Synaptic Inhibition and Disinhibition in the Spinal Dorsal Horn

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.

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“…23,37,41). A potential manifestation of this change in GABAergic function is altered GABA A R-mediated pharmacology after peripheral injury.…”

Section: Discussionmentioning

confidence: 99%

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

Kim

Megat

Moy

et al. 2016

Pain

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“…This disruption in the transmembrane chloride gradient depolarizes the equilibrium potential of currents generated by GABA A receptors (E GABAA ), reducing the inhibitory effects of GABA responses, and, in a small number of spinal neurons, renders the GABA responses paradoxically excitatory. 9, 36 Subsequent studies provided further support for this chloride dysregulation hypothesis, and implicated also changes in the chloride importer, NKCC1, as well as in microglia-derived growth factors that regulate chloride transporters. 18, 29, 36, 37 …”

Section: Introductionmentioning

confidence: 95%

“…36, 43 In their seminal study, Coull et al 9 showed that this reduced spinal inhibition can result from reduced expression of the potassium-chloride exporter, KCC2, and a consequent increase in chloride in nociceptive dorsal horn neurons. This disruption in the transmembrane chloride gradient depolarizes the equilibrium potential of currents generated by GABA A receptors (E GABAA ), reducing the inhibitory effects of GABA responses, and, in a small number of spinal neurons, renders the GABA responses paradoxically excitatory.…”

Section: Introductionmentioning

confidence: 99%

Neuropathic pain after chronic nerve constriction may not correlate with chloride dysregulation in mouse trigeminal nucleus caudalis neurons

Castro

Liu

Raver

et al. 2017

Pain

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Changes in chloride reversal potential in rat spinal cord neurons have previously been associated with persistent pain in nerve injury and inflammation models. These changes correlate with a decrease in the expression of the potassium chloride transporter, KCC2, and with increases in neuronal excitability. Here, we test the hypothesis that similar changes occur in mice with neuropathic pain induced by chronic constriction injury of the trigeminal infraorbital nerve (CCI-ION). This model allows us to distinguish an acute pain phase (3-5 days after injury) from a persistent pain phase (12-14 days after CCI-ION). Chronic constriction injury of the trigeminal infraorbital nerve induced significant decreases in mechanical pain thresholds in both the acute and persistent phases. To estimate GABAA reversal potentials in neurons from trigeminal nucleus caudalis, we obtained perforated patch recordings in vitro. GABAA reversal potential decreased by 8% during the acute phase in unidentified neurons, but not in GABAergic interneurons. However, at 12 to 14 days after CCI-ION, GABAA reversal potential recovered to normal values. Quantitative real-time polymerase chain reaction analysis revealed no significant changes, at either 3 to 5 days or 12 to 14 days after CCI-ION, in either KCC2 or NKCC1. These findings suggest that CCI-ION in mice results in transient and modest changes in chloride reversal potentials, and that these changes may not persist during the late phase. This suggests that, in the mouse model of CCI-ION, chloride dysregulation may not have a prominent role in the central mechanisms leading to the maintenance of chronic pain.

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“…Similar synergism would be expected with modulators of glycinergic transmission or even with a neural stem cell-based approach. Likewise synergism would be expected between GABA A receptor PAMs and drugs directly targeting KCC2, whereas modulating KCC2 while blocking carbonic anhydrase would likely be redundant [18]. …”

Section: Implications For Therapeutic Interventionmentioning

confidence: 99%

Inhibitory regulation of the pain gate and how its failure causes pathological pain

Price

Prescott

2015

Pain

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Synaptic Inhibition and Disinhibition in the Spinal Dorsal Horn

Cited by 48 publications

References 143 publications

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

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

Neuropathic pain after chronic nerve constriction may not correlate with chloride dysregulation in mouse trigeminal nucleus caudalis neurons

Inhibitory regulation of the pain gate and how its failure causes pathological pain

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