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1.
Cell ; 178(3): 653-671.e19, 2019 07 25.
Article in English | MEDLINE | ID: mdl-31348890

ABSTRACT

Nociceptin and its receptor are widely distributed throughout the brain in regions associated with reward behavior, yet how and when they act is unknown. Here, we dissected the role of a nociceptin peptide circuit in reward seeking. We generated a prepronociceptin (Pnoc)-Cre mouse line that revealed a unique subpopulation of paranigral ventral tegmental area (pnVTA) neurons enriched in prepronociceptin. Fiber photometry recordings during progressive ratio operant behavior revealed pnVTAPnoc neurons become most active when mice stop seeking natural rewards. Selective pnVTAPnoc neuron ablation, inhibition, and conditional VTA nociceptin receptor (NOPR) deletion increased operant responding, revealing that the pnVTAPnoc nucleus and VTA NOPR signaling are necessary for regulating reward motivation. Additionally, optogenetic and chemogenetic activation of this pnVTAPnoc nucleus caused avoidance and decreased motivation for rewards. These findings provide insight into neuromodulatory circuits that regulate motivated behaviors through identification of a previously unknown neuropeptide-containing pnVTA nucleus that limits motivation for rewards.


Subject(s)
Motivation/drug effects , Opioid Peptides/pharmacology , Reward , Ventral Tegmental Area/metabolism , Action Potentials , Animals , Behavior, Animal/drug effects , Female , Male , Mice , Mice, Inbred C57BL , Mice, Transgenic , Neurons/physiology , Patch-Clamp Techniques , Protein Precursors/genetics , Receptors, Opioid/agonists , Receptors, Opioid/deficiency , Receptors, Opioid/genetics , Nociceptin Receptor , Nociceptin
2.
Eur Neuropsychopharmacol ; 27(12): 1298-1307, 2017 12.
Article in English | MEDLINE | ID: mdl-29102248

ABSTRACT

The endogenous neuropeptide nociceptin (N/OFQ), which mediates its actions via the nociceptin receptor (NOP), is implicated in multiple behavioural and physiological functions. This study examined the effects of the NOP agonists N/OFQ and the synthetic agonist Ro 64-6198, the antagonists NNN and NalBzoH, as well as deletion of the Pronociceptin gene on emotional memory in mice. The animals were tested in the passive avoidance (PA) task, dependent on hippocampal and amygdala functions. N/OFQ injected intraventricularly (i.c.v.) prior to training produced a biphasic effect on PA retention; facilitation at a low dose and impairment at higher doses. Ro 64-6198 also displayed a biphasic effect with memory facilitation at lower doses and impairment at a high dose. None of the agonists influenced PA training latencies. NNN did not significantly modulate retention in the PA task but antagonized the inhibitory effects of N/OFQ. NalBzoH facilitated memory retention in a dose-dependent manner and blocked the impairing effects of N/OFQ. However, neither NNN nor NalBzoH blocked the memory-impairing effects of Ro 64-6198. Finally, the Pnoc knockout mice exhibited enhanced PA retention latencies compared to the wild type mice. The biphasic effect of the natural ligand and Ro 64-6198 and the failure of the antagonists to block the action of Ro 64-6198 indicate complexity in ligand-receptor interaction. These results indicate that brain nociceptin and its NOP has a subtle role in regulation of mechanisms of relevance for treatment of disorders with processing disturbances of aversive events e.g. Alzheimer's disease, anxiety, depression and PTSD.


Subject(s)
Avoidance Learning/physiology , Opioid Peptides/metabolism , Receptors, Opioid/deficiency , Animals , Association Learning/drug effects , Avoidance Learning/drug effects , Dose-Response Relationship, Drug , Imidazoles/pharmacology , Injections, Intraventricular , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Naloxone/analogs & derivatives , Naloxone/pharmacology , Narcotic Antagonists/pharmacology , Opioid Peptides/genetics , Opioid Peptides/pharmacology , Peptide Fragments/pharmacology , Receptors, Opioid/agonists , Receptors, Opioid/genetics , Retention, Psychology/drug effects , Spiro Compounds/pharmacology , Nociceptin Receptor , Nociceptin
3.
Glia ; 65(12): 2003-2023, 2017 12.
Article in English | MEDLINE | ID: mdl-28906039

ABSTRACT

Our previous results showed that oligodendrocyte development is regulated by both nociceptin and its G-protein coupled receptor, the nociceptin/orphanin FQ receptor (NOR). The present in vitro and in vivo findings show that nociceptin plays a crucial conserved role regulating the levels of the glutamate/aspartate transporter GLAST/EAAT1 in both human and rodent brain astrocytes. This nociceptin-mediated response takes place during a critical developmental window that coincides with the early stages of astrocyte maturation. GLAST/EAAT1 upregulation by nociceptin is mediated by NOR and the downstream participation of a complex signaling cascade that involves the interaction of several kinase systems, including PI-3K/AKT, mTOR, and JAK. Because GLAST is the main glutamate transporter during brain maturation, these novel findings suggest that nociceptin plays a crucial role in regulating the function of early astrocytes and their capacity to support glutamate homeostasis in the developing brain.


Subject(s)
Amino Acid Transport System X-AG/metabolism , Astrocytes/metabolism , Gene Expression Regulation, Developmental/genetics , Opioid Peptides/metabolism , Receptors, Opioid/deficiency , Aldehyde Dehydrogenase 1 Family , Animals , Animals, Newborn , Astrocytes/drug effects , Cells, Cultured , Enzyme Inhibitors/pharmacology , Fetus/cytology , Glial Fibrillary Acidic Protein/metabolism , Glutamic Acid/metabolism , Humans , Hydroxylamines/pharmacology , Mice, Knockout , Neurons/drug effects , Neurons/metabolism , Opioid Peptides/pharmacology , Rats , Rats, Sprague-Dawley , Receptors, Opioid/genetics , Retinal Dehydrogenase/metabolism , Signal Transduction/drug effects , Signal Transduction/physiology , Nociceptin Receptor , Nociceptin
4.
Neurosci Lett ; 643: 16-21, 2017 03 16.
Article in English | MEDLINE | ID: mdl-28192197

ABSTRACT

Oxymorphone, one of oxycodone's metabolic products, is a potent opioid receptor agonist which is thought to contribute to the analgesic effect of its parent compound and may have high potential abuse liability. Nonetheless, the in vivo pharmacological binding profile of this drug is still unclear. This study uses mice lacking mu (MOP), kappa (KOP) or delta (DOP) opioid receptors as well as mice lacking all three opioid receptors to provide full characterisation of oxymorphone binding sites in the brain. Saturation binding studies using [3H]oxymorphone revealed high affinity binding sites in mouse brain displaying Kd of 1.7nM and Bmax of 147fmol/mg. Furthermore, we performed quantitative autoradiography binding studies using [3H]oxymorphone in mouse brain. The distribution of [3H]oxymorphone binding sites was found to be similar to the selective MOP agonist [3H]DAMGO in the mouse brain. [3H]Oxymorphone binding was completely abolished across the majority of the brain regions in mice lacking MOP as well as in mice lacking all three opioid receptors. DOP and KOP knockout mice retained [3H]oxymorphone binding sites suggesting oxymorphone may not target DOP or KOP. These results confirm that the MOP, and not the DOP or the KOP is the main high affinity binding target for oxymorphone.


Subject(s)
Brain/metabolism , Oxymorphone/pharmacology , Receptors, Opioid/metabolism , Animals , Autoradiography/methods , Binding Sites , Mice, Knockout , Receptors, Opioid/deficiency , Receptors, Opioid, delta/genetics , Receptors, Opioid, delta/metabolism , Receptors, Opioid, kappa/genetics , Receptors, Opioid, kappa/metabolism , Receptors, Opioid, mu/agonists , Receptors, Opioid, mu/genetics
5.
Elife ; 42015 Apr 21.
Article in English | MEDLINE | ID: mdl-25898004

ABSTRACT

Neuropeptides are essential for the regulation of appetite. Here we show that neuropeptides could regulate feeding in mutants that lack neurotransmission from the motor neurons that stimulate feeding muscles. We identified nlp-24 by an RNAi screen of 115 neuropeptide genes, testing whether they affected growth. NLP-24 peptides have a conserved YGGXX sequence, similar to mammalian opioid neuropeptides. In addition, morphine and naloxone respectively stimulated and inhibited feeding in starved worms, but not in worms lacking NPR-17, which encodes a protein with sequence similarity to opioid receptors. Opioid agonists activated heterologously expressed NPR-17, as did at least one NLP-24 peptide. Worms lacking the ASI neurons, which express npr-17, did not response to naloxone. Thus, we suggest that Caenorhabditis elegans has an endogenous opioid system that acts through NPR-17, and that opioids regulate feeding via ASI neurons. Together, these results suggest C. elegans may be the first genetically tractable invertebrate opioid model.


Subject(s)
Caenorhabditis elegans/metabolism , Feeding Behavior/physiology , Neurons/metabolism , Neuropeptides/metabolism , Receptors, Opioid/genetics , Amino Acid Sequence , Animals , Caenorhabditis elegans/drug effects , Caenorhabditis elegans/genetics , Caenorhabditis elegans Proteins/genetics , Caenorhabditis elegans Proteins/metabolism , Conserved Sequence , Feeding Behavior/drug effects , Gene Expression Regulation , Molecular Sequence Data , Morphine/pharmacology , Naloxone/pharmacology , Neurons/cytology , Neurons/drug effects , Neuropeptides/genetics , Receptors, Opioid/deficiency , Signal Transduction , Starvation/metabolism
6.
Br J Pharmacol ; 171(17): 4138-53, 2014 Sep.
Article in English | MEDLINE | ID: mdl-24903280

ABSTRACT

BACKGROUND AND PURPOSE: An innovative chemical approach, named peptide welding technology (PWT), allows the synthesis of multibranched peptides with extraordinary high yield, purity and reproducibility. With this approach, three different tetrabranched derivatives of nociceptin/orphanin FQ (N/OFQ) have been synthesized and named PWT1-N/OFQ, PWT2-N/OFQ and PWT3-N/OFQ. In the present study we investigated the in vitro and in vivo pharmacological profile of PWT N/OFQ derivatives and compared their actions with those of the naturally occurring peptide. EXPERIMENTAL APPROACH: The following in vitro assays were used: receptor and [(35)S]-GTPγS binding, calcium mobilization in cells expressing the human N/OFQ peptide (NOP) receptor, or classical opioid receptors and chimeric G proteins, electrically stimulated mouse vas deferens bioassay. In vivo experiments were performed; locomotor activity was measured in normal mice and in animals with the NOP receptor gene knocked out [NOP(-/-)]. KEY RESULTS: In vitro PWT derivatives of N/OFQ behaved as high affinity potent and rather selective full agonists at human recombinant and animal native NOP receptors. In vivo PWT derivatives mimicked the inhibitory effects exerted by the natural peptide on locomotor activity showing 40-fold higher potency and extremely longer lasting action. The effects of PWT2-N/OFQ were no longer evident in NOP(-/-) mice. CONCLUSIONS AND IMPLICATIONS: The results showed that the PWT can be successfully applied to the peptide sequence of N/OFQ to generate tetrabranched derivatives characterized by a pharmacological profile similar to the native peptide and associated with a higher potency and marked prolongation of action in vivo.


Subject(s)
Opioid Peptides/chemistry , Opioid Peptides/pharmacology , Receptors, Opioid/agonists , Animals , CHO Cells , Cells, Cultured , Cricetulus , Dose-Response Relationship, Drug , Humans , Locomotion/drug effects , Male , Mice , Mice, Knockout , Molecular Conformation , Opioid Peptides/chemical synthesis , Receptors, Opioid/deficiency , Structure-Activity Relationship
7.
Neuropharmacology ; 76 Pt B: 204-17, 2014 Jan.
Article in English | MEDLINE | ID: mdl-24035914

ABSTRACT

The endogenous opioid system is expressed throughout the brain reinforcement circuitry, and plays a major role in reward processing, mood control and the development of addiction. This neuromodulator system is composed of three receptors, mu, delta and kappa, interacting with a family of opioid peptides derived from POMC (ß-endorphin), preproenkephalin (pEnk) and preprodynorphin (pDyn) precursors. Knockout mice targeting each gene of the opioid system have been created almost two decades ago. Extending classical pharmacology, these mutant mice represent unique tools to tease apart the specific role of each opioid receptor and peptide in vivo, and a powerful approach to understand how the opioid system modulates behavioral effects of drugs of abuse. The present review summarizes these studies, with a focus on major drugs of abuse including morphine/heroin, cannabinoids, psychostimulants, nicotine or alcohol. Genetic data, altogether, set the mu receptor as the primary target for morphine and heroin. In addition, this receptor is essential to mediate rewarding properties of non-opioid drugs of abuse, with a demonstrated implication of ß-endorphin for cocaine and nicotine. Delta receptor activity reduces levels of anxiety and depressive-like behaviors, and facilitates morphine-context association. pEnk is involved in these processes and delta/pEnk signaling likely regulates alcohol intake. The kappa receptor mainly interacts with pDyn peptides to limit drug reward, and mediate dysphoric effects of cannabinoids and nicotine. Kappa/dynorphin activity also increases sensitivity to cocaine reward under stressful conditions. The opioid system remains a prime candidate to develop successful therapies in addicted individuals, and understanding opioid-mediated processes at systems level, through emerging genetic and imaging technologies, represents the next challenging goal and a promising avenue in addiction research. This article is part of a Special Issue entitled 'NIDA 40th Anniversary Issue'.


Subject(s)
Biomedical Research/history , Opioid Peptides/deficiency , Receptors, Opioid/deficiency , Substance-Related Disorders/genetics , Animals , Disease Models, Animal , History, 20th Century , History, 21st Century , Humans , Mice , Mice, Knockout , Opioid Peptides/genetics , Receptors, Opioid/genetics , Substance-Related Disorders/history
8.
Trends Neurosci ; 36(3): 195-206, 2013 Mar.
Article in English | MEDLINE | ID: mdl-23219016

ABSTRACT

The roles of opioid receptors in pain and addiction have been extensively studied, but their function in mood disorders has received less attention. Accumulating evidence from animal research reveals that mu, delta and kappa opioid receptors (MORs, DORs and KORs, respectively) exert highly distinct controls over mood-related processes. DOR agonists and KOR antagonists have promising antidepressant potential, whereas the risk-benefit ratio of currently available MOR agonists as antidepressants remains difficult to evaluate, in addition to their inherent abuse liability. To date, both human and animal studies have mainly examined MORs in the etiology of depressive disorders, and future studies will address DOR and KOR function in established and emerging neurobiological aspects of depression, including neurogenesis, neurodevelopment, and social behaviors.


Subject(s)
Mood Disorders/physiopathology , Opioid Peptides/physiology , Receptors, Opioid/physiology , Reward , Affect/drug effects , Affect/physiology , Analgesics, Opioid/pharmacology , Animals , Antidepressive Agents/pharmacology , Antidepressive Agents/therapeutic use , Brain Chemistry , Brain-Derived Neurotrophic Factor/physiology , Comorbidity , Female , Humans , Male , Maternal Behavior/drug effects , Maternal Behavior/physiology , Mice , Mice, Knockout , Models, Neurological , Mood Disorders/drug therapy , Mood Disorders/metabolism , Narcotic Antagonists/pharmacology , Nerve Tissue Proteins/physiology , Neurogenesis/drug effects , Neurogenesis/physiology , Neuronal Plasticity/drug effects , Neuronal Plasticity/physiology , Neurotransmitter Agents/physiology , Pregnancy , Prenatal Exposure Delayed Effects , Receptors, Opioid/agonists , Receptors, Opioid/deficiency , Social Behavior , Substance-Related Disorders/drug therapy , Substance-Related Disorders/physiopathology
9.
Eur J Pharmacol ; 661(1-3): 63-71, 2011 Jul 01.
Article in English | MEDLINE | ID: mdl-21545797

ABSTRACT

The endogenous opioid-like peptide, nociceptin, produces anxiolytic-like effects that are mediated via the nociceptin (NOP) receptor. Similarly, synthetic, non-peptide NOP agonists produce robust anxiolytic-like effects although these effects are limited by marked side effects. In the present studies, the effects of a novel NOP receptor agonist, SCH 655842, were examined in rodent models sensitive to anxiolytic drugs and tests measuring potential adverse affects. Oral administration of SCH 655842 produced robust, anxiolytic-like effects in three species, i.e., rat, guinea pig, and mouse. Specifically, SCH 655842 was effective in rat conditioned lick suppression (3-10 mg/kg) and fear-potentiated startle (3-10 mg/kg) tests, a guinea pig pup vocalization test (1-3 mg/kg), as well as in mouse Geller-Seifter (30 mg/kg) and marble burying (30 mg/kg) tests. The anxiolytic-like effect of SCH 655842 in the conditioned lick suppression test was attenuated by the NOP antagonist, J-113397. In mice, SCH 655842 reduced locomotor activity and body temperature at doses similar to the anxiolytic-like dose and these effects were absent in NOP receptor knockout mice. In rats, SCH 655842 did not produce adverse behavioral effects up to doses of 70-100 mg/kg. Pharmacokinetic studies in the rat confirmed dose-related increases in plasma and brain levels of SCH 655842 across a wide oral dose range. Taken together, SCH 655842 may represent a NOP receptor agonist with improved tolerability compared to other members of this class although further studies are necessary to establish whether this extends to higher species.


Subject(s)
Anti-Anxiety Agents/adverse effects , Anti-Anxiety Agents/pharmacology , Azabicyclo Compounds/adverse effects , Azabicyclo Compounds/pharmacology , Receptors, Opioid/agonists , Animals , Anti-Anxiety Agents/blood , Anti-Anxiety Agents/pharmacokinetics , Azabicyclo Compounds/blood , Azabicyclo Compounds/pharmacokinetics , Behavior, Animal/drug effects , Behavior, Animal/physiology , Body Temperature/drug effects , Brain/drug effects , Brain/metabolism , Conditioning, Psychological/drug effects , Conditioning, Psychological/physiology , Dose-Response Relationship, Drug , Fear/drug effects , Fear/physiology , Female , Gene Knockout Techniques , Guinea Pigs , Male , Mice , Motor Activity/drug effects , Rats , Receptors, Opioid/deficiency , Receptors, Opioid/genetics , Rotarod Performance Test , Species Specificity , Vocalization, Animal/drug effects , Nociceptin Receptor
10.
Neuropharmacology ; 59(3): 190-200, 2010 Sep.
Article in English | MEDLINE | ID: mdl-20510254

ABSTRACT

We evaluated the role of the nociceptin/orphanin FQ (NOP) receptor in regulating food intake, meal pattern and the activity of hypothalamic arcuate (ARC) neurons. The microstructural analysis of food intake and meal pattern was performed under both food-deprived and ad libitum conditions. Whole-cell patch clamp recordings were obtained using the in vitro hypothalamic slice preparation and biocytin-filled electrodes. NOP receptor knockout mice exhibited significantly reduced body weight. Fasting-induced hyperphagia was diminished for the first 2h of a 6-h re-feeding period, and was associated with decreased meal duration and size, as well as a biphasic effect on meal frequency. The genotype effect observed under ad libitum conditions was comparatively unremarkable. Orphanin FQ/nociceptin (OFQ/N) was able to decrease evoked excitatory postsynaptic current amplitude, increase the S(2):S(1) ratio via the paired-pulse paradigm, and decrease miniature excitatory postsynaptic current frequency in ARC neurons from wild type animals but not NOP receptor knockouts. In addition OFQ/N activated a reversible outward current that was antagonized by the G-protein activated, inwardly-rectifying K(+) (GIRK) channel blocker tertiapin in wild type but not NOP knockout animals. Both the presynaptic and postsynaptic actions of OFQ/N were observed in ARC neurons subsequently determined to be immunopositive for characteristic phenotypic markers of anorexigenic proopiomelanocortin (POMC) neurons. Taken together, these results demonstrate the contribution of the NOP receptor in controlling food intake and meal pattern, as well as glutamate release and GIRK1 channel activity at POMC synapses.


Subject(s)
Appetite Regulation/genetics , Excitatory Postsynaptic Potentials/genetics , Feeding Behavior/physiology , Neurons/physiology , Pro-Opiomelanocortin/metabolism , Receptors, Opioid/metabolism , Analysis of Variance , Animals , Appetite Regulation/drug effects , Biophysics , Electric Stimulation/methods , Excitatory Postsynaptic Potentials/drug effects , Feeding Behavior/drug effects , G Protein-Coupled Inwardly-Rectifying Potassium Channels/metabolism , Hypothalamus/cytology , In Vitro Techniques , Mice , Mice, Knockout , Neurons/drug effects , Opioid Peptides/pharmacology , Patch-Clamp Techniques/methods , Receptors, Opioid/deficiency , Sodium Channel Blockers/pharmacology , Tetrodotoxin/pharmacology , Nociceptin Receptor , Nociceptin
11.
Neuroscience ; 169(1): 269-78, 2010 Aug 11.
Article in English | MEDLINE | ID: mdl-20417255

ABSTRACT

Antagonists selectively inhibiting activation of the nociceptin/orphanin FQ (N/OFQ) receptor reduce motor symptoms in experimental models of Parkinson's disease, and genetic deletion of the ppN/OFQ gene offers partial protection of mid-brain dopamine neurons against the neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). MPTP increased ppN/OFQ mRNA expression in the substantia nigra (SN). We have evaluated the temporal relationship of dopamine cell loss to increased ppN/OFQ mRNA expression in the substantia nigra after MPTP treatment, and characterized the cellular locations in which increased ppN/OFQ mRNA expression was observed after MPTP treatment. MPTP increased by about 5-fold the number of neurons expressing ppN/OFQ mRNA in the pars reticulata of SN (SNr) by 24 h after treatment and the elevation remained significant for at least 7 days. This period coincided with the timing of the loss of dopamine neurons from the pars compacta of substantia nigra (SNc) after MPTP. The increased expression of ppN/OFQ mRNA co-localized with a neuronal marker in the SNr. MPTP treatment resulted in a small increase in the numbers of neurons expressing ppN/OFQ in the SNc in mice from one mouse colony but the increase did not reach statistical significance in mice from another colony. No changes in ppN/OFQ-mRNA expression were observed in the ventral tegmental area (VTA), the caudate-putamen, the subthalamic nucleus, or in two other brains areas. These results demonstrate that increased N/OFQ expression in the SNr is closely associated with the MPTP-induced loss of dopamine neurons in the SNc in a widely used animal model of Parkinson's disease.


Subject(s)
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine/pharmacology , Gene Expression Regulation/drug effects , MPTP Poisoning/genetics , Neurons/drug effects , Parkinsonian Disorders/genetics , Protein Precursors/biosynthesis , RNA, Messenger/biosynthesis , Receptors, Opioid/biosynthesis , Substantia Nigra/drug effects , Animals , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Neurons/classification , Neurons/metabolism , Opioid Peptides/biosynthesis , Opioid Peptides/genetics , Protein Precursors/deficiency , Protein Precursors/genetics , RNA, Messenger/genetics , Receptors, Opioid/deficiency , Receptors, Opioid/genetics , Substantia Nigra/metabolism , Ventral Tegmental Area/drug effects , Ventral Tegmental Area/metabolism , Nociceptin
12.
J Neurochem ; 107(6): 1683-96, 2008 Dec.
Article in English | MEDLINE | ID: mdl-19014386

ABSTRACT

In this study we investigated whether the recently discovered antagonist of the nociceptin/orphanin FQ (N/OFQ) opioid peptide (NOP) receptor, 1-[1-(cyclooctylmethyl)-1,2,3,6-tetrahydro-5-(hydroxymethyl)-4-pyridinyl]-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one (Trap-101) changed motor activity in naïve rats and mice, and alleviated parkinsonism in 6-hydroxydopamine hemilesioned rats. In naïve rats, Trap-101 stimulated motor activity at 10 mg/Kg and inhibited it at 30 mg/Kg. Such dual action was also observed in wild-type but not NOP receptor knockout mice suggesting specific involvement of NOP receptors. Trap-101 alleviated akinesia/bradykinesia and improved overall gait ability in hemiparkinsonian rats, being effective starting at 1 mg/Kg and without worsening motor deficit at 30 mg/Kg. To investigate the circuitry involved in the Trap-101 action, behavioral tests were performed in rats undergoing microdialysis. The anti-akinetic/anti-bradykinetic effects of Trap-101, given systemically (10 mg/Kg) or perfused in substantia nigra reticulata (10 microM), were associated with reduced glutamate and enhanced GABA release in substantia nigra, and reduced GABA release in ipsilateral ventro-medial thalamus. When combined with ineffective doses of l-DOPA (0.1 mg/Kg), Trap-101 evoked larger neurochemical and behavioral responses. These data show that Trap-101 is an effective NOP receptor antagonist in vivo and confirm that NOP receptor antagonists alleviate parkinsonism through blockade of nigral NOP receptors and impairment of nigro-thalamic transmission.


Subject(s)
Antiparkinson Agents/therapeutic use , Levodopa/therapeutic use , Narcotic Antagonists , Parkinsonian Disorders/drug therapy , Substantia Nigra/physiopathology , Thalamus/physiopathology , Animals , Benzimidazoles/pharmacology , Benzimidazoles/therapeutic use , Disease Models, Animal , Dose-Response Relationship, Drug , Drug Interactions , Dyskinesia, Drug-Induced/drug therapy , Dyskinesia, Drug-Induced/metabolism , Functional Laterality/drug effects , Glutamic Acid/metabolism , Mice , Mice, Inbred C57BL , Mice, Knockout , Microdialysis/methods , Motor Activity/drug effects , Motor Activity/physiology , Neural Pathways/drug effects , Neural Pathways/physiopathology , Oxidopamine , Parkinsonian Disorders/chemically induced , Parkinsonian Disorders/pathology , Parkinsonian Disorders/physiopathology , Psychomotor Performance/drug effects , Psychomotor Performance/physiology , Pyridines/pharmacology , Pyridines/therapeutic use , Rats , Rats, Sprague-Dawley , Receptors, Opioid/deficiency , Substantia Nigra/drug effects , Thalamus/drug effects , Time Factors , gamma-Aminobutyric Acid/metabolism , Nociceptin Receptor
13.
Neuroscience ; 155(3): 597-602, 2008 Aug 26.
Article in English | MEDLINE | ID: mdl-18634857

ABSTRACT

We have previously shown that the ability of buprenorphine to activate the opioid receptor-like (ORL1) receptor compromises its antinociceptive effect. Furthermore, morphine has been shown to alter the level of orphanin FQ/nociceptin (OFQ/N), the endogenous ligand of the ORL1 receptor, raising the possibility that the endogenous OFQ/N/ORL1 receptor system may be involved in the actions of these opioids. Thus, using mice lacking the ORL1 receptor and their wild-type littermates, the present study assessed the role of the ORL1 receptor in psychomotor stimulant and rewarding actions of buprenorphine and morphine. Morphine (5, 10 mg/kg) dose-dependently increased motor activity and induced conditioned place preference. However, the magnitude of each response was comparable for the mutant mice and their wild-type littermates. In contrast, buprenorphine (1 mg/kg) induced greater motor stimulation in ORL1 receptor knockout mice as compared with their wild-type littermates. Further, single conditioning with buprenorphine (3 mg/kg) induced place preference in mutant mice but not in their wild-type littermates. The results of binding assay showed that buprenorphine concentration-dependently (0-1000 nM) displaced specific binding of [(3)H]-OFQ/N in brain membrane of wild-type mice. Together, the present results suggest that the ability of buprenorphine to interact with the ORL1 receptor modulates its acute motor stimulatory and rewarding effects.


Subject(s)
Buprenorphine/pharmacology , Morphine/pharmacology , Narcotics/pharmacology , Psychomotor Performance/drug effects , Receptors, Opioid/physiology , Reward , Analysis of Variance , Animals , Behavior, Animal/drug effects , Behavior, Animal/physiology , Conditioning, Operant/drug effects , Conditioning, Operant/physiology , Discrimination, Psychological/drug effects , Discrimination, Psychological/physiology , Dose-Response Relationship, Drug , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Motor Activity/drug effects , Motor Activity/genetics , Protein Binding/drug effects , Protein Binding/genetics , Psychomotor Performance/physiology , Receptors, Opioid/deficiency , Time Factors , Nociceptin Receptor
14.
Neuroreport ; 19(1): 83-6, 2008 Jan 08.
Article in English | MEDLINE | ID: mdl-18281898

ABSTRACT

Using nociceptin-receptor-deficient mice, we studied the participation of nociceptin in herpetic and postherpetic allodynia in mice. Although nociceptin-receptor deficiency did not affect the development of skin lesions and herpetic allodynia, it prevented postherpetic allodynia. Messenger ribonucleic acid (mRNA) of pronociceptin increased in the dorsal horn of lumbar enlargement on day 6, but not on day 40, after inoculation. No changes were observed in the mRNA of the nociceptin receptor. Inhibition of herpetic allodynia by repeated oral administration of gabapentin (100 mg/kg) alleviated the overexpression of mRNA of pronociceptin, as well as the severity of postherpetic allodynia. These results suggest that the spinal nociceptin system is involved in the transitional process from herpetic allodynia to postherpetic allodynia.


Subject(s)
Herpes Simplex/complications , Herpesvirus 1, Human , Hyperalgesia/prevention & control , Receptors, Opioid/deficiency , Acute Disease , Amines/administration & dosage , Analgesics/administration & dosage , Animals , Cyclohexanecarboxylic Acids/administration & dosage , Disease Models, Animal , Gabapentin , Gene Expression Regulation/drug effects , Hyperalgesia/drug therapy , Hyperalgesia/etiology , Mice , Mice, Inbred C57BL , Mice, Knockout , Pain Measurement , Protein Precursors/genetics , Protein Precursors/metabolism , RNA, Messenger/metabolism , Receptors, Opioid/genetics , Receptors, Opioid/metabolism , Spinal Cord/metabolism , Spinal Cord/pathology , Time Factors , gamma-Aminobutyric Acid/administration & dosage , Nociceptin Receptor
15.
Neuropharmacology ; 54(3): 564-8, 2008 Mar.
Article in English | MEDLINE | ID: mdl-18082848

ABSTRACT

Previous studies have shown that orphanin FQ/nociceptin (OFQ/N), the endogenous ligand of the opioid receptor-like (ORL-1) receptor, reduces the rewarding and addictive properties of cocaine and other drugs of abuse. In the present study, using the conditioned place preference (CPP) paradigm, as an animal model of drug reward, we assessed whether the rewarding action of acute cocaine would be altered in mice lacking the ORL-1 receptor or in wild type mice treated with J-113397, an ORL-1 receptor antagonist, relative to their saline-treated controls. On day 1, mice were tested for their baseline place preferences, in which each mouse was placed in the neutral chamber of a three-chambered CPP apparatus, allowed to freely explore all the chambers and the amount of time that a mouse spent in each conditioning chamber was recorded for 15 min. On days 2-3, mice received once daily alternate-day saline/cocaine (15 or 30 mg/kg) conditioning for 30 min. On day 4, mice were tested for their postconditioning preferences, as described for day 1. In a subsequent study, the effect of J-113397 (3 mg/kg) on the rewarding action of acute cocaine (15 mg/kg) was also examined in wild type mice. Our results showed that mice lacking the ORL-1 receptor expressed greater CPP than their wild type littermates. Furthermore, the rewarding action of cocaine was enhanced in the presence of J-113397 in wild type mice. Together, the present results suggest that the endogenous OFQ/N/ORL-1 receptor system is involved in the rewarding action of acute cocaine.


Subject(s)
Anesthetics, Local/administration & dosage , Cocaine/administration & dosage , Conditioning, Operant/drug effects , Receptors, Opioid/physiology , Reward , Analysis of Variance , Animals , Behavior, Animal/drug effects , Benzimidazoles/pharmacology , Dose-Response Relationship, Drug , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Narcotic Antagonists , Piperidines/pharmacology , Receptors, Opioid/deficiency , Time Factors , Nociceptin Receptor
16.
Neuropsychopharmacology ; 33(4): 877-91, 2008 Mar.
Article in English | MEDLINE | ID: mdl-17522627

ABSTRACT

The opioid peptide nociceptin (orphanin FQ) suppresses drug reward, drug self-administration, and impedes some of the processes believed to underlie the transition to addiction. As virtually all previous studies have used administration of nociceptin receptor agonists to evaluate the role of nociceptin on addiction-like behavior, the current study used a pharmacological (nociceptin receptor antagonist) and genetic (nociceptin receptor knockout mice) approach to elucidate the role of endogenous nociceptin. The nociceptin receptor antagonist UFP-101 induced a modest place preference, and enhanced the conditioned place preference induced by methamphetamine. In agreement with this, nociceptin receptor knockout mice had slightly enhanced methamphetamine and ethanol conditioned place preferences compared to wild-type mice. This effect did not appear to depend on differences in learning ability, as nociceptin receptor knockout mice had slightly weaker-conditioned place aversions to lithium chloride, the kappa-opioid receptor agonist, U50488H, and the general opiate antagonist, naloxone. The development of behavioral sensitization to methamphetamine was lower in nociceptin receptor knockout mice, and attenuated by UFP-101 administration to wild-type mice. Additionally, ethanol consumption and preference in a two-bottle choice test was lower in nociceptin receptor knockout mice, though ethanol-stimulated locomotion was stronger. Whereas the rewarding effect of methamphetamine and ethanol following chronic treatment, as measured by place conditioning, strengthened in wild-type mice, this effect was absent in nociceptin receptor knockout mice. These results suggest that endogenous N/OFQ suppresses basal and drug-stimulated increases in hedonic state, and plays either a permissive or facilitatory role in the development of addiction.


Subject(s)
Central Nervous System Depressants/pharmacology , Central Nervous System Stimulants/pharmacology , Conditioning, Operant/drug effects , Ethanol/pharmacology , Methamphetamine/pharmacology , Opioid Peptides/metabolism , Reward , Animals , Behavior, Animal/drug effects , Behavior, Animal/physiology , Dose-Response Relationship, Drug , Drug Interactions , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Opioid Peptides/pharmacology , Receptors, Opioid/deficiency , Time Factors , Nociceptin Receptor , Nociceptin
17.
Eur Neuropsychopharmacol ; 17(5): 366-74, 2007 Apr.
Article in English | MEDLINE | ID: mdl-17030115

ABSTRACT

The acute effects of opiate drugs and opiate addiction have been associated with modulation of Fas/FADD (Fas-Associated protein with Death Domain) signaling complex in the rat brain. This study investigated the possible existence of endogenous opioid tones regulating the basal activities of Fas receptor forms and FADD in the brain, using gene-targeted mice lacking mu-, delta- or kappa-opioid peptide receptors (KO mice). In mu-KO mice, but not in delta- or kappa-KO mice, the basal immunodensity of native Fas (35 kDa monomeric form) was decreased in the cerebral cortex (33%) when compared with WT littermates. In delta-KO mice, but not in mu- or kappa-KO mice, the basal content of 120 kDa Fas aggregates (complexes of monomers relevant in Fas signaling) was markedly increased in the cortex (93%). In contrast, no differences between genotypes were observed in the basal expression of glycosylated Fas (51/48/45 kDa forms). Notably, the basal content of FADD (the adaptor protein that couples Fas to caspases and transmits the death signal) was increased in the cerebral cortex of delta-KO mice (48%), but not in mu- or kappa-KO mice. In addition, the basal content of phosphorylated FADD at Ser191 (the relevant species of FADD implicated in nonapoptotic signals) was also upregulated in the cortices of delta-opioid receptor KO mice (6.5-11.0-fold). The results suggest that mu-receptors tonically stimulate (through endogenous opioid peptides) the activation of native Fas, whereas delta-receptors tonically inhibit the expression of Fas aggregates and that of FADD and phosphorylated FADD (Ser191) in the mouse brain. These data are in line with the acute opposite modulation of Fas and FADD induced by mu- and delta-opiate agonists, and strongly support the notion of an anti-apoptotic delta-opioid tone that restrains Fas signaling.


Subject(s)
Brain/metabolism , Fas-Associated Death Domain Protein/metabolism , Receptors, Opioid/deficiency , fas Receptor/metabolism , Animals , Gene Expression Regulation/genetics , Mice , Mice, Inbred C57BL , Mice, Knockout , Serine/metabolism
18.
Peptides ; 28(3): 663-9, 2007 Mar.
Article in English | MEDLINE | ID: mdl-17161885

ABSTRACT

Nociceptin/orphanin FQ (N/OFQ) modulates various biological functions, including nociception, via selective stimulation of the N/OFQ peptide receptor (NOP). Here we used the NOP selective antagonist UFP-101 to characterize the receptor involved in the spinal antinociceptive effects of N/OFQ evaluated in the mouse tail withdrawal assay and to investigate the mechanism underlying this action by assessing excitatory postsynaptic currents (EPSC) in laminas I and II of the mouse spinal cord dorsal horn with patch-clamp techniques. Intrathecal (i.t.) injection of N/OFQ in the range of 0.1-10 nmol produced a dose dependent antinociceptive effect, which was prevented by UFP-101, but not by naloxone. In contrast the antinociceptive effect of the mu-opioid peptide receptor agonist endomorphin-1 was blocked by naloxone but not by UFP-101. Moreover, N/OFQ and endomorphin-1 induced a significant antinociceptive effect in wild type mice while in mice knockout for the NOP receptor gene only endomorphin-1 was found to be active. In mouse spinal cord slices 1 microM N/OFQ reduced EPSC to 60+/-4% of control values. This inhibitory effect was reversed in a concentration dependent manner by UFP-101 (pA2 value 6.44). The present results demonstrate that N/OFQ-induced spinal antinociception in vivo and inhibition of spinal excitatory transmission in vitro are mediated by receptors of the NOP type.


Subject(s)
Opioid Peptides/pharmacology , Spinal Cord/drug effects , Spinal Cord/physiology , Analgesics/pharmacology , Animals , Behavior, Animal/drug effects , Behavior, Animal/physiology , Electrophysiology , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Narcotic Antagonists , Oligopeptides/pharmacology , Opioid Peptides/physiology , Receptors, Opioid/deficiency , Receptors, Opioid/genetics , Receptors, Opioid/physiology , Nociceptin Receptor , Nociceptin
19.
Eur J Neurosci ; 23(4): 995-1004, 2006 Feb.
Article in English | MEDLINE | ID: mdl-16519664

ABSTRACT

Pain often outlasts its usefulness as warning and aid in wound healing, and becomes chronic and intractable after tissue damage and nerve injury. Many molecules have been implicated as mediators and modulators in persistent pain such as hyperalgesia and tactile pain (allodynia). We previously showed that prostaglandin (PG) E(2), PGF(2alpha) or the neuropeptide nociceptin, also called orphanin FQ (N/OFQ) administered intrathecally (i.t.) produced allodynia in conscious mice. In the present study, we examined the relationship of pain responses between PGs and N/OFQ using the N/OFQ receptor (NOP) antagonist, N-(4-amino-2-methylquinolin-6-yl)-2-(4-ethylphenoxy-methyl)benzamide monohydrochloride (JTC-801), and in mice lacking the N/OFQ prepropeptide (ppN/OFQ(-/-)) and the NOP receptor (NOP(-/-)). JTC-801 dose-dependently blocked the N/OFQ- and PGE(2)-induced allodynia, but not the PGF(2alpha)-induced one. Neither N/OFQ nor PGE(2) induced allodynia in NOP(-/-) mice. By contrast, the N/OFQ-induced allodynia was not affected by inhibition of PG production by a 60-min pretreatment with the non-steroidal anti-inflammatory drug, indomethacin. Among PGE receptor (EP) subtype-selective agonists, the EP4 agonist, AE1-329, markedly stimulated the release of N/OFQ from spinal slices and induced allodynia. AE1-329 also increased nitric oxide production in spinal slices using fluorescent nitric oxide detection, which was blocked by pretreatment with JTC-801. Conversely, PGE(2)-induced allodynia was not observed in ppN/OFQ(-/-) mice. N/OFQ immunoreactive puncta were colocalized with EP4. Taken together, these results demonstrate that PGE(2) induced allodynia by stimulation of N/OFQ release in the spinal cord via EP4 receptor subtypes.


Subject(s)
Dinoprostone/adverse effects , Hyperalgesia/physiopathology , Neuralgia/physiopathology , Opioid Peptides/physiology , Receptors, Opioid/physiology , Touch , Aminoquinolines/administration & dosage , Animals , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Behavior, Animal , Benzamides/administration & dosage , Drug Interactions , Hyperalgesia/etiology , Immunohistochemistry/methods , In Vitro Techniques , Indomethacin/administration & dosage , Injections, Intraventricular , Male , Mice , Mice, Knockout , Neuralgia/etiology , Nitric Oxide/metabolism , Opioid Peptides/administration & dosage , Opioid Peptides/deficiency , Pain Measurement/methods , Receptors, Opioid/administration & dosage , Receptors, Opioid/deficiency , Spinal Cord/drug effects , Spinal Cord/metabolism , Teprotide/administration & dosage , Time Factors , Nociceptin Receptor , Nociceptin
20.
Neuropsychopharmacology ; 31(8): 1733-44, 2006 Aug.
Article in English | MEDLINE | ID: mdl-16237385

ABSTRACT

Exposure to stress triggers hormonal and behavioral responses. It has been shown that the endogenous opioid system plays a role in some physiological reactions to stress. The opioid system was described to mediate analgesia induced by mild stressors and to modulate the activation of the hypothalamic-pituitary-adrenal axis. Our study assessed the contribution of opioid receptors in stress-induced analgesia and adrenocorticotropic hormone (ACTH) and corticosterone release by a genetic approach. We performed a parallel analysis of mice deficient in mu, delta, or kappa opioid receptors, as well as of triple opioid receptor knockout mice, following exposure to a mild stress (3-min swim at 32 degrees C). In wild-type mice, stress elicited an increase in jumping latency on the hot plate, which was influenced by gender and genetic background. This analgesic response was reversed both by naloxone and by the triple mutation, and decreased in mu and delta opioid receptor knockout females. In wild-type females, stress also delayed front- and hindpaw behaviors in the hot plate test and increased tail-flick latency in the tail immersion test. Opioid receptor deletion however did not affect these stress responses. In addition, stress produced an increase in ACTH and corticosterone plasma levels. This endocrine response remained unchanged in all mutant strains. Therefore our data indicate that, under our stress conditions, the endogenous opioid system is recruited to produce some analgesia whereas it does not influence hypothalamic-pituitary-adrenal axis activity. This implies that brain circuits mediating analgesic and hormonal responses to stress can be dissociated.


Subject(s)
Adrenocorticotropic Hormone/metabolism , Analgesia/methods , Corticosterone/metabolism , Receptors, Opioid/deficiency , Receptors, Opioid/metabolism , Stress, Physiological/metabolism , Swimming , Animals , Female , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Pain Measurement/methods , Reaction Time/physiology , Stress, Physiological/psychology , Swimming/psychology
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