title: Remote optogenetic activation and sensitization of pain pathways in freely moving mice.
abstract: We report a novel model in which remote activation of peripheral nociceptive pathways in transgenic mice is achieved optogenetically, without any external noxious stimulus or injury. Taking advantage of a binary genetic approach, we selectively targeted Nav1.8(+) sensory neurons for conditional expression of channelrhodopsin-2 (ChR2) channels. Acute blue light illumination of the skin produced robust nocifensive behaviors, evoked by the remote stimulation of both peptidergic and nonpeptidergic nociceptive fibers as indicated by c-Fos labeling in laminae I and II of the dorsal horn of the spinal cord. A non-nociceptive component also contributes to the observed behaviors, as shown by c-Fos expression in lamina III of the dorsal horn and the expression of ChR2-EYFP in a subpopulation of large-diameter Nav1.8(+) dorsal root ganglion neurons. Selective activation of Nav1.8(+) afferents in vivo induced central sensitization and conditioned place aversion, thus providing a novel paradigm to investigate plasticity in the pain circuitry. Long-term potentiation was similarly evoked by light activation of the same afferents in isolated spinal cord preparations. These findings demonstrate, for the first time, the optical control of nociception and central sensitization in behaving mammals and enables selective activation of the same class of afferents in both in vivo and ex vivo preparations. Our results provide a proof-of-concept demonstration that optical dissection of the contribution of specific classes of afferents to central sensitization is possible. The high spatiotemporal precision offered by this non-invasive model will facilitate drug development and target validation for pain therapeutics.
authors.affiliation: Montreal Neurological Institute, Department of Neurology and Neurosurgery, The Alan Edwards Centre for Research on Pain, and Departments of Psychology and Pharmacology and Therapeutics, McGill University, Montreal, Canada, H3A 2B4, Quebec Mental Health Institute, Department of Psychiatry and Neuroscience, Laval University, Quebec City, Canada, G1J 2G3, and Wolfson Institute for Biomedical Research, University College London, London, United Kingdom, WC1E 6BT.
authors.forename: Ihab
authors.initials: I
authors.lastname: Daou
authors.forename: Alexander H
authors.initials: AH
authors.lastname: Tuttle
authors.forename: Geraldine
authors.initials: G
authors.lastname: Longo
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Wieskopf
authors.forename: Robert P
authors.initials: RP
authors.lastname: Bonin
authors.forename: Ariel R
authors.initials: AR
authors.lastname: Ase
authors.forename: John N
authors.initials: JN
authors.lastname: Wood
authors.forename: Yves
authors.initials: Y
authors.lastname: De Koninck
authors.forename: Alfredo
authors.initials: A
authors.lastname: Ribeiro-da-Silva
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Mogil
authors.forename: Philippe
authors.initials: P
authors.lastname: Séguéla
mesh_terms: D000344:Afferent Pathways / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D000075402:Channelrhodopsins; D005260:Female; D005727:Ganglia, Spinal / Q000166:cytology; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006930:Hyperalgesia / Q000235:genetics / Q000503:physiopathology; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009020:Morphine / Q000494:pharmacology / Q000627:therapeutic use; D062559:NAV1.8 Voltage-Gated Sodium Channel / Q000235:genetics; D062308:Optogenetics; D010146:Pain / Q000188:drug therapy / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology; D017288:Pain Threshold / Q000187:drug effects / Q000502:physiology*; D058477:Receptors, Purinergic P2X3 / Q000378:metabolism; D011984:Sensory Receptor Cells / Q000187:drug effects / Q000502:physiology; D014633:Valine / Q000031:analogs & derivatives / Q000494:pharmacology; D014851:Wakefulness / Q000235:genetics / Q000502:physiology*; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D000075402:Channelrhodopsins; D062559:NAV1.8 Voltage-Gated Sodium Channel; D058477:Receptors, Purinergic P2X3; C568318:Scn10a protein, mouse; C485184:enhanced green fluorescent protein; D016875:tau Proteins; D049452:Green Fluorescent Proteins; C056639:2-amino-5-phosphopentanoic acid; D009020:Morphine; D014633:Valine