title: Neuroligin 2 regulates spinal GABAergic plasticity in hyperalgesic priming, a model of the transition from acute to chronic pain.
abstract: Plasticity in inhibitory receptors, neurotransmission, and networks is an important mechanism for nociceptive signal amplification in the spinal dorsal horn. We studied potential changes in GABAergic pharmacology and its underlying mechanisms in hyperalgesic priming, a model of the transition from acute to chronic pain. We find that while GABAA agonists and positive allosteric modulators reduce mechanical hypersensitivity to an acute insult, they fail to do so during the maintenance phase of hyperalgesic priming. In contrast, GABAA antagonism promotes antinociception and a reduction in facial grimacing after the transition to a chronic pain state. During the maintenance phase of hyperalgesic priming, we observed increased neuroligin (nlgn) 2 expression in the spinal dorsal horn. This protein increase was associated with an increase in nlgn2A splice variant mRNA, which promotes inhibitory synaptogenesis. Disruption of nlgn2 function with the peptide inhibitor, neurolide 2, produced mechanical hypersensitivity in naive mice but reversed hyperalgesic priming in mice previously exposed to brain-derived neurotrophic factor. Neurolide 2 treatment also reverses the change in polarity in GABAergic pharmacology observed in the maintenance of hyperalgesic priming. We propose that increased nlgn2 expression is associated with hyperalgesic priming where it promotes dysregulation of inhibitory networks. Our observations reveal new mechanisms involved in the spinal maintenance of a pain plasticity and further suggest that disinhibitory mechanisms are central features of neuroplasticity in the spinal dorsal horn.
authors: Department of Pharmacology, University of Arizona, Tucson, AZ, USA School of Behavioral and Brain Sciences, University of Texas at Dallas, Richardson, TX, USA Bio5 Institute, University of Arizona, Tucson, AZ, USA.
authors: Ji-Young V
authors: JV
authors: Kim
authors: Salim
authors: S
authors: Megat
authors: Jamie K
authors: JK
authors: Moy
authors: Marina N
authors: MN
authors: Asiedu
authors: Galo L
authors: GL
authors: Mejia
authors: Josef
authors: J
authors: Vagner
authors: Theodore J
authors: TJ
authors: Price
mesh_terms: D059787:Acute Pain / Q000378:metabolism* / Q000503:physiopathology; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology; D015816:Cell Adhesion Molecules, Neuronal / Q000378:metabolism*; D059350:Chronic Pain / Q000378:metabolism* / Q000503:physiopathology; D004195:Disease Models, Animal; D059330:GABAergic Neurons / Q000187:drug effects / Q000378:metabolism*; D006930:Hyperalgesia / Q000378:metabolism* / Q000503:physiopathology; D051379:Mice; D008813:Mice, Inbred ICR; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology*; D017288:Pain Threshold / Q000502:physiology; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism*
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D015816:Cell Adhesion Molecules, Neuronal; D009419:Nerve Tissue Proteins; C098003:neuroligin 2