Role of nociceptin systems in learning and memory

doi:10.1016/S0196-9781(00)00244-8

Peptides

Volume 21, Issue 7, July 2000, Pages 1063-1069

https://doi.org/10.1016/S0196-9781(00)00244-8 Get rights and content

Abstract

This article summarizes our recent finding that the nociceptin system is involved in the regulation of learning and memory. The nociceptin-knockout mice show greater learning ability in the water maze task, an enhanced latent learning in the water finding task, better memory in the passive avoidance task, and further, larger long-term potentiation in the hippocampal CA1 region than wild-type mice. Nociceptin itself induces an impairment of passive avoidance task in wild-type mice, which is reversed by naloxone benzoylhydrazone (NalBzoH). Thus, the nociceptin system seems to play negative roles in learning and memory, and NalBzoH may act as a potent antagonist for the nociceptin receptor.

Introduction

Recent DNA cloning studies have shown that the G protein-coupled opioid receptor family is comprised of three distinct opioid receptors (μ-, δ-, and κ-opioid receptors) and the nociceptin/orphanin FQ receptor (the ORL-1 receptor) [22], [24], [31], [43]. The endogenous ligand for the ORL-1 receptor has been isolated and named nociceptin or orphanin FQ. Nociceptin has sequence similarities with an endogenous κ-opioid receptor ligand, dynorphin A [31], [43].

A regional distribution of mRNA for the nociceptin precursor has been shown in the brain and spinal cord [14], [33], [39]. Expression levels of ORL-1 receptor mRNA are high in the periaqueductal gray, dorsal raphe nucleus, locus coeruleus, and the dorsal horn of the spinal cord [3]. An in situ hybridization study indicated that mRNA for the ORL-1 receptor is expressed in the cortical and limbic regions of the brain, suggesting that ORL-1 receptor plays an important role in cognitive, mnemonic, and attentional processes [13]. Immunohistochemical localization of ORL-1 receptor in rat brain indicates a high concentration in the hippocampus, brainstem, and cortex, which is relevant to the processes of learning and memory [6], [13], [32]. Nociceptin has been reported to induce impairment of learning [44] and inhibit synaptic transmission and synaptic plasticity such as long-term potentiation (LTP) in the rat hippocampus and dentate gyrus [49], [50]. On the other hand, a number of studies have indicated that endogenous opioids modulate memory processes. In general, the post-training administration of β-endorphin or enkephalins impairs memory in different behavioral tasks [4], [19], [45]. There have been several reports on the effects of dynorphins, κ-opioid receptor agonists, on memory function, but the results are not consistent: dynorphin A (1–13) had no effect on inhibitory or shuttle avoidance response [20], while it impaired the habituation of exploration and the retention of inhibitory avoidance but not of Y-maze discrimination [18]. In contrast, dynorphin A(1–17) facilitates the retention of inhibitory avoidance [7] and atttenuates the impairment of retention produced by adrenalectomy [21]. Thus, there is a possibility that nociceptin and/or the ORL-1 receptor are also involved in learning and memory. However, since specific antagonists are not available, their roles in learning and memory have yet to be elucidated at the whole-animal level. One approach to this issue would be to produce mutant mice lacking the ORL-1 receptor by gene targeting and to analyze the physiological phenotype of the ORL-1 receptor knockout mice.

Recently, we reported that ORL-1 receptor knockout mice show no change in either nociceptive sensitivity or locomotor activity [26], [27], [37], although nociceptin induces hyperalgesia and hypolocomotion by interacting specifically with the ORL-1 receptor in the central nervous system [31], [43]. However, these experimental results cannot eliminate the possibility that the ORL-1 receptor is involved in the modulation of nociceptive sensitivity and locomotor activity at the basal level, because the redundancy of other regulatory systems may compensate for the abnormalities caused by the deficiency of the ORL-1 receptor. In spite of many experiments [6], [13], [32], the nociceptin system has not yet been fully elucidated.

Another approach would be to search for specific nonpeptide drugs modulating the ORL-1 receptor activity in vivo. As described above, nociceptin shows sequence similarity with dynorphin, a κ-opioid receptor ligand. Naloxone benzoylhydrazone (NalBzoH) is a derivative of the μ-opioid receptor antagonist, naloxone, and produces antinociceptive effects in vivo [10]. Previous ligand-binding studies suggested that NalBzoH interacts with the μ-, κ₁-, and κ₃-opioid receptor subtypes [5], [51]. However, since the κ-opioid receptor defined by cloning studies shows the pharmacological characteristics of the κ₁-subtype when the cDNA is functionally expressed in cultured cells, the molecular profile of the κ₃-subtype has yet to be elucidated. Recent studies have suggested a molecular biologic relationship between the κ₃-subtype and the ORL-1 receptor, but some data have negated the relationship [42], [48]. We have reported that hyperalgesia and hypolocomotion induced by nociceptin (i.c.v.) were reversed by NalBzoH in a dose-dependent manner in mice [38], suggesting that NalBzoH acts as an ORL-1 receptor antagonist in vivo.

This article summarizes our recent findings in ORL-1 receptor-knockout mice and the role of NalBzoH as a ORL-1 receptor antagonist: the nociceptin system is involved in the regulation of learning and memory, and NalBzoH is identified as an antagonist for the ORL-1 receptor.

Section snippets

Generation of mutant mice lacking the ORL-1 receptor

Genomic DNA fragments from the mouse ORL-1 receptor gene [36] were used to construct a targeting vector, in which the first protein-coding sequence (P1) is replaced with a lacZ-neo cassette and the sequence of the lacZ gene encoding bacterial β-galactosidase is linked to the 5′-noncoding sequence. With the expected mutant allele, it is thus possible to express the lacZ gene under the control of the transcription machinery of the ORL-1receptor gene. The gene targeting and generation of mutant

Spontaneous alternation behavior in a Y-maze test (Table 1)

Memory consists of short- and long-term memory and processes such as acquisition, consolidation, retention, and retrieval. Short-term memory performance was examined by monitoring spontaneous alternation behavior in a Y-maze, such behavior also being an index of spatial working memory.

Deficiency of the ORL-1 receptor did not affect the spontaneous alternation behavior [26]. In line with the data using the ORL-1 receptor knockout mice, nociceptin (1–10 pmol/mouse i.c.v.) administered to

Neuronal plasticity (Table 1)

It is known that spatial learning and memory require integrative control functions of the hippocampus [1]. Nissl-stained material from the entire hippocampal region of the ORL-1 receptor-deficient mice showed no histologic abnormality [28]. The β-galactosidase staining showed that the receptor message for the ORL-1 receptor in the knockout mice [37] is highly expressed in the dentate gyrus granule cells and in CA1 and CA3 pyramidal cells [28]. In situ hybridization analysis showed that the

NalBzoH as a ORL-1 receptor antagonist (Table 1)

We have searched for a specific antagonist to the ORL-1 receptor biochemically and pharmacologically. In the tail-flick test, the ORL-1 receptor knockout mice lack response not only to nociceptin (1 and 10 μmol/mouse) but also to NalBzoH (10–75 mg/kg), whereas these mice respond to other traditional opioids such as morphine (μ-opioid agonist; 1 and 5 mg/kg), U-50,488H (κ₁-opioid agonist; 1 and 5 mg/kg), and naloxone (μ-opioid antagonist; 5 mg/kg) [38]. Furthermore, NalBzoH (50 and 75 mg/kg)

Conclusion

Our results suggest that loss of the ORL-1 receptor results in a gain-of-function mutation in both memory processes and in long-term potentiation mechanisms in CA1, perhaps as a result of altered intracellular signal transduction systems in neurons. Furthermore, these studies suggest that memory processes, especially the retention of memory, can be modulated by NalBzoH, a ligand to the ORL-1 receptor, and also that NalBzoH is worth testing for the alleviation of memory disorders.

Acknowledgements

The above studies were performed in collaboration with Drs T. Takahashi, H. Katagiri (Tokyo University), T. Houtani, T. Noda, and T. Sugimoto (Kansai University).

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Citation Excerpt :
The N/OFQ system has been associated with a variety of physiological and biological functions in the PNS and CNS (Calo et al., 2000; Civelli, 2008; Lambert, 2008; Toll et al., 2016). The localization and expression of N/OFQ and NOP in the brain and pharmacological evidence (Darland et al., 1998; Henderson and McKnight, 1997; Meunier, 1997; Neal et al., 1999; Sim-Selley et al., 2003) have implicated the N/OFQ system in nociceptive activity, motor function, stress, depression, addiction and anxiety (Gavioli and Calo' 2013; Jenck et al., 2000; Kuzmin et al., 2003; Mallimo and Kusnecov, 2013; Toll et al., 2016) as well as learning and memory (Manabe et al., 1998; Nagai et al., 2007; Noda et al., 2000; Reinscheid et al., 1995; Sandin et al., 1997, 2004). Studies in mice and rats have shown that intraventricular (i.c.v.) or intrahippocampal (i.h.) administration of N/OFQ can modify learning and memory in tasks such as contextual fear, step down/through passive avoidance (PA), and hippocampal-dependent spatial learning (Fornari et al., 2008; Goeldner et al., 2009; Hiramatsu and Inoue, 1999; Kuzmin et al., 2004; Mamiya et al., 1999; Roozendaal et al., 2007; Sandin et al., 1997, 2004).
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.
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We also demonstrated reduced levels of transcripts for CaMKIIα, the most abundant protein in the postsynaptic density and a nodal signaling protein at the synapse (Cheng et al., 2006). Decreased transcripts for CaMKIIα and Grin1 together may be predicted to impair LTP, learning and synaptic plasticity (Mamiya et al., 2003; Manabe et al., 1998; Noda et al., 2000). As well as changes that might predict decreased excitatory neurotransmission, we also observed decreased transcript levels for the GABA-B receptor, prominent in inhibitory neurotransmission, possibly indicating generalized depression of neural activity.
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Depression and anxiety disorders present several genetic and neurobiological similarities. Drugs with antidepressant activity are effective in the treatment of a wide spectrum of anxiety disorders. Preclinical results showed that acute and chronic treatment with the NOP antagonist [Nphe¹,Arg¹⁴,Lys¹⁵]N/OFQ-NH₂ (UFP-101) produced antidepressant-like effects in rodents. Thus, the present study aimed to investigate the effect of central administration of UFP-101 on the anxiety-related behavior in rats as evaluated in the elevated T-maze (ETM) test. Our results showed that UFP-101 reduced the latency of inhibitory avoidance in the ETM, indicating an anxiolytic-like effect. The endogenous peptide N/OFQ prevented this anxiolytic-like action of UFP-101, demonstrating its modulation via central NOP receptors. However, UFP-101 failed to interfere with the latency to escape. No change was observed in locomotor activity after UFP-101 treatment, ruling out any nonspecific motor effect. In conclusion, our results showed that the central administration of UFP-101 presents an anxiolytic-like effect in rats evaluated in the ETM test, providing new insights for drug development to treat anxiety disorders targeting the N/OFQ-NOP receptor system.
Neuropeptides in learning and memory processes with focus on galanin
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Neuropeptides represent by far the most common signalling molecules in the central nervous system. They are involved in a wide range of physiological functions and can act as neurotransmitters, neuromodulators or hormones in the central nervous system and in the periphery. Accumulating evidence during the past 40 years has implicated a number of neuropeptides in various cognitive functions including learning and memory. A major focus has been on the possibility that neuropeptides, by coexisting with classical neurotransmitters, can modulate classical transmitter function of importance for cognition. It has become increasingly clear that most transmitter systems in the brain can release a cocktail of signalling molecules including classical transmitters and several neuropeptides. However, the neuropeptides seem to come into action mainly under conditions of severe stress or aversive events, which have linked their action also to regulation of affective components of behaviour. This paper summarises some of the results of three neuropeptides, which can impact on hippocampal cognition by intrinsic (dynorphins, nociceptin) or extrinsic (galanin) modulation. The results obtained with these neuropeptides in rodent studies indicate that they are important for various aspects of hippocampal learning and memory as well as hippocampal plasticity. Recent studies in humans have also shown that dysregulation of these neuropeptides may be of importance for both neurodegenerative and neuropsychiatric disorders associated with cognitive impairments. It is concluded that compounds acting on neuropeptide receptor subtypes will represent novel targets for a number of disorders, which involve cognitive deficiencies.
The nociceptin system and hippocampal cognition in mice A pharmacological and genetic analysis
2009, Brain Research
Citation Excerpt :
The enrichment of NOP and its mRNA in cortical and limbic regions of the brain (Henderson and McKnight, 1997; Sim-Selley et al., 2003) and the immunohistochemical localization of NOP receptors in the hippocampus, brainstem and cortex (Darland et al., 1998; Meunier 1997; Neal et al., 1999a,b; Henderson and McKnight, 1997) have led to the suggestion that N/OFQ and its receptor may be important in cognitive, emotional and attentional processes. The neuropeptide N/OFQ has been implicated in cognitive processes, based also on pharmacological evidences (Higgins et al., 2002; Kuzmin et al., 2003; Mamiya et al., 2003; Manabe et al., 1998; Nagai et al., 2007; Noda et al., 2000; Sandin et al., 1997, 2004, Walker et al., 2002). Several studies have indicated a possible role of N/OFQ in hippocampal plasticity and hippocampally dependent learning and memory.
This study examines the effects of NOP agonists nociceptin/orphanin FQ (N/OFQ) and Ro 64-6198, NOP antagonists [Nphe¹]N/OFQ(1-13)-NH₂ Nphe¹ and naloxone benzoylhydrazone (NalBzoH) on spatial memory in NMRI mice and pronociceptin (proNC) knockout (KO) mice using the water maze task. N/OFQ, administered i.c.v. (1, 5 and 10 nmol/mouse) and into hippocampal CA3 (1 nmol/mouse, bilaterally), impaired acquisition and retention in the maze. Impairments were blocked by pre-treatment with Nphe¹ (10 nmol, i.c.v.). Ro 64-6198 (0.1–0.3–1 mg/kg i.p.) also dose-dependently impaired learning. However, pre-treatment with NalBzoH (1 mg/kg, s.c.) failed to modify the effects of Ro 64-6198. Nphe¹ (10 nmol/mouse i.c.v.) and NalBzoH (1 mg/kg, s.c.) by themselves failed to affect maze performance, despite a tendency for enhanced performance. Prepro N/OFQ knockout (ppN/OFQ -/-) showed evidence of improved learning, evident at retention trials and in reversal training. ppN/OFQ -/- mice were not impaired by N/OFQ (10 nmol i.c.v.) in the task, suggesting that changes in postsynaptic NOP receptors may occur in such KO mice. It is concluded that N/OFQ and NOP receptors have an important role in hippocampus-dependent spatial learning and memory, probably by modulation of glutamatergic functions.
Complete knockout of the nociceptin/orphanin FQ receptor in the rat does not induce compensatory changes in μ, δ and κ opioid receptors
2009, Neuroscience
The nociceptin/orphanin FQ (N/OFQ) opioid peptide receptor (NOPr) is a new member of the opioid receptor family consisting of μ, δ and κ opioid receptors. The anti-opioid properties of its endogenous ligand, N/OFQ provide the receptor interesting potentials in symptoms and processes related to drug addiction, learning and memory, anxiety and depression, and nociception. Using target-selected N-ethyl-N-nitrosourea (ENU)-driven mutagenesis we recently generated a rat model bearing a premature stop codon in the opioid-like receptor (oprl1) gene, and here we describe the primary characterization of this novel model. Data revealed that [³H]N/OFQ binding to brain slices was completely absent in rats homozygous for the premature stop codon (oprl1^−/−). Heterozygous rats displayed an intermediate level of NOPr binding. Oprl1 receptor transcript levels, as determined by Northern blot analysis, were reduced by approximately 50% in oprl1^−/− rats compared to wild-type controls (oprl1^+/+), and no alternative spliced transcripts were observed. Quantitative autoradiographic mapping of μ, δ and κ opioid receptors using [³H]DAMGO, [³H]deltorphin and [³H]CI-977, respectively, did not show any changes in opioid receptor binding. In conclusion, we present a novel mutant rat lacking NOPr without compensatory changes in μ, δ and κ opioid receptors. We anticipate that this mutant rat will have heuristic value to further understand the function of NOPr.

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^☆: This study was supported, in part, by Grants-in-Aid for Center of Excellence (COE), Science Research (nos. 07557009 and 10897005) from the Ministry of Education, Science and Culture and by an SRF Grant for Biomedical Research.

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Regular paperRole of nociceptin systems in learning and memory☆

Abstract

Introduction

Section snippets

Generation of mutant mice lacking the ORL-1 receptor

Spontaneous alternation behavior in a Y-maze test (Table 1)

Neuronal plasticity (Table 1)

NalBzoH as a ORL-1 receptor antagonist (Table 1)

Conclusion

Acknowledgements

A synaptic model of memorylong-term potentiation in the hippocampus

Nature (London)

Postsynaptic cAMP pathway gates early LTP in hippocampal CA1 region

Neuron

Molecular cloning and tissue distribution of a putative member of the rat opioid receptor gene family that is not a μ, δ or κ opioid receptor type

FEBS Lett

Dose- and strain-dependent effects of dermorphin and [D-Ala2-D-Leu5]enkephalin on passive avoidance behavior in mice

Behav Neurosci

Kappa opiate receptor multiplicityevidence for two U50,488-sensitive kappa 1 subtypes and a novel kappa 3 subtype

J Pharmacol Exp Ther

Orphanin GQ/nociceptin; a role in pain and analgesia, but so much more

Trends Neurosci

Dynorphin1–17 can enhance or impair retention of an inhibitory avoidance response in rats

Life Sci

Vasopressin potentiation in the performance of a learned appetitive taskreversal by a pressor antagonist analog of vasopressin

Pharmacol Biochem Behav

Effects of cAMP stimulate a late phase of LTP in hippocampal CA1 neurons

Science

Pharmacological actions of a novel mixed opiate agonist/antagonistnaloxone benzoylhydrazone

J Pharmacol Exp Ther

Effects of nocistatin on nociceptin-induced impairment of learning and memory in mice

Eur J Pharmacol

Nociceptin/orphanin FQ, and nocistatin on learning and memory impairment induced by scopolamine in mice

Br J Pharmacol

, Mcknight, AT

The orphan opioid receptor and its endogenous ligand -nociceptin/orphanin FQ. Trends Pharmacol Sci

Structure and regional distribution of nociceptin/orphanin FQ precursor

Biochem Biophys Res Commun

Differential effects of pimozide and SCH 23390 on acquisition of learning in mice

Eur J Pharmacol

Dopaminergic agonists impair latent learning in micepossible modulation by noradrenergic function

J Pharmacol Exp Ther

Functional coupling of the nociceptin/orphanin FQ receptor with the G-protein-activated K+ (GIRK) channel

Mol Brain Res

Dynorphin induces task-specific impairment of memory

Psychobiology

Effect of β-endorphin and naloxone on acquisition, memory, and retrieval of shuttle avoidance and habituation learning in rats

Psychopharmacology

Unlike β-endorphin, dynorphin 1–13 does not cause retrograde amnesia for shuttle avoidance or inhibitory avoidance learning in rats

Psychopharmacology

A κ-selective opioidergic pathway is involved in the reversal of a behavioural effect of adrenalectomy

Eur J Pharmacol

Molecular biology and pharmacology of cloned opioid receptors

FASEB J

Targeted disruption of the orphanin FQ/nociceptin gene increases stress susceptibility and impairs stress adaptation in mice

Proc Natl Acad Sci USA

Molecular cloning of a novel G protein-coupled receptor related to the opiate receptor family

J Neurochem

Noradrenaline blocks accommodation of pyramidal cell discharge in the hippocampus

Nature (London)

Regular paper
Role of nociceptin systems in learning and memory☆

Dose- and strain-dependent effects of dermorphin and [D-Ala²-D-Leu⁵]enkephalin on passive avoidance behavior in mice

Functional coupling of the nociceptin/orphanin FQ receptor with the G-protein-activated K⁺ (GIRK) channel