Nonphotic entrainment of the circadian body temperature rhythm by the selective ORL1 receptor agonist W-212393 in rats

Koji Teshima, Masanori Minoguchi, Sayuri Tounai, Atsuyuki Ashimori, Junichi Eguchi, Charles N. Allen, Shigenobu Shibata

    Research output: Contribution to journalArticle

    22 Citations (Scopus)

    Abstract

    We synthesized a small-molecule opioid receptor-like 1 (ORL1) receptor agonist, 2-{3-[1-((1R)-acenaphthen-1-yl)piperidin-4-yl]-2,3-dihydro-2-oxo- benzimidazol-1-yl}-N-methylacetamide (W-212393), and investigated its effect on the circadian body temperature rhythm of rats. W-212393 has high affinity for ORL1 receptors in the rat cerebral cortex and human ORL1 receptors expressed in HEK293 cells with K i values of 0.76 and 0.50 nM, respectively. W-212393 concentration-dependently stimulated GTPγ 35S binding and its efficacy was similar to nociceptin/orphanin FQ (N/OFQ), suggesting that W-212393 is a full agonist at ORL1 receptors. W-212393 dose-dependently occupied ORL1 receptors following intraventricular or intraperitoneal administration, suggesting that W-212393 is a brain-penetrating compound. W-212393 (100nM) and N/OFQ (100nM) significantly suppressed the activity of spontaneously firing rat suprachiasmatic nucleus neurons. These suppressive effects were blocked by an ORL1 receptor antagonist, J-113397 (1 μM). W-212393 (3 mg kg -1, i.p.) induced a significant phase advance at circadian time 6 (CT6) and CT9, but not at other CTs. The magnitude of the W-212393 (0.3-3 mg kg -1, i.p.)-induced phase advance was dose-dependent and greater than those produced by 8-hydroxy-2-(di-n-propylamino)tetralin (0.3-3 mg kg -1, i.p.) or melatonin (0.3-3 mg kg -1, i.p.). The W-212393 (3 mgkg -1, i.p.)-induced phase advance was antagonized by J-113397 (10 mg kg -1, i.p.). W-212393 (3 mg kg -1, i.p.) significantly accelerated the re-entrainment of the body temperature rhythm to a 6 h advanced light-dark cycle. These results indicate that activation of ORL1 receptors contributes to the circadian entrainment and W-212393 may represent an interesting agent for the study of circadian rhythms.

    Original languageEnglish
    Pages (from-to)33-40
    Number of pages8
    JournalBritish Journal of Pharmacology
    Volume146
    Issue number1
    DOIs
    Publication statusPublished - 2005

    Fingerprint

    Opioid Receptors
    Body Temperature
    2-(3-(1-(acenaphthen-1-yl)piperidin-4-yl)-2,3-dihydro-2-oxobenzimidazol-1-yl)-N-methylacetamide
    8-Hydroxy-2-(di-n-propylamino)tetralin
    Suprachiasmatic Nucleus
    HEK293 Cells
    Photoperiod
    Melatonin
    Circadian Rhythm
    Guanosine Triphosphate
    Cerebral Cortex
    Neurons

    Keywords

    • Circadian rhythm
    • Nociceptin
    • Nonphotic entrainment
    • ORL1
    • Orphanin FQ
    • SCN
    • W-212393

    ASJC Scopus subject areas

    • Pharmacology

    Cite this

    Nonphotic entrainment of the circadian body temperature rhythm by the selective ORL1 receptor agonist W-212393 in rats. / Teshima, Koji; Minoguchi, Masanori; Tounai, Sayuri; Ashimori, Atsuyuki; Eguchi, Junichi; Allen, Charles N.; Shibata, Shigenobu.

    In: British Journal of Pharmacology, Vol. 146, No. 1, 2005, p. 33-40.

    Research output: Contribution to journalArticle

    Teshima, Koji ; Minoguchi, Masanori ; Tounai, Sayuri ; Ashimori, Atsuyuki ; Eguchi, Junichi ; Allen, Charles N. ; Shibata, Shigenobu. / Nonphotic entrainment of the circadian body temperature rhythm by the selective ORL1 receptor agonist W-212393 in rats. In: British Journal of Pharmacology. 2005 ; Vol. 146, No. 1. pp. 33-40.
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    AU - Teshima, Koji

    AU - Minoguchi, Masanori

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    AU - Ashimori, Atsuyuki

    AU - Eguchi, Junichi

    AU - Allen, Charles N.

    AU - Shibata, Shigenobu

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    N2 - We synthesized a small-molecule opioid receptor-like 1 (ORL1) receptor agonist, 2-{3-[1-((1R)-acenaphthen-1-yl)piperidin-4-yl]-2,3-dihydro-2-oxo- benzimidazol-1-yl}-N-methylacetamide (W-212393), and investigated its effect on the circadian body temperature rhythm of rats. W-212393 has high affinity for ORL1 receptors in the rat cerebral cortex and human ORL1 receptors expressed in HEK293 cells with K i values of 0.76 and 0.50 nM, respectively. W-212393 concentration-dependently stimulated GTPγ 35S binding and its efficacy was similar to nociceptin/orphanin FQ (N/OFQ), suggesting that W-212393 is a full agonist at ORL1 receptors. W-212393 dose-dependently occupied ORL1 receptors following intraventricular or intraperitoneal administration, suggesting that W-212393 is a brain-penetrating compound. W-212393 (100nM) and N/OFQ (100nM) significantly suppressed the activity of spontaneously firing rat suprachiasmatic nucleus neurons. These suppressive effects were blocked by an ORL1 receptor antagonist, J-113397 (1 μM). W-212393 (3 mg kg -1, i.p.) induced a significant phase advance at circadian time 6 (CT6) and CT9, but not at other CTs. The magnitude of the W-212393 (0.3-3 mg kg -1, i.p.)-induced phase advance was dose-dependent and greater than those produced by 8-hydroxy-2-(di-n-propylamino)tetralin (0.3-3 mg kg -1, i.p.) or melatonin (0.3-3 mg kg -1, i.p.). The W-212393 (3 mgkg -1, i.p.)-induced phase advance was antagonized by J-113397 (10 mg kg -1, i.p.). W-212393 (3 mg kg -1, i.p.) significantly accelerated the re-entrainment of the body temperature rhythm to a 6 h advanced light-dark cycle. These results indicate that activation of ORL1 receptors contributes to the circadian entrainment and W-212393 may represent an interesting agent for the study of circadian rhythms.

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