title: Identification of Early RET+ Deep Dorsal Spinal Cord Interneurons in Gating Pain.
abstract: The gate control theory (GCT) of pain proposes that pain- and touch-sensing neurons antagonize each other through spinal cord dorsal horn (DH) gating neurons. However, the exact neural circuits underlying the GCT remain largely elusive. Here, we identified a new population of deep layer DH (dDH) inhibitory interneurons that express the receptor tyrosine kinase Ret neonatally. These early RET+ dDH neurons receive excitatory as well as polysynaptic inhibitory inputs from touch- and/or pain-sensing afferents. In addition, they negatively regulate DH pain and touch pathways through both pre- and postsynaptic inhibition. Finally, specific ablation of early RET+ dDH neurons increases basal and chronic pain, whereas their acute activation reduces basal pain perception and relieves inflammatory and neuropathic pain. Taken together, our findings uncover a novel spinal circuit that mediates crosstalk between touch and pain pathways and suggest that some early RET+ dDH neurons could function as pain "gating" neurons.
authors.affiliation: Department of Neuroscience, Perelman School of Medicine, the University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Lian
authors.initials: L
authors.lastname: Cui
authors.affiliation: Department of Anesthesiology, New Jersey Medical School, Rutgers, the State University of New Jersey, Newark, NJ 07103, USA.
authors.forename: Xuerong
authors.initials: X
authors.lastname: Miao
authors.affiliation: Department of Anesthesiology, New Jersey Medical School, Rutgers, the State University of New Jersey, Newark, NJ 07103, USA.
authors.forename: Lingli
authors.initials: L
authors.lastname: Liang
authors.affiliation: Department of Neuroscience, Perelman School of Medicine, the University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Ishmail
authors.initials: I
authors.lastname: Abdus-Saboor
authors.affiliation: Department of Neuroscience, Perelman School of Medicine, the University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: William
authors.initials: W
authors.lastname: Olson
authors.affiliation: Department of Neuroscience, Perelman School of Medicine, the University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Fleming
authors.affiliation: Department of Neuroscience, Perelman School of Medicine, the University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Minghong
authors.initials: M
authors.lastname: Ma
authors.affiliation: Department of Anesthesiology, New Jersey Medical School, Rutgers, the State University of New Jersey, Newark, NJ 07103, USA. Electronic address: yuanxiang.tao@njms.rutgers.edu.
authors.forename: Yuan-Xiang
authors.initials: YX
authors.lastname: Tao
authors.affiliation: Department of Neuroscience, Perelman School of Medicine, the University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: luow@mail.med.upenn.edu.
authors.forename: Wenqin
authors.initials: W
authors.lastname: Luo
mesh_terms: D000818:Animals; D003024:Clozapine / Q000031:analogs & derivatives / Q000494:pharmacology; D005260:Female; D007395:Interneurons / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009433:Neural Inhibition / Q000502:physiology; D009474:Neurons / Q000502:physiology; D010146:Pain / Q000503:physiopathology*; D010147:Pain Measurement; D051096:Proto-Oncogene Proteins c-ret / Q000378:metabolism*; D013116:Spinal Cord / Q000378:metabolism / Q000502:physiology*; D066148:Spinal Cord Dorsal Horn / Q000378:metabolism; D014110:Touch / Q000502:physiology*
chemical_list: D051096:Proto-Oncogene Proteins c-ret; C494999:Ret protein, mouse; D003024:Clozapine; C079149:clozapine N-oxide