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. 2017 May 11:10:1125-1134.
doi: 10.2147/JPR.S131104. eCollection 2017.

Reduced GABAergic neuronal activity in zona incerta causes neuropathic pain in a rat sciatic nerve chronic constriction injury model

Hyeong Cheol Moon  1 , Young Seok Park  1   2
Affiliations

Reduced GABAergic neuronal activity in zona incerta causes neuropathic pain in a rat sciatic nerve chronic constriction injury model

Hyeong Cheol Moon et al. J Pain Res. .

Abstract

Purpose: The zona incerta (ZI) is below the ventral tier of the thalamus and has a strong influence selectively in higher-order thalamic relays. Although neuropathic pain has been suggested to result from reduced gamma-aminobutyric acid (GABA) and GABAergic signaling in the ZI, the mechanisms remain unclear. Here, the role of GABA and GABAergic signaling was investigated in the ZI in neuropathic pain using sciatic nerve chronic constriction injury (CCI) rats.

Materials and methods: Single-unit neuronal activity was recorded, and microdialysis was performed in the ZI of CCI rats and sham-treated rats in vivo. This study also compared ZI neuronal activity after treatment with saline, the GABAA receptor agonist (muscimol), or the GABAA receptor antagonist (bicuculline).

Results and conclusion: CCI rats exhibited hypersensitivity to pain as evidenced by decreased hind paw withdrawal threshold and latency. CCI rats also showed reduced GABA level and decreased neuronal activity in the ZI compared with sham-treated rats. Treatment with GABAA receptor agonist, but not GABAA receptor antagonist, ameliorated pain hypersensitivity and increased the firing rate (spikes/s) of ZI neurons in CCI rats.

Keywords: GABA; chronic pain; neural cell recording; neuropathic pain; sciatic nerve injury; zona incerta.

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Conflict of interest statement

Disclosure The authors report no conflicts of interest in this work.

Figures

Figure 1
Figure 1
Flowchart illustrating the study procedure. Abbreviations: CCI, chronic constriction injury; GABA, gamma-aminobutyric acid.
Figure 2
Figure 2
Change in PWTs on days 1, 4, 7, and 10 after CCI and sham treatment. Notes: PWTs were assessed by plantar test. (A) Mechanical withdrawal thresholds in plantar surface of hind paw decrease over time, and hyperalgesia develops ipsilaterally after sciatic nerve injury. (B) Mechanical withdrawal latency also decreased over time. All data points represent the mean ± SD. Two-way ANOVA was used to assess statistical differences; *P<0.05. CCI rats responded with significantly shorter latencies to mechanical stimulation of the plantar area of the ipsilateral hind paw than did sham-treated rats. Sham-treated (n=10); CCI (n=20). Abbreviations: ANOVA, analysis of variance; CCI, chronic constriction injury; PWTs, paw withdrawal thresholds; SD, standard deviation.
Figure 3
Figure 3
Analysis of neurotransmitter concentrations in the ZI using microdialysis in vivo. Notes: CCI rats (n=10) showed lower GABA concentrations than sham-treated rats (n=10). Two-tailed t-test was used to compare GABA levels. *P<0.05. Abbreviations: CCI, chronic constriction injury; GABA, gamma-aminobutyric acid; ZI, zona incerta.
Figure 4
Figure 4
Changes in mechanical hyperalgesia induced by agonist, antagonist, or saline injection in sham-treated and CCI rats. Notes: (A) Hind PWTs change from GABAergic concentrations in the ipsilateral developed hyperalgesia. (B) Hind PWL increased after injection of a high concentration of GABA agonist. One-way ANOVA was used to compare the effect of injection in each group. Sham-treated (n=10); CCI (n=10). *P<0.05 Abbreviations: ANOVA, analysis of variance; CCI, chronic constriction injury; GABA, gamma-aminobutyric acid; PWL, paw withdrawal latency; PWTs, paw withdrawal thresholds.
Figure 5
Figure 5
Spontaneous neuronal activity in the ZI in sham-treated and CCI rats. Notes: (A) ZI is shown in the schematic diagram of a coronal section. (B) Overall thalamic neuronal activity in sham-treated and CCI rats. (C) Injection of high concentrations of GABAA agonist and antagonist into the ZI changed the firing rate (spikes/s) for 30 min in sham-treated animals. (D) Firing rate increased after injection of GABA agonist in CCI rats. PSTH shows firing rate as time progresses after injection of GABAA agonist (E) and GABAA antagonist (F) in CCI rats. In total, 12 rats were used in the current analysis. One-way ANOVA was used to compare each data point with saline-baseline. *P<0.05. Sham-treated (n=6); CCI (n=6). Abbreviations: ANOVA, analysis of variance; CCI, chronic constriction injury; GABA, gamma-aminobutyric acid; PSTH, peristimulus time histogram; ZI, zona incerta.
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