Research ReportNociceptin/orphanin FQ reverses mecamylamine-induced learning and memory impairment as well as decrease in hippocampal acetylcholine release in the rat
Introduction
Nociceptin, also known as orphanin FQ, is an endogenous ligand for the opioid receptor-like 1 (NOP) receptor and has some structural homology with the endogenous opioid peptide dynorphin A (1–17) (Meunier et al., 1995, Reinscheid et al., 1995). Nociceptin has important roles in several physiological functions including pain, anxiety, locomotion, learning, and memory. Similarly to dynorphin A, higher doses of nociceptin appear to inhibit synaptic function, although it is not known whether these concentrations are physiologically relevant. For example, nociceptin inhibited voltage-gated Ca2+ channels in cultured hippocampal neurons (Knoflach et al., 1996) as well as long-term potentiation in the dentate gyrus and CA1 region of hippocampal slices (Higgins et al., 2002, Yu et al., 1997, Yu and Xie, 1998).
In behavioral studies, intrahippocampal infusion of nociceptin impaired spatial learning in the Morris water-maze task (Sandin et al., 1997, Sandin et al., 2004) and intracerebroventricular injection of nociceptin impaired learning and memory in the passive avoidance test (Hiramatsu and Inoue, 1999, Mamiya et al., 1999). Furthermore, Ro 64-6198, a non-peptide NOP receptor agonist, also impaired learning and memory (Higgins et al., 2002). In genetic studies, NOP receptor knockout mice showed facilitated learning and memory as well as and long-term potentiation (Mamiya et al., 2003, Manabe et al., 1998, Taverna et al., 2005). Nociceptin gene knockout mice also showed facilitated learning and memory function (Higgins et al., 2002). These reports indicate that nociceptin and NOP receptors inhibit synaptic plasticity, learning, and memory. Interestingly, we reported that low doses of nociceptin ameliorate the scopolamine-induced impairment of learning and memory in mice (Hiramatsu and Inoue, 2000). However, the mechanisms of this ameliorating effect have not yet been elucidated.
In Alzheimer's disease patients, not only the muscarinic but also the nicotinic receptors are markedly decreased (Nordberg and Winblad, 1986, Quirion et al., 1986, Whitehouse et al., 1986). Scopolamine, a muscarinic acetylcholine receptor antagonist, is widely used to investigate the cholinergic influence on learning ability in experimental animals. However, we previously reported that blockade of nicotinic receptors by mecamylamine also impairs learning ability (Hiramatsu et al., 1998, Hiramatsu and Watanabe, 2006). Nicotinic receptors are localized both on presynaptic axon terminals and at the postsynaptic somatodendritic level (Clarke, 1993, Sargent, 1993). The importance of presynaptic nicotinic receptors was demonstrated in a previous study by McGehee et al. (1995). The sensitivity of presynaptic nicotinic autoreceptors might increase during degeneration of cholinergic neurons as a compensatory mechanism. Although most of the functions of postsynaptic receptors involved in cholinergic signaling in the CNS are not well established (Wonnacott et al., 1989), presynaptic nicotinic receptors on brain cholinergic neurons are known to be tonically active and mediate a positive feedback mechanism that controls cholinergic neuronal activity (Marchi and Raiteri, 1996).
In this study, we therefore investigated the effect of low doses of nociceptin on the impairment of learning and memory and reduction of the acetylcholine release in the hippocampus induced by mecamylamine using a step-through type passive avoidance test and in vivo microdialysis in rats.
Section snippets
Effects of nociceptin on mecamylamine-induced learning and memory impairment
Mecamylamine (49 μmol/kg, s.c.) significantly impaired learning when administered 30 min before the acquisition trial (Fig. 1), as reported previously (Hiramatsu et al., 1998, Hiramatsu and Watanabe, 2006). Nociceptin (10 fmol/rat, i.c.v.) administered 25 min before the acquisition trial significantly attenuated the impairment of learning and memory induced by mecamylamine, whereas nociceptin (1 and 100 fmol/rat, i.c.v.) showed no such effect (Fig. 1). No significant differences were observed
Discussion
Nociceptin is an endogenous heptadecapeptide that binds to NOP receptors (Meunier et al., 1995, Reinscheid et al., 1995). The administration of nociceptin caused impairment of learning and memory (Hiramatsu and Inoue, 1999, Mamiya et al., 1999, Sandin et al., 1997) that was blocked by nocistatin, naloxone benzoylhydrazone, [NPhe1]nociceptin(1–13)NH2 and [Phe1Ψ(CH2–NH)Gly2]nociceptin (1–13)NH2 (Hiramatsu and Inoue, 1999, Mamiya et al., 1999, Mamiya et al., 2003, Redrobe et al., 2000, Sandin et
Animals
Eight-week-old male Sprague–Dawley rats (Japan SLC Inc., Japan) were housed in a room with controlled lighting (12-h light/dark cycle, lights on: 08:00 to 20:00) and temperature (23 ± 2 °C) for at least 3 days before the experiments, and given free access to food and water. Experimental protocols concerning the use of laboratory animals were approved by the animal use committee of Meijo University and followed the guidelines of the Japanese Pharmacological Society [(1992) Guiding Principles for
Acknowledgments
This study was supported in part by grants from the Japan Smoking Research Foundation, and by a Grant-in-Aids for Scientific Research (No. 16590442 and 19500333) from the Ministry of Education, Science and Culture, Japan. We wish to thank Dr. Toshitaka Nabeshima for help in conducting this study.
References (39)
- et al.
Effects of nocistatin on nociceptin-induced impairment of learning and memory in mice
Eur. J. Pharmacol.
(1999) - et al.
Improvement by low doses of nociceptin on scopolamine-induced impairment of learning and/or memory
Eur. J. Pharmacol.
(2000) - et al.
Dynorphin A (2–13) improves mecamylamine-induced learning impairment accompanied by reversal of reductions in acetylcholine release in rats
Neuropeptides
(2006) - et al.
Modification of acetylcholine release by nociceptin in conscious rat striatum
Brain Res.
(1999) - et al.
Regulation of cyclic AMP-dependent response element-binding protein (CREB) by the nociceptin/orphanin FQ in human dopaminergic SH-SY5Y cells
Biochem. Biophys. Res. Commun.
(2002) - et al.
Nociceptin/orphanin FQ receptors modulate glutamate extracellular levels in the substantia nigra pars reticulata. A microdialysis study in the awake freely moving rat
Neuroscience
(2002) - et al.
Biochemical evidence for orphanin FQ/nociceptin receptor heterogeneity in mouse brain
Biochem. Biophys. Res. Commun.
(1997) - et al.
Nociceptin/orphanin FQ inhibits glutamate release from rat cerebellar and brain stem slices
Neurosci. Lett.
(2002) - et al.
Nociceptin/orphanin FQ modulates spatial learning via ORL-1 receptors in the dorsal hippocampus of the rat
Brain Res.
(2004) - et al.
Enhanced hippocampal acetylcholine release in nociceptin–receptor knockout mice
Brain Res.
(2005)