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.
journal_name
Painjournal_title
Painauthors
Kim JV,Megat S,Moy JK,Asiedu MN,Mejia GL,Vagner J,Price TJdoi
10.1097/j.pain.0000000000000513subject
Has Abstractpub_date
2016-06-01 00:00:00pages
1314-1324issue
6eissn
0304-3959issn
1872-6623pii
00006396-201606000-00018journal_volume
157pub_type
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