title: Optogenetic Silencing of Nav1.8-Positive Afferents Alleviates Inflammatory and Neuropathic Pain.
abstract: We report a novel transgenic mouse model in which the terminals of peripheral nociceptors can be silenced optogenetically with high spatiotemporal precision, leading to the alleviation of inflammatory and neuropathic pain. Inhibitory archaerhodopsin-3 (Arch) proton pumps were delivered to Nav1.8(+) primary afferents using the Nav1.8-Cre driver line. Arch expression covered both peptidergic and nonpeptidergic nociceptors and yellow light stimulation reliably blocked electrically induced action potentials in DRG neurons. Acute transdermal illumination of the hindpaws of Nav1.8-Arch(+) mice significantly reduced mechanical allodynia under inflammatory conditions, while basal mechanical sensitivity was not affected by the optical stimulation. Arch-driven hyperpolarization of nociceptive terminals was sufficient to prevent channelrhodopsin-2 (ChR2)-mediated mechanical and thermal hypersensitivity in double-transgenic Nav1.8-ChR2(+)-Arch(+) mice. Furthermore, prolonged optical silencing of peripheral afferents in anesthetized Nav1.8-Arch(+) mice led to poststimulation analgesia with a significant decrease in mechanical and thermal hypersensitivity under inflammatory and neuropathic conditions. These findings highlight the role of peripheral neuronal inputs in the onset and maintenance of pain hypersensitivity, demonstrate the plasticity of pain pathways even after sensitization has occurred, and support the involvement of Nav1.8(+) afferents in both inflammatory and neuropathic pain. Together, we present a selective analgesic approach in which genetically identified subsets of peripheral sensory fibers can be remotely and optically inhibited with high temporal resolution, overcoming the compensatory limitations of genetic ablations.
authors.affiliation: Department of Neurology and Neurosurgery, Montreal Neurological Institute, Montreal, Quebec H3A 2B4, Canada; The Alan Edwards Centre for Research on Pain, Montreal, Quebec H3A 0G1, Canada.
authors.forename: Ihab
authors.initials: I
authors.lastname: Daou
authors.affiliation: Department of Neurology and Neurosurgery, Montreal Neurological Institute, Montreal, Quebec H3A 2B4, Canada; The Alan Edwards Centre for Research on Pain, Montreal, Quebec H3A 0G1, Canada; Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec H3G 1Y6, Canada.
authors.forename: Hélène
authors.initials: H
authors.lastname: Beaudry
authors.affiliation: Department of Neurology and Neurosurgery, Montreal Neurological Institute, Montreal, Quebec H3A 2B4, Canada; The Alan Edwards Centre for Research on Pain, Montreal, Quebec H3A 0G1, Canada.
authors.forename: Ariel R
authors.initials: AR
authors.lastname: Ase
authors.affiliation: The Alan Edwards Centre for Research on Pain, Montreal, Quebec H3A 0G1, Canada; Department of Psychology, McGill University, Montreal, Quebec H3A 1B1, Canada.
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Wieskopf
authors.affiliation: The Alan Edwards Centre for Research on Pain, Montreal, Quebec H3A 0G1, Canada; Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec H3G 1Y6, Canada.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Ribeiro-da-Silva
authors.affiliation: The Alan Edwards Centre for Research on Pain, Montreal, Quebec H3A 0G1, Canada; Department of Psychology, McGill University, Montreal, Quebec H3A 1B1, Canada.
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Mogil
authors.affiliation: Department of Neurology and Neurosurgery, Montreal Neurological Institute, Montreal, Quebec H3A 2B4, Canada; The Alan Edwards Centre for Research on Pain, Montreal, Quebec H3A 0G1, Canada.
authors.forename: Philippe
authors.initials: P
authors.lastname: Séguéla
mesh_terms: D000200:Action Potentials; D000698:Analgesia / Q000379:methods*; D000818:Animals; D019843:Archaeal Proteins / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D005727:Ganglia, Spinal / Q000503:physiopathology; D006614:Hindlimb / Q000503:physiopathology; D007249:Inflammation / Q000150:complications*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D062559:NAV1.8 Voltage-Gated Sodium Channel / Q000502:physiology*; D009434:Neural Pathways / Q000503:physiopathology; D009437:Neuralgia / Q000503:physiopathology* / Q000517:prevention & control*; D009474:Neurons / Q000502:physiology; D009619:Nociceptors / Q000378:metabolism / Q000502:physiology*; D062308:Optogenetics / Q000379:methods*; D010146:Pain / Q000503:physiopathology / Q000517:prevention & control; D017288:Pain Threshold
chemical_list: D019843:Archaeal Proteins; D062559:NAV1.8 Voltage-Gated Sodium Channel; C568318:Scn10a protein, mouse
keywords: allodynia; dorsal root ganglia; inflammation; neuropathy; optogenetics; spinal cord