Nociceptin and its metabolite attenuate U0126-induced memory impairment through a nociceptin opioid peptide (NOP) receptor-independent mechanism

<p>Kappa opioid peptide receptors (KOPrs) are a class of opioid receptors which shown analgesic and anti-addictive properties. Nonaddictive analgesics would be beneficial as morphine, one of the most commonly prescribed opioids for chronic pain, activates the brain reward system and can lead to addiction. Although medical research is progressing rapidly, there is still no treatment for psychostimulant abuse. KOPr agonists show promise in this regard but display undesirable side effects and could negatively affect memory. Salvinorin A (Sal A), a structurally unusual KOPr agonist, has a reduced side effect profile compared to the more traditional KOPr agonists such as U50,488. The effect of Sal A and U50,488 on memory is controversial as they have both been shown to induce a memory impairment and also to improve memory impairments. Sal A also has a poor pharmacokinetic profile with a short duration of action. Structural analogues of Sal A have improved pharmacokinetic and side effect profiles compared to Sal A yet retain the analgesic and anti-addiction properties. This thesis will investigate whether Sal A analogues, namely Ethynyl Sal A (Ethy Sal A), Mesyl Salvinorin B (Mesyl Sal B), and Bromo Salvinorin A (Bromo Sal A), produce a memory impairment. Male Sprague-Dawley rats were evaluated in the novel object recognition (NOR) task to determine whether novel Sal A analogues impair long term recognition memory. The degree of novelty was also investigated on a cellular basis through quantifying c-Fos immunoreactive neurons within the perirhinal cortex, an area of the brain shown to respond to novelty. Acute administration of Sal A (0.3 and 1 mg/kg) and novel analogues Ethy Sal A (0.3 and 1 mg/kg), Mesyl Sal B (0.3 and 1 mg/kg), and Bromo Sal A (1 mg/kg) showed no significant differences compared to vehicle when tested in the NOR task. The prototypical KOPr agonist, U50,488 (10 mg/kg), produced a significant decrease in recognition index compared to vehicle when tested in the same task as the novel analogues. Correlating the recognition indices calculated from U50,488 in the NOR to c-Fos counts in the perirhinal cortex showed a strong positive correlation with an increase in RI relating to an increase in c-Fos activation. U50,488 (10 mg/kg) showed a non-significant trend compared to vehicle in the number of c-Fos immunoreactive cells within the perirhinal cortex. Neither Sal A nor novel analogues affected NOR, suggesting no impairment of long term recognition memory. The lack of this side-effect, among others, demonstrates that the development of potent KOPr agonists with reduced side-effect profiles is feasible. These novel analogues show improvement over the traditional KOPr agonists.</p>

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Biased Opioid Ligands

Molecules ◽

10.3390/molecules25184257 ◽

2020 ◽

Vol 25 (18) ◽

pp. 4257 ◽

Cited By ~ 4

Author(s):

Abdelfattah Faouzi ◽

Balazs R. Varga ◽

Susruta Majumdar

Keyword(s):

G Protein ◽

Opioid Receptor ◽

Opioid Receptors ◽

Signal Transduction Pathway ◽

Opioid Peptide ◽

Nop Receptor ◽

Biased Agonism ◽

Opioid Ligands ◽

Substance Abuse Disorders ◽

Δ Opioid Receptor

Achieving effective pain management is one of the major challenges associated with modern day medicine. Opioids, such as morphine, have been the reference treatment for moderate to severe acute pain not excluding chronic pain modalities. Opioids act through the opioid receptors, the family of G-protein coupled receptors (GPCRs) that mediate pain relief through both the central and peripheral nervous systems. Four types of opioid receptors have been described, including the μ-opioid receptor (MOR), κ-opioid receptor (KOR), δ-opioid receptor (DOR), and the nociceptin opioid peptide receptor (NOP receptor). Despite the proven success of opioids in treating pain, there are still some inherent limitations. All clinically approved MOR analgesics are associated with adverse effects, which include tolerance, dependence, addiction, constipation, and respiratory depression. On the other hand, KOR selective analgesics have found limited clinical utility because they cause sedation, anxiety, dysphoria, and hallucinations. DOR agonists have also been investigated but they have a tendency to cause convulsions. Ligands targeting NOP receptor have been reported in the preclinical literature to be useful as spinal analgesics and as entities against substance abuse disorders while mixed MOR/NOP receptor agonists are useful as analgesics. Ultimately, the goal of opioid-related drug development has always been to design and synthesize derivatives that are equally or more potent than morphine but most importantly are devoid of the dangerous residual side effects and abuse potential. One proposed strategy is to take advantage of biased agonism, in which distinct downstream pathways can be activated by different molecules working through the exact same receptor. It has been proposed that ligands not recruiting β-arrestin 2 or showing a preference for activating a specific G-protein mediated signal transduction pathway will function as safer analgesic across all opioid subtypes. This review will focus on the design and the pharmacological outcomes of biased ligands at the opioid receptors, aiming at achieving functional selectivity.

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Central nociceptin/orphanin FQ system elevates food consumption by both increasing energy intake and reducing aversive responsiveness

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00556.2009 ◽

2010 ◽

Vol 299 (2) ◽

pp. R655-R663 ◽

Cited By ~ 25

Author(s):

Pawel K. Olszewski ◽

Martha K. Grace ◽

Shahrzad Shirazi Fard ◽

Madeleine Le Grevès ◽

Anica Klockars ◽

...

Keyword(s):

Energy Intake ◽

Low Dose ◽

Opioid Peptide ◽

Central Nucleus ◽

Mrna Levels ◽

Solitary Tract ◽

Nop Receptor ◽

Orphanin Fq ◽

Receptor Ligand ◽

Anorexigenic Effect

Nociceptin/orphanin FQ (N/OFQ), the nociceptin opioid peptide (NOP) receptor ligand, increases feeding when injected centrally. Initial data suggest that N/OFQ blocks the development of a conditioned taste aversion (CTA). The current project further characterized the involvement of N/OFQ in the regulation of hunger vs. aversive responses in rats by employing behavioral, immunohistochemical, and real-time PCR methodology. We determined that the same low dose of the NOP antagonist [Nphe1]N/OFQ(1-13)NH2 delivered via the lateral ventricle diminishes both N/OFQ- and deprivation-induced feeding. This anorexigenic effect did not stem from aversive consequences, as the antagonist did not cause the development of a CTA. When [Nphe1]N/OFQ(1-13)NH2 was administered with LiCl, it moderately delayed extinction of the LiCl-induced CTA. Injection of LiCl + antagonist compared with LiCl alone generated an increase in c-Fos immunoreactivity in the central nucleus of the amygdala. The antagonist alone elevated Fos immunoreactivity in the paraventricular nucleus of the hypothalamus, nucleus of the solitary tract, and central nucleus of the amygdala. Hypothalamic NOP mRNA levels were decreased during energy intake restriction induced by aversion, as well as in non-CTA rats food-restricted to match CTA-reduced consumption. Brain stem NOP was upregulated only in aversion. Prepro-N/OFQ mRNA showed a trend toward upregulation in restricted rats ( P = 0.068). We conclude that the N/OFQ system promotes feeding by affecting the need to replenish lacking calories and by reducing aversive responsiveness. It may belong to mechanisms that shift a balance between the drive to ingest energy and avoidance of potentially tainted food.

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Contribution of nociceptin/orphanin FQ receptors to the anti-nociceptive and hypothermic effects of dipyrone

Acta Neuropsychiatrica ◽

10.1017/neu.2014.38 ◽

2014 ◽

Vol 27 (1) ◽

pp. 48-52 ◽

Cited By ~ 6

Author(s):

Ismet Hande Ertin ◽

Ozgur Gunduz ◽

Ahmet Ulugol

Keyword(s):

Rectal Temperature ◽

Opioid Analgesic ◽

Opioid Peptide ◽

Tail Flick ◽

Induced Hypothermia ◽

Nop Receptor ◽

Orphanin Fq ◽

Hot Plate ◽

Pain Transmission

BackgroundDipyrone is one of the most commonly used non-opioid analgesic and antipyretic drug. Its anti-nociceptive and hypothermic effects have long been suspected to be centrally mediated. The involvement of the most recently discovered opioid peptide, nociceptin/orphanin FQ (N/OFQ), and its receptor (NOP) in pain transmission is controversial. It appears to be pro-nociceptive when administered supra-spinally, but exerts anti-nociceptive effects when injected spinally or systemically.ObjectiveInvestigation of the role of the N/OFQ system in paracetamol-induced anti-nociception and hypothermia led us to determine its role in the anti-nociceptive and hypothermic effects of dipyrone.Material and MethodsHot-plate and tail-flick tests were used to assess nociception, and a rectal thermometer was used to measure rectal temperature in mice.ResultsMice injected with dipyrone (150, 300, 600 mg/kg, i.p.) displayed dose-related anti-nociception and hypothermia. The NOP receptor antagonist JTC-801 (3 mg/kg, i.p.), at a dose that exerted no effect when used alone, alleviated dipyrone-induced anti-nociception but did not reverse dipyrone-induced hypothermia.ConclusionWe conclude that NOP receptors participate in the anti-nociceptive, but not in the hypothermic, effects of dipyrone.

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Activation of nociceptin opioid peptide (NOP) receptor impairs contextual fear learning in mice through glutamatergic mechanisms

Neurobiology of Learning and Memory ◽

10.1016/j.nlm.2008.12.001 ◽

2009 ◽

Vol 91 (4) ◽

pp. 393-401 ◽

Cited By ~ 28

Author(s):

Celia Goeldner ◽

Davids Reiss ◽

Jürgen Wichmann ◽

Brigitte L. Kieffer ◽

Abdel-Mouttalib Ouagazzal

Keyword(s):

Opioid Peptide ◽

Fear Learning ◽

Nop Receptor ◽

Contextual Fear

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Nociceptin/orphanin FQ opioid peptide (NOP) receptor and µ-opioid peptide (MOP) receptors both contribute to the anti-hypersensitive effect of cebranopadol in a rat model of arthritic pain

European Journal of Pharmacology ◽

10.1016/j.ejphar.2018.05.005 ◽

2018 ◽

Vol 832 ◽

pp. 90-95 ◽

Cited By ~ 7

Author(s):

Klaus Schiene ◽

Wolfgang Schröder ◽

Klaus Linz ◽

Stefanie Frosch ◽

Thomas M. Tzschentke ◽

...

Keyword(s):

Rat Model ◽

Opioid Peptide ◽

Nop Receptor ◽

Orphanin Fq

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Nociceptin/Orphanin FQ Peptide Receptor-Related Ligands as Novel Analgesics

Current Topics in Medicinal Chemistry ◽

10.2174/1568026620666200508082615 ◽

2020 ◽

Vol 20 (31) ◽

pp. 2878-2888 ◽

Cited By ~ 2

Author(s):

Norikazu Kiguchi ◽

Huiping Ding ◽

Shiroh Kishioka ◽

Mei-Chuan Ko

Keyword(s):

Opioid Receptor ◽

Receptor Agonist ◽

Physical Dependence ◽

Opioid Peptide ◽

Receptor Activation ◽

Abuse Liability ◽

Similar Distribution ◽

Nop Receptor ◽

Orphanin Fq ◽

Receptor Agonists

Despite similar distribution patterns and intracellular events observed in the nociceptin/ orphanin FQ peptide (NOP) receptor and other opioid receptors, NOP receptor activation displays unique pharmacological profiles. Several researchers have identified a variety of peptide and nonpeptide ligands to determine the functional roles of NOP receptor activation and observed that NOP receptor- related ligands exhibit pain modality-dependent pain processing. Importantly, NOP receptor activation results in anti-nociception and anti-hypersensitivity at the spinal and supraspinal levels regardless of the experimental settings in non-human primates (NHPs). Given that the NOP receptor agonists synergistically enhance mu-opioid peptide (MOP) receptor agonist-induced anti-nociception, it has been hypothesized that dual NOP and MOP receptor agonists may display promising functional properties as analgesics. Accumulating evidence indicates that the mixed NOP/opioid receptor agonists demonstrate favorable functional profiles. In NHP studies, bifunctional NOP/MOP partial agonists (e.g., AT-121, BU08028, and BU10038) exerted potent anti-nociception via NOP and MOP receptor activation; however, dose-limiting adverse effects associated with the MOP receptor activation, including respiratory depression, itch sensation, physical dependence, and abuse liability, were not observed. Moreover, a mixed NOP/opioid receptor agonist, cebranopadol, presented promising outcomes in clinical trials as a novel analgesic. Collectively, the dual agonistic actions on NOP and MOP receptors, with appropriate binding affinities and efficacies, may be a viable strategy to develop innovative and safe analgesics.

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The effect of novel kappa opioid peptide receptor agonists on learning and memory in rats

10.26686/wgtn.17065427.v1 ◽

2021 ◽

Author(s):

◽

Susan Adele Welsh

Keyword(s):

Recognition Memory ◽

Side Effect ◽

Memory Impairment ◽

Perirhinal Cortex ◽

Opioid Peptide ◽

Salvinorin A ◽

The Novel ◽

Kappa Opioid ◽

The Brain

<p>Kappa opioid peptide receptors (KOPrs) are a class of opioid receptors which shown analgesic and anti-addictive properties. Nonaddictive analgesics would be beneficial as morphine, one of the most commonly prescribed opioids for chronic pain, activates the brain reward system and can lead to addiction. Although medical research is progressing rapidly, there is still no treatment for psychostimulant abuse. KOPr agonists show promise in this regard but display undesirable side effects and could negatively affect memory. Salvinorin A (Sal A), a structurally unusual KOPr agonist, has a reduced side effect profile compared to the more traditional KOPr agonists such as U50,488. The effect of Sal A and U50,488 on memory is controversial as they have both been shown to induce a memory impairment and also to improve memory impairments. Sal A also has a poor pharmacokinetic profile with a short duration of action. Structural analogues of Sal A have improved pharmacokinetic and side effect profiles compared to Sal A yet retain the analgesic and anti-addiction properties. This thesis will investigate whether Sal A analogues, namely Ethynyl Sal A (Ethy Sal A), Mesyl Salvinorin B (Mesyl Sal B), and Bromo Salvinorin A (Bromo Sal A), produce a memory impairment. Male Sprague-Dawley rats were evaluated in the novel object recognition (NOR) task to determine whether novel Sal A analogues impair long term recognition memory. The degree of novelty was also investigated on a cellular basis through quantifying c-Fos immunoreactive neurons within the perirhinal cortex, an area of the brain shown to respond to novelty. Acute administration of Sal A (0.3 and 1 mg/kg) and novel analogues Ethy Sal A (0.3 and 1 mg/kg), Mesyl Sal B (0.3 and 1 mg/kg), and Bromo Sal A (1 mg/kg) showed no significant differences compared to vehicle when tested in the NOR task. The prototypical KOPr agonist, U50,488 (10 mg/kg), produced a significant decrease in recognition index compared to vehicle when tested in the same task as the novel analogues. Correlating the recognition indices calculated from U50,488 in the NOR to c-Fos counts in the perirhinal cortex showed a strong positive correlation with an increase in RI relating to an increase in c-Fos activation. U50,488 (10 mg/kg) showed a non-significant trend compared to vehicle in the number of c-Fos immunoreactive cells within the perirhinal cortex. Neither Sal A nor novel analogues affected NOR, suggesting no impairment of long term recognition memory. The lack of this side-effect, among others, demonstrates that the development of potent KOPr agonists with reduced side-effect profiles is feasible. These novel analogues show improvement over the traditional KOPr agonists.</p>

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