Regular paperRole of nociceptin systems in learning and memory☆
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).
References (51)
- et al.
A synaptic model of memorylong-term potentiation in the hippocampus
Nature (London)
(1993) - et al.
Postsynaptic cAMP pathway gates early LTP in hippocampal CA1 region
Neuron
(1995) - et al.
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
(1994) - et al.
Dose- and strain-dependent effects of dermorphin and [D-Ala2-D-Leu5]enkephalin on passive avoidance behavior in mice
Behav Neurosci
(1985) - et al.
Kappa opiate receptor multiplicityevidence for two U50,488-sensitive kappa 1 subtypes and a novel kappa 3 subtype
J Pharmacol Exp Ther
(1989) - et al.
Orphanin GQ/nociceptin; a role in pain and analgesia, but so much more
Trends Neurosci
(1998) - et al.
Dynorphin1–17 can enhance or impair retention of an inhibitory avoidance response in rats
Life Sci
(1990) - et al.
Vasopressin potentiation in the performance of a learned appetitive taskreversal by a pressor antagonist analog of vasopressin
Pharmacol Biochem Behav
(1983) - et al.
Effects of cAMP stimulate a late phase of LTP in hippocampal CA1 neurons
Science
(1993) - et al.
Pharmacological actions of a novel mixed opiate agonist/antagonistnaloxone benzoylhydrazone
J Pharmacol Exp Ther
(1989)
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)
Cited by (43)
Nociceptin and the NOP receptor in aversive learning in mice
2017, European NeuropsychopharmacologyCitation 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).
Brain transcriptome perturbations in the Hfe <sup>-/-</sup> mouse model of genetic iron loading
2012, Brain ResearchCitation Excerpt :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.
Anxiolytic-like effect of central administration of NOP receptor antagonist UFP-101 in rats submitted to the elevated T-maze
2011, Behavioural Brain ResearchNeuropeptides in learning and memory processes with focus on galanin
2010, European Journal of PharmacologyThe nociceptin system and hippocampal cognition in mice A pharmacological and genetic analysis
2009, Brain ResearchCitation 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 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.