title: Acute spinal cord injury (SCI) transforms how GABA affects nociceptive sensitization.
abstract: Noxious input can sensitize pain (nociceptive) circuits within the spinal cord, inducing a lasting increase in spinal cord neural excitability (central sensitization) that is thought to contribute to chronic pain. The development of spinally-mediated central sensitization is regulated by descending fibers and GABAergic interneurons. The current study provides evidence that spinal cord injury (SCI) transforms how GABA affects nociceptive transmission within the spinal cord, recapitulating an earlier developmental state wherein GABA has an excitatory effect. In spinally transected rats, noxious electrical stimulation and inflammation induce enhanced mechanical reactivity (EMR), a behavioral index of nociceptive sensitization. Pretreatment with the GABAAreceptor antagonist bicuculline blocked these effects. Peripheral application of an irritant (capsaicin) also induced EMR. Both the induction and maintenance of this effect were blocked by bicuculline. Cellular indices of central sensitization [c-fos expression and ERK phosphorylation (pERK)] were also attenuated. In intact (sham operated) rats, bicuculline had the opposite effect. Pretreatment with a GABA agonist (muscimol) attenuated nociceptive sensitization in intact, but not spinally injured, rats. The effect of SCI on GABA function was linked to a reduction in the Cl-transporter, KCC2, leading to a reduction in intracellular Cl-that would attenuate GABA-mediated inhibition. Pharmacologically blocking the KCC2 channel (with i.t. DIOA) in intact rats mimicked the effect of SCI. Conversely, a pharmacological treatment (bumetanide) that should increase intracellular Cl-levels blocked the effect of SCI. The results suggest that GABAergic neurons drive, rather than inhibit, the development of nociceptive sensitization after spinal injury.
authors.affiliation: Behavioral and Cellular Neuroscience, Department of Psychology, Texas A&M University, College Station, TX 77843, USA. Electronic address: redkie@gmail.com.
authors.forename: Yung-Jen
authors.initials: YJ
authors.lastname: Huang
authors.affiliation: Center for Pain Research, Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
authors.forename: Kuan H
authors.initials: KH
authors.lastname: Lee
authors.affiliation: Behavioral and Cellular Neuroscience, Department of Psychology, Texas A&M University, College Station, TX 77843, USA.
authors.forename: Lauren
authors.initials: L
authors.lastname: Murphy
authors.affiliation: Department of Physiology, Emory University School of Medicine, Atlanta, GA 30307, USA.
authors.forename: Sandra M
authors.initials: SM
authors.lastname: Garraway
authors.affiliation: Behavioral and Cellular Neuroscience, Department of Psychology, Texas A&M University, College Station, TX 77843, USA.
authors.forename: James W
authors.initials: JW
authors.lastname: Grau
mesh_terms: D000085:Acetates / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D001640:Bicuculline / Q000494:pharmacology; D002034:Bumetanide / Q000494:pharmacology; D002211:Capsaicin / Q000009:adverse effects; D004195:Disease Models, Animal; D018682:GABA Agents / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D006930:Hyperalgesia / Q000188:drug therapy* / Q000503:physiopathology*; D007192:Indenes / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D009118:Muscimol / Q000494:pharmacology; D059225:Nociception / Q000187:drug effects / Q000502:physiology*; D010147:Pain Measurement; D010812:Physical Stimulation / Q000009:adverse effects; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D049994:Sodium Potassium Chloride Symporter Inhibitors / Q000494:pharmacology; D013119:Spinal Cord Injuries / Q000503:physiopathology*; D027981:Symporters / Q000378:metabolism; D013997:Time Factors; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*; D000096922:K Cl- Cotransporters
chemical_list: D000085:Acetates; D001640:Bicuculline; D002034:Bumetanide; D002211:Capsaicin; D018682:GABA Agents; D007192:Indenes; D008070:Lipopolysaccharides; D009118:Muscimol; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D049994:Sodium Potassium Chloride Symporter Inhibitors; D027981:Symporters; D005680:gamma-Aminobutyric Acid; D000096922:K Cl- Cotransporters; C095651:((2-n-butyl-6,7-dichloro-2-cyclopentyl-2,3-dihydro-1-oxo-1H-inden-5-yl)oxy)acetic acid
keywords: Allodynia; Central sensitization; GABA; GABA(A) receptor; KCC2; Pain; SCI