title: Optogenetic and chemogenetic strategies for sustained inhibition of pain.
abstract: Spatially targeted, genetically-specific strategies for sustained inhibition of nociceptors may help transform pain science and clinical management. Previous optogenetic strategies to inhibit pain have required constant illumination, and chemogenetic approaches in the periphery have not been shown to inhibit pain. Here, we show that the step-function inhibitory channelrhodopsin, SwiChR, can be used to persistently inhibit pain for long periods of time through infrequent transdermally delivered light pulses, reducing required light exposure by >98% and resolving a long-standing limitation in optogenetic inhibition. We demonstrate that the viral expression of the hM4D receptor in small-diameter primary afferent nociceptor enables chemogenetic inhibition of mechanical and thermal nociception thresholds. Finally, we develop optoPAIN, an optogenetic platform to non-invasively assess changes in pain sensitivity, and use this technique to examine pharmacological and chemogenetic inhibition of pain.
authors.affiliation: Bioengineering, Stanford University, Stanford, CA 94305, USA.
authors.forename: Shrivats M
authors.initials: SM
authors.lastname: Iyer
authors.affiliation: Bioengineering, Stanford University, Stanford, CA 94305, USA.
authors.forename: Sam
authors.initials: S
authors.lastname: Vesuna
authors.affiliation: Bioengineering, Stanford University, Stanford, CA 94305, USA.
authors.forename: Charu
authors.initials: C
authors.lastname: Ramakrishnan
authors.affiliation: Bioengineering, Stanford University, Stanford, CA 94305, USA.
authors.forename: Karen
authors.initials: K
authors.lastname: Huynh
authors.affiliation: Bioengineering, Stanford University, Stanford, CA 94305, USA.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Young
authors.affiliation: Bioengineering, Stanford University, Stanford, CA 94305, USA.
authors.forename: Andre
authors.initials: A
authors.lastname: Berndt
authors.affiliation: Bioengineering, Stanford University, Stanford, CA 94305, USA.
authors.forename: Soo Yeun
authors.initials: SY
authors.lastname: Lee
authors.affiliation: Bioengineering, Stanford University, Stanford, CA 94305, USA.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Gorini
authors.affiliation: Bioengineering, Stanford University, Stanford, CA 94305, USA.|Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA 94305, USA.|Howard Hughes Medical Institute, Stanford University, Stanford, CA 94305, USA.
authors.forename: Karl
authors.initials: K
authors.lastname: Deisseroth
authors.affiliation: Bioengineering, Stanford University, Stanford, CA 94305, USA.|Mechanical Engineering, Stanford University, Stanford, CA 94305, USA.
authors.forename: Scott L
authors.initials: SL
authors.lastname: Delp
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D000075402:Channelrhodopsins / Q000235:genetics*; D003024:Clozapine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D003131:Combined Modality Therapy; D004195:Disease Models, Animal; D028022:Low-Level Light Therapy; D051379:Mice; D059225:Nociception; D062308:Optogenetics / Q000379:methods*; D010146:Pain / Q000188:drug therapy* / Q000532:radiotherapy*
chemical_list: D000075402:Channelrhodopsins; D003024:Clozapine; C079149:clozapine N-oxide