Elsevier

Brain Research

Volume 783, Issue 2, 9 February 1998, Pages 236-240
Brain Research

Research report
Enhancement of spatial attention in nociceptin/orphanin FQ receptor-knockout mice

https://doi.org/10.1016/S0006-8993(97)01406-6Get rights and content

Abstract

We isolated genes for the opioid receptor homologue MOR-C, namely nociceptin receptor (designated alternatively as orphanin FQ receptor) and generated nociceptin receptor-knockout mice. Previously, we have reported that the nociceptin system appears to participate in the regulation of the auditory system. However, the behavior of the nociceptin receptor-knockout mice has yet to be fully characterized. In the present study, we investigated changes in several behavioral performances in mice which lack nociceptin receptor. Nociceptive thresholds of nociceptin receptor-knockout mice were unchanged in the hot-plate and electric foot-shock tests as well as tail-flick and acetic acid-induced writhing tests compared to those of wild-type mice. The nociceptin receptor-knockout mice did not show any behavioral changes in the elevated plus-maze task. Surprisingly, in the water-finding test, the nociceptin receptor-knockout mice showed an enhanced retention of spatial attention (latent learning) compared to wild-type mice. In a biochemical study, dopamine content in the frontal cortex was lower in nociceptin receptor-knockout mice than wild-type mice. These results suggest that nociceptin receptor plays an important role in spatial attention by regulating the dopaminergic system in the brain.

Introduction

Soon after the cloning of the δ opioid receptor 6, 11, the receptor for unknown ligand belonging to the opioid receptor family has been reported from several groups and designated independently as ORL1, ROR-C, LC132 and C3 2, 7, 12, 14. This receptor exhibited 68% homology with μ receptor, 67% with δ receptor, 66% with κ receptor, and 32% with somatostatin receptor, and is abundantly expressed in rat and mouse brain [5]. Recently, the endogenous ligand for this receptor has been isolated and named nociceptin or orphanin FQ 16, 24. Nociceptin is derived from a larger precursor which shows sequence similarity to the opioid peptide precursors, particularly pre-prodynorphin 9, 15, 21. Several studies have reported the physiological functions of nociceptin. For example, in contrast to the opioid peptides with analgesic effects, nociceptin induces hyperalgesia 16, 24and allodynia [22], when administered intracerebroventricularly (i.c.v.) and intrathecally, respectively. Nociceptin or orphanin FQ inhibits adenylyl cyclase activity in cells transfected with ORL1 [16]or LC132 [24]. Furthermore, nociceptin was shown to increase K+ conductance in rat dorsal raphe neurons in vitro [27], and to inhibit voltage-dependent Ca2+ channel currents in the human neuroblastoma cell line, SH-SY5Y [4]. In situ hybridization analysis 2, 3, 7, 14and immunohistochemistry [1]revealed distribution of ORL1 in many areas of the central nervous system. However, specific antagonists for nociceptin receptor are not available, and the physiological roles of nociceptin have yet to be elucidated at the whole-animal level. One approach would be to produce knockout mice lacking the nociceptin receptor by means of gene targeting and analyze the physiological phenotype of the mutants. Recently, we have reported that the nociceptin system appears to participate in the regulation of the auditory system [19].

To characterize the role of nociceptin receptor in whole animals, we investigated several behavioral performances in nociceptin receptor-knockout mice.

Section snippets

Animals

We used male nociceptin receptor-knockout and wild-type mice (9–12 weeks old) which have been reported [19]. The animals were housed in a controlled environment (23±1°C, 50±5% humidity) and allowed food and water ad libitum. The room lights were off between 2000 and 0800.

All experimental protocols were conducted with due regard for the Japanese Experimental Animal Research Association standards as defined in the Guidelines for Animal Experiments (1987), and were approved in advance by the

Elevated plus-maze test

Fig. 1A shows the performance on the elevated plus-maze test in wild-type and knockout mice. Total arm entries and closed arm entries were not significantly different between the two groups (data not shown). No significant differences were detected in percent open arm entries and percent time spent in open arms between wild-type and knockout mice.

Nociceptive test

Nociceptive thresholds in two nociceptive tests are shown in Fig. 1B. No measurable difference in the antinociceptive thresholds to thermal and

Discussion

We have previously reported generation and characterization of mice lacking the nociceptin receptor [19]. No obvious morphological abnormalities could be detected in the knockout mice. Further, the knockout mice did not differ from wild-type littermates in health, growth and reproduction. As shown previously, a statistical analysis revealed no significant difference between wild-type and knockout mice in locomotor activity [19].

The state of anxiety in knockout mice was evaluated by elevated

Conclusion

Our behavioral analysis reveals that the nociceptin receptor-knockout mice display a significant enhancement of latent learning, although no obvious morphological or behavioral abnormalities could be detected. Our results suggest that nociceptin receptor plays an important role in latent learning by modulating the dopaminergic system in the brain.

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