Nociceptin/Orphanin FQ Microinjected into Hippocampus Impairs Spatial Learning in Rats

Abstract

The newly discovered peptide nociceptin/orphanin FQ has been found to increase reactivity to pain and to influence locomotor activity after intracerebroventricular administration. This study investigated the possible role of hippocampal nociceptin/orphanin FQ in spatial learning and in spontaneous locomotion. Male rats were trained in the Morris water task after microinjection of 10 nmol nociceptin/orphanin FQ or artificial cerebrospinal fluid (as control) into the CA3 region of the dorsal hippocampus. Nociceptin/orphanin FQ was found to severely impair spatial learning without interfering with swimming performance. Intrahippocampal injection of nociceptin/ orphanin FQ markedly decreased exploratory locomotor activity including vertical movements (rearing). The data suggest that nociceptin/orphanin FQ is a potent modulator of synaptic plasticity within the hippocampus.

[Nphe1]‐Nociceptin (1‐13)‐NH2, a nociceptin receptor antagonist, reverses nociceptin‐induced spatial memory impairments in the Morris water maze task in rats

“…In summary, the results from the present study support and extend those of Sandin et al (1997) in that bilateral intrahippocampal (CA3 region) injection of nociceptin provoked marked impairments in spatial learning in the Morris water maze task, results which are consistent with the dense localization of OP 4 /nociceptin receptors in the hippocampal formation (Mollereau et al, 1994). Most interestingly, this study demonstrates that such learning impairments are truly mediated by OP 4 /nociceptin receptors, as pretreatment with the recently developed nociceptin receptor antagonist, [Nphe 1 ]-Nociceptin (1-13)-NH 2 , reversed nociceptin-induced de®cits in escape latency.…”

“…Such changes in locomotor activity were detected in the ®rst 5 min of testing, and support the use of a 3 min testing period in the present study. However, this subject remains controversial with both decreases (Reinscheid et al, 1995;Devine et al, 1996;Sandin et al, 1997) and increases (Florin et al, 1996) in locomotion being reported. A possible explanation is related to doses, with lower doses of nociceptin inducing increased locomotor activity while higher doses decreased exploratory locomotor behaviour.…”

“…Few experiments have been performed investigating the metabolism of the peptide in vitro in human blood (Yu et al, 1996), in cell culture (Vlaskovska et al, 1999), and in mouse brain cortical slices (Montiel et al, 1997). In vivo experiments in the rat hippocampus (Sandin et al, 1997) and in the mouse brain after intracerebroventricular administration have also been performed. In the latter study, it was demonstrated that the association of di erent peptidase inhibitors potentiated the behavioural e ects of nociceptin on motor behaviour, suggesting that as for other neuropeptides, interruption of the responses induced by nociceptin is ensured by enzymes which cleave the peptide into inactive fragments.…”

“…Pretreatment was performed 5 min before the second injection, and testing began 15 min after the second intrahippocampal injection. Doses (considered intermediate) were chosen on the basis of previously reported in vivo studies, together with binding data of nociceptin and [Nphe 1 ]-Nociceptin (1-13)-NH 2 in transfected CHO cells expressing recombinant human OP 4 receptors (Calo' et al, 2000a,b;Sandin et al, 1997).…”

“…For example, the hippocampal administration of nociceptin impaired learning of a spatial memory task in rats (Sandin et al, 1997) and mice (Hiramatsu & Inoue, 1999), whereas nociceptin receptor knockout mice presented enhanced performance in spatial learning/attention tasks Manabe et al, 1998;Nabeshima et al, 1999).…”