title: Optoactivation of locus ceruleus neurons evokes bidirectional changes in thermal nociception in rats.
abstract: Pontospinal noradrenergic neurons are thought to form part of a descending endogenous analgesic system that exerts inhibitory influences on spinal nociception. Using optogenetic targeting, we tested the hypothesis that excitation of the locus ceruleus (LC) is antinociceptive. We transduced rat LC neurons by direct injection of a lentiviral vector expressing channelrhodopsin2 under the control of the PRS promoter. Subsequent optoactivation of the LC evoked repeatable, robust, antinociceptive (+4.7°C ± 1.0, p < 0.0001) or pronociceptive (-4.4°C ± 0.7, p < 0.0001) changes in hindpaw thermal withdrawal thresholds. Post hoc anatomical characterization of the distribution of transduced somata referenced against the position of the optical fiber and subsequent further functional analysis showed that antinociceptive actions were evoked from a distinct, ventral subpopulation of LC neurons. Therefore, the LC is capable of exerting potent, discrete, bidirectional influences on thermal nociception that are produced by specific subpopulations of noradrenergic neurons. This reflects an underlying functional heterogeneity of the influence of the LC on the processing of nociceptive information.
authors.affiliation: School of Physiology and Pharmacology, University of Bristol, Bristol BS8 1TD, United Kingdom, Department of Anesthesia, University Hospitals Bristol, Bristol BS2 8HW, United Kingdom, Department of Information Physiology, National Institute for Physiological Sciences, Myodaiji, Okazaki 444-8787, Japan, Wellcome Trust Sanger Institute, Cambridge CB10 1SA, United Kingdom, and Sorbonne Universités, Université Pierre et Marie Curie Paris 6, Unité Mixte de Recherche-Scientifique 8246, Neuroscience Paris Seine, Navigation Memory and Aging team, F-75005 Paris, France.
authors.forename: Louise
authors.initials: L
authors.lastname: Hickey
authors.forename: Yong
authors.initials: Y
authors.lastname: Li
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Fyson
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Watson
authors.forename: Ray
authors.initials: R
authors.lastname: Perrins
authors.forename: James
authors.initials: J
authors.lastname: Hewinson
authors.forename: Anja G
authors.initials: AG
authors.lastname: Teschemacher
authors.forename: Hidemasa
authors.initials: H
authors.lastname: Furue
authors.forename: Bridget M
authors.initials: BM
authors.lastname: Lumb
authors.forename: Anthony E
authors.initials: AE
authors.lastname: Pickering
mesh_terms: D000818:Animals; D006358:Hot Temperature; D008125:Locus Coeruleus / Q000503:physiopathology*; D008297:Male; D009474:Neurons / Q000502:physiology*; D059225:Nociception / Q000502:physiology*; D062308:Optogenetics; D010146:Pain / Q000503:physiopathology*; D010147:Pain Measurement; D051381:Rats; D017208:Rats, Wistar
keywords: ChannelRhodopsin2; endogenous analgesia; lentiviral vector; locus ceruleus; noradrenergic; pain