receptors, and somewhat lower activity at kappa-opioid peptide (KOP) and delta-opioid peptide (DOP) receptors. We addressed the question of which of these pharmacological activities contribute to the stimulus properties of cebranopadol using a rat drug discrimination procedure. First, cebranopadol was tested in generalization tests against a morphine cue, including receptor-specific antagonism. Second, cebranopadol was established as a cue, and MOP, NOP, KOP and DOP receptor-selective agonists were tested in generalization tests. Third, cebranopadol in combination with receptor-selective antagonists was tested against the cebranopadol cue. Cebranopadol generalized to the morphine cue. Full generalization was only seen at clearly supra-analgesic doses. The effect of cebranopadol was reduced by naloxone, but was enhanced by the NOP receptor antagonist J-113397. In cebranopadol-trained rats, cebranopadol as well as morphine produced generalization. A NOP receptor agonist did not, while a DOP receptor agonist and a KOP receptor agonist weakly generalized to the cebranopadol cue. Conversely, generalization of cebranopadol was reduced by naloxone and J-113397, but not by a DOP or a KOP receptor antagonist. These results suggest a contribution of MOP receptor activity and a relative lack of contribution of DOP and KOP receptor activity to cebranopadol's stimulus properties. The findings regarding the contribution of NOP receptor activity were equivocal, but interestingly, the morphine-like stimulus property of cebranopadol appears to be reduced by its intrinsic NOP receptor activity.

Mitigation of adverse behavioral impact from predator exposure by the nociceptin/orphanin FQ peptide antagonist J-113397 in rats.

The nociceptin/orphanin FQ peptide (NOP) receptor is believed to have an integral modulatory function in the stress response system. We evaluated the highly selective NOP antagonist J-113397 (7.5 and 20.0 mg/kg), using a predator exposure in which rats were exposed to predator cats as a stressor. A single dose of J-113397 or vehicle was administered (intraperitoneally) shortly before exposure to the predators or a sham exposure. Behavioral impact was measured using elevated plus maze (EPM), open field activity (OFA), and an olfactory discrimination (OD). The predator exposure produced a relatively long-lasting deficit (decreased time in open arms, decreased basic activity) on the EPM while having little effect on performance on the OFA or OD. J-113397 mitigated the performance deficits on the EPM in a dose-dependent manner while having little effect on performance on the OFA or OD. The largest dose of J-113397, administered with a sham exposure, was essentially devoid of effects on the EPM, OFA, and OD. These results demonstrate that J-113397 can significantly and selectively mitigate the effects of a stressor typically used in a preclinical model of post-traumatic stress disorder. Furthermore, these results are consistent with and extend previous results showing that the NOP receptor has an important role in the response to stress and that NOP antagonism may, potentially, have therapeutic benefit in stress disorders.

Limited potential of cebranopadol to produce opioid-type physical dependence in rodents.

Cebranopadol is a novel potent analgesic agonist at the nociceptin/orphanin FQ peptide (NOP) and classical opioid receptors. As NOP receptor activation has been shown to reduce side effects related to the activation of μ-opioid peptide (MOP) receptors, the present study evaluated opioid-type physical dependence produced by cebranopadol in mice and rats. In a naloxone-precipitated withdrawal assay in mice, a regimen of seven escalating doses of cebranopadol over 2days produced only very limited physical dependence as evidenced by very little withdrawal symptoms (jumping) even at cebranopadol doses clearly exceeding the analgesic dose range. In contrast, mice showed clear withdrawal symptoms when treated with morphine within the analgesic dose range. In the rat, spontaneous withdrawal (by cessation of drug treatment; in terms of weight loss and behavioral score) was studied after 4-week subacute administration. Naloxone-precipitated withdrawal (in terms of weight loss and behavioral score) was studied in the same groups of rats after 1-week re-administration following the spontaneous withdrawal period. In both tests, cebranopadol-treated rats showed only few signs of withdrawal, while withdrawal effects in rats treated with morphine were clearly evident. These findings demonstrate a low potential of cebranopadol to produce opioid-type physical dependence in rodents. The prospect of this promising finding into the clinical setting remains to be established.