Targeting multiple opioid receptors – improved analgesics with reduced side effects?

Günther, Thomas; Dasgupta, Pooja; Mann, Anika; Miess, Elke; Kliewer, Andrea; Fritzwanker, Sebastian; Steinborn, Ralph; Schulz, Stefan

doi:10.1111/bph.13809

Cited by 137 publications

(136 citation statements)

References 102 publications

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“…Kappa receptor shows absent related to respiratory depression, nausea, and vomiting. The mu receptor has strong effects on respiratory depression and is associated with nausea and vomiting [19]. Our experimental results are consistent with previous findings; they also confirm that butorphanol is less likely to cause nausea and vomiting and show that butorphanol resulted in a lower postoperative VAS score than the pure mu-opioid receptor agonist sufentanil at the ED 95 dose.…”

Section: Discussionsupporting

confidence: 91%

Comparison of ED95 of Butorphanol and Sufentanil for gastrointestinal endoscopy sedation: a randomized controlled trial

et al. 2020

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Background: Butorphanol, a synthetic opioid partial agonist analgesic, has been widely used to control perioperative pain. However, the ideal dose and availability of butorphanol for gastrointestinal (GI) endoscopy are not well known. The aim of this study was to evaluated the 95% effective dose (ED 95 ) of butorphanol and sufentanil in GI endoscopy and compared their clinical efficacy, especially regarding the recovery time. Methods:The study was divided into two parts. For the first part, voluntary patients who needed GI endoscopy anesthesia were recruited to measure the ED 95 of butorphanol and sufentanil needed to achieve successful sedation before GI endoscopy using the sequential method (the Dixon up-and-down method). The second part was a double-blind, randomized study. Two hundred cases of painless GI endoscopy patients were randomly divided into two groups (n = 100), including group B (butorphanol at the ED 95 dose) and group S (sufentanil at the ED 95 dose). Propofol was infused intravenously as the sedative in both groups. The recovery time, visual analogue scale (VAS) score, hand grip strength, fatigue severity scores, incidence of nausea and vomiting, and incidence of dizziness were recorded.Results: The ED 95 of butorphanol for painless GI endoscopy was 9.07 μg/kg (95% confidence interval: 7.81-19.66 μg/kg). The ED 95 of sufentanil was 0.1 μg/kg (95% CI, 0.079-0.422 μg/kg). Both butorphanol and sufentanil provided a good analgesic effect for GI endoscopy. However, the recovery time for butorphanol was significantly shorter than that for sufentanil (P < 0.05, group B vs. group S:21.26 ± 7.70 vs. 24.03 ± 7.80 min).Conclusions: Butorphanol at 9.07 μg/kg was more effective than sufentanil for GI endoscopy sedation and notably reduced the recovery time.

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Section: Discussionsupporting

confidence: 91%

Comparison of ED95 of Butorphanol and Sufentanil for gastrointestinal endoscopy sedation: a randomized controlled trial

et al. 2020

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“…2 Through decades of research, numerous scientific strategies have tried to develop safe, non-addictive analgesics, but none has been demonstrated in humans. [3][4][5] The Nociceptin/Orphanin FQ (N/OFQ) peptide (NOP) receptor is the fourth opioid receptor subtype, which generally inhibits neuronal transmission. [6][7][8] Unlike a partial MOP agonist buprenorphine alone producing respiratory depression, 9 NOP agonists do not inhibit respiratory function.…”

Section: Introductionmentioning

confidence: 99%

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

Kiguchi

Ding

Cami‐Kobeci

et al. 2019

British Journal of Anaesthesia

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BACKGROUND: The marked increase in misuse and abuse 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. METHODS: A series of behavioral 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. RESULTS: Following systemic administration, BU10038 (0.001-0.01 mg kg -1 ) dosedependently 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 ). Following 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. CONCLUSIONS: These in vivo findings demonstrate the translational potential of bifunctional MOP/NOP receptor agonists like BU10038 as a safe, non-addictive

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“…The anti-analgesic function of NOP is mediated by inhibition of activity in the periaqueductal gray which controls pain modulation directed from the CNS (130)(131)(132). NOP has potential as a method to reduce morphine dose and decrease the development of tolerance and dependence in pain patients (133).…”

Section: Functional Role Of Nociceptin/orphanin Fqmentioning

confidence: 99%

Neuropeptide Receptors as Treatment Targets in Alcohol Use Disorders

Aziz¹

2017

Linköping University Medical Dissertations

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Alcohol use disorder (AUD) is a complex disorder with multiple pathophysiological processes contributing to the initiation, progression and development of the disease state. AUD is a chronic relapsing disease with escalation of alcohol-intake over time in repeated cycles of tolerance, abstinence and relapse and hence, it is very difficult to treat. There are only a few currently available treatments with narrow efficacy and variable patient response. Thus it is important to find new, more effective medications to increase the number of patients who can benefit from pharmacological treatment of AUD.The research presented in this thesis work focuses on the critical involvement of central neuropeptides in alcohol-related behaviors. The overall aim was to evaluate the nociceptin/orphanin FQ (NOP) receptor, the neuropeptide Y (NPY) Y2 receptor and the melanin-concentrating hormone (MCH) receptor 1 as novel and potential pharmacological treatment targets for AUD by testing the NOP receptor agonist SR-8993, the NPY-Y2 receptor antagonist CYM-9840 and the MCH1 receptor antagonist GW803430 in established animal models.In the first study (Paper I), the novel and selective NOP agonist SR-8993 was assessed in rat models of motivation to obtain alcohol and relapse to alcohol-seeking behavior using the operant self-administration (SA) paradigm. Firstly, treatment with SR-8993 (1 mg/kg) showed a mildly anxiolytic effect and reversed acute alcohol withdrawal-induced "hangover" anxiety in the elevated plus-maze (EPM). Next, it potently attenuated alcohol SA and motivation to obtain alcohol in the progressive ratio responding (PRR) and reduced both alcohol cue-induced and yohimbine stressinduced reinstatement of alcohol seeking, without affecting the pharmacology and metabolism of alcohol nor other control behaviors. To extend these findings, SR-8993 was evaluated in escalated alcohol-intake in rats. Treatment with SR-8993 significantly suppressed alcohol-intake and preference in rats that were trained to consume high amounts of alcohol in the two-bottle free choice intermittent access (IA) paradigm. SR-8993 also blocked operant SA of alcohol in rats that showed robust escalation in operant alcohol SA following chronic IA exposure to alcohol.In the second study (Paper II), SR-8993 was further evaluated in a model for escalated alcohol-intake induced by long-term IA exposure to alcohol. The effect of previous experience on operant alcohol SA on two-bottle free choice preference drinking was evaluated and sensitivity to treatment with SR-8993 was tested in rats selected for escalated and non-escalated alcohol seeking behavior. We found that rats exposed to the combined SA-IA paradigm showed greater sensitivity to SR-8993 treatment. In addition, acute escalation of alcohol SA after a three-week period of abstinence was completely abolished by pretreatment with SR-8993.In the third study (Paper III), the effects of the novel, small molecule NPY-Y2 antagonist CYM-9840 were tested in operant alcohol SA, PRR which is a model for...

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Targeting multiple opioid receptors – improved analgesics with reduced side effects?

Abstract: This article is part of a themed section on Emerging Areas of Opioid Pharmacology. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.14/issuetoc.

Cited by 137 publications

References 102 publications

Comparison of ED95 of Butorphanol and Sufentanil for gastrointestinal endoscopy sedation: a randomized controlled trial

Comparison of ED95 of Butorphanol and Sufentanil for gastrointestinal endoscopy sedation: a randomized controlled trial

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

Neuropeptide Receptors as Treatment Targets in Alcohol Use Disorders

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