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Neuroligin 2 regulates spinal GABAergic plasticity in hyperalgesic priming, a model of the transition from acute to chronic pain

Kim, Ji-Young V.; Megat, Salim; Moy, Jamie K.; Asiedu, Marina N.; Mejia, Galo L.; Vagner, Josef; Price, Theodore J.

doi: 10.1097/j.pain.0000000000000513
Research Paper
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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.

Hyperalgesic priming promotes an inversion of the pharmacological action of GABAA receptors and increases neuroligin 2 expression. Neuroligin 2 disruption reverses this experimental chronic pain state.

aDepartment of Pharmacology, University of Arizona, Tucson, AZ, USA

bSchool of Behavioral and Brain Sciences, University of Texas at Dallas, Richardson, TX, USA

cBio5 Institute, University of Arizona, Tucson, AZ, USA

Corresponding author. Address: School of Behavioral and Brain Sciences, University of Texas at Dallas, JO 4.212, 800 W Campbell Rd, Richardson, TX 75080, USA. Tel.: 972-883-4311. E-mail address: Theodore.price@utdallas.edu (T. J. Price).

Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.

Received November 03, 2015

Received in revised form January 21, 2016

Accepted February 02, 2016

© 2016 International Association for the Study of Pain
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