title: Inhibition Mediated by Glycinergic and GABAergic Receptors on Excitatory Neurons in Mouse Superficial Dorsal Horn Is Location-Specific but Modified by Inflammation.
abstract: The superficial dorsal horn is the synaptic termination site for many peripheral sensory fibers of the somatosensory system. A wide range of sensory modalities are represented by these fibers, including pain, itch, and temperature. Because the involvement of local inhibition in the dorsal horn, specifically that mediated by the inhibitory amino acids GABA and glycine, is so important in signal processing, we investigated regional inhibitory control of excitatory interneurons under control conditions and peripheral inflammation-induced mechanical allodynia. We found that excitatory interneurons and projection neurons in lamina I and IIo are dominantly inhibited by GABA while those in lamina IIi and III are dominantly inhibited by glycine. This was true of identified neuronal subpopulations: neurokinin 1 receptor-expressing (NK1R+) neurons in lamina I were GABA-dominant while protein kinase C gamma-expressing (PKCγ+) neurons at the lamina IIi-III border were glycine-dominant. We found this pattern of synaptic inhibition to be consistent with the distribution of GABAergic and glycinergic neurons identified by immunohistochemistry. Following complete Freund's adjuvant injection into mouse hindpaw, the frequency of spontaneous excitatory synaptic activity increased and inhibitory synaptic activity decreased. Surprisingly, these changes were accompanied by an increase in GABA dominance in lamina IIi. Because this shift in inhibitory dominance was not accompanied by a change in the number of inhibitory synapses or the overall postsynaptic expression of glycine receptor α1 subunits, we propose that the dominance shift is due to glycine receptor modulation and the depressed function of glycine receptors is partially compensated by GABAergic inhibition.SIGNIFICANCE STATEMENTPain associated with inflammation is a sensation we would all like to minimize. Persistent inflammation leads to cellular and molecular changes in the spinal cord dorsal horn, including diminished inhibition, which may be responsible for enhance excitability. Investigating inhibition in the dorsal horn following peripheral inflammation is essential for development of improved ways to control the associated pain. In this study, we have elucidated regional differences in inhibition of excitatory interneurons in mouse dorsal horn. We have also discovered that the dominating inhibitory neurotransmission within specific regions of dorsal horn switches following peripheral inflammation and the accompanying hypersensitivity to thermal and mechanical stimuli. Our novel findings contribute to a more complete understanding of inflammatory pain.
authors.affiliation: Department of Anesthesiology, Gunma University, Maebashi, Gunma, Japan 371-8511, takazawt@gunma-u.ac.jp.
authors.forename: Tomonori
authors.identifier: 0000-0002-0119-3532
authors.initials: T
authors.lastname: Takazawa
authors.affiliation: Department of Physiology and Cellular Biophysics.
authors.forename: Papiya
authors.initials: P
authors.lastname: Choudhury
authors.affiliation: Department of Dermatology, and.
authors.forename: Chi-Kun
authors.identifier: 0000-0003-0188-7638
authors.initials: CK
authors.lastname: Tong
authors.affiliation: Neuroscience Biology, Bristol-Myers Squibb, Wallingford, Connecticut 06492.
authors.forename: Charles M
authors.initials: CM
authors.lastname: Conway
authors.affiliation: Department of Anesthesiology, Perioperative and Pain Medicine.|Department of Neurosurgery.|Department of Molecular and Cellular Physiology, and.|Stanford Neurosciences Institute, Stanford University School of Medicine, Palo Alto, California 94304.
authors.forename: Grégory
authors.initials: G
authors.lastname: Scherrer
authors.affiliation: Department of Anesthesiology, Perioperative and Pain Medicine.
authors.forename: Pamela D
authors.initials: PD
authors.lastname: Flood
authors.affiliation: Department of Physiology and Cellular Biophysics.
authors.forename: Jun
authors.identifier: 0000-0003-3212-6129
authors.initials: J
authors.lastname: Mukai
authors.affiliation: Department of Physiology and Cellular Biophysics.|Department of Neuroscience, Columbia University, New York, New York 10032.
authors.forename: Amy B
authors.initials: AB
authors.lastname: MacDermott
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D004195:Disease Models, Animal; D005620:Freund's Adjuvant / Q000633:toxicity; D005998:Glycine / Q000494:pharmacology; D006930:Hyperalgesia / Q000503:physiopathology; D066298:In Vitro Techniques; D007249:Inflammation / Q000139:chemically induced / Q000473:pathology*; D007395:Interneurons / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology*; D010147:Pain Measurement / Q000187:drug effects; D020671:Posterior Horn Cells / Q000187:drug effects / Q000502:physiology*; D011493:Protein Kinase C / Q000378:metabolism; D018079:Receptors, GABA / Q000378:metabolism*; D018009:Receptors, Glycine / Q000378:metabolism*; D018040:Receptors, Neurokinin-1 / Q000378:metabolism; D013116:Spinal Cord / Q000166:cytology*; D055366:Synaptic Potentials / Q000187:drug effects; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
chemical_list: D018079:Receptors, GABA; D018009:Receptors, Glycine; D018040:Receptors, Neurokinin-1; D005680:gamma-Aminobutyric Acid; D005620:Freund's Adjuvant; C087857:protein kinase C gamma; D011493:Protein Kinase C; D005998:Glycine
keywords: GABA; dorsal horn; glycine; inflammatory pain; synaptic inhibition