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