title: Possible involvement of activated locus coeruleus-noradrenergic neurons in pain-related sleep disorders.
abstract: The locus coeruleus (LC) is a noradrenergic brainstem structure that is considered to play a role in promoting arousal. To further clarify the role of LC noradrenergic neurons, we performed an optogenetic assay by injecting AAV-channelrhodopsin-2 (ChR2) into the LC of cre-tyrosine hydrolase (TH) mice. We found here that the specific activation of LC noradrenergic neurons produced a significant increase in wakefulness and a significant decrease in non-rapid eye movement (NREM) sleep during photostimulation. On the other hand, neuropathic pain is believed to significantly interfere with sleep, and inadequate sleep may contribute to the stressful negative consequences of living with pain. In the present study, sciatic nerve ligation, which produced significant thermal hyperalgesia, significantly increased the levels of noradrenaline released in the prefrontal cortex (PFC) by the weak electrical stimulation of neurons in the LC. Under these conditions, the systemic administration of adrenaline α and β inhibitor cocktail at 7 days after sciatic nerve ligation restored the increased wakefulness and decreased NREM sleep to normal levels. These results suggest that neuropathic pain may accelerate neurons in the LC, and its overactivation may be, at least in part, associated with sleep disturbance under neuropathic pain.
authors.affiliation: Department of Pharmacology, Hoshi University School of Pharmaceutical Sciences, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan; Department of Anesthesiology and Pain Medicine, Juntendo University School of Medicine, 2-1-1Hongou, Bunkyou-ku, Tokyo 113-8421, Japan.
authors.forename: Keito
authors.initials: K
authors.lastname: Koh
authors.affiliation: Department of Pharmacology, Hoshi University School of Pharmaceutical Sciences, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan.
authors.forename: Asami
authors.initials: A
authors.lastname: Hamada
authors.affiliation: Department of Pharmacology, Hoshi University School of Pharmaceutical Sciences, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Hamada
authors.affiliation: Department of Pharmacology, Hoshi University School of Pharmaceutical Sciences, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Yanase
authors.affiliation: Department of Pharmacology, Hoshi University School of Pharmaceutical Sciences, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan.
authors.forename: Mamiko
authors.initials: M
authors.lastname: Sakaki
authors.affiliation: Department of Pharmacology, Hoshi University School of Pharmaceutical Sciences, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan.
authors.forename: Kazuki
authors.initials: K
authors.lastname: Someya
authors.affiliation: Department of Pharmacology, Hoshi University School of Pharmaceutical Sciences, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan.
authors.forename: Michiko
authors.initials: M
authors.lastname: Narita
authors.affiliation: Department of Pharmacology, Hoshi University School of Pharmaceutical Sciences, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan.
authors.forename: Naoko
authors.initials: N
authors.lastname: Kuzumaki
authors.affiliation: Department of Pharmacology, Hoshi University School of Pharmaceutical Sciences, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan.
authors.forename: Daigo
authors.initials: D
authors.lastname: Ikegami
authors.affiliation: Department of Pharmacology, Hoshi University School of Pharmaceutical Sciences, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan.
authors.forename: Hiroyasu
authors.initials: H
authors.lastname: Sakai
authors.affiliation: Department of Anesthesiology and Pain Medicine, Juntendo University School of Medicine, 2-1-1Hongou, Bunkyou-ku, Tokyo 113-8421, Japan.
authors.forename: Masako
authors.initials: M
authors.lastname: Iseki
authors.affiliation: Department of Anesthesiology and Pain Medicine, Juntendo University School of Medicine, 2-1-1Hongou, Bunkyou-ku, Tokyo 113-8421, Japan.
authors.forename: Eiichi
authors.initials: E
authors.lastname: Inada
authors.affiliation: Department of Pharmacology, Hoshi University School of Pharmaceutical Sciences, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan; Department of Anesthesiology and Pain Medicine, Juntendo University School of Medicine, 2-1-1Hongou, Bunkyou-ku, Tokyo 113-8421, Japan; Life Science Tokyo Advanced Research Center (L-StaR), 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan. Electronic address: narita@hoshi.ac.jp.
authors.forename: Minoru
authors.initials: M
authors.lastname: Narita
mesh_terms: D059331:Adrenergic Neurons / Q000378:metabolism*; D000818:Animals; D000075402:Channelrhodopsins; D004558:Electric Stimulation; D004569:Electroencephalography; D004576:Electromyography; D008027:Light; D008125:Locus Coeruleus / Q000378:metabolism* / Q000528:radiation effects; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D009437:Neuralgia / Q000150:complications / Q000378:metabolism* / Q000503:physiopathology; D017397:Prefrontal Cortex / Q000378:metabolism / Q000528:radiation effects; D012584:Sciatic Nerve / Q000293:injuries; D012893:Sleep Wake Disorders / Q000209:etiology / Q000378:metabolism* / Q000503:physiopathology
chemical_list: D000075402:Channelrhodopsins
keywords: Locus coeruleus; Neuropathic pain; Noradrenergic neurons; Optogenetics; Sleep disturbance