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Thalamocortical circuits drive remifentanil-induced postoperative hyperalgesia
Yan Jin, … , Zhi Zhang, Wenjuan Tao
Yan Jin, … , Zhi Zhang, Wenjuan Tao
Published December 15, 2022
Citation Information: J Clin Invest. 2022;132(24):e158742. https://doi.org/10.1172/JCI158742.
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Research Article Neuroscience Article has an altmetric score of 1

Thalamocortical circuits drive remifentanil-induced postoperative hyperalgesia

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Abstract

Remifentanil-induced hyperalgesia (RIH) is a severe but common postoperative clinical problem with elusive underlying neural mechanisms. Here, we discovered that glutamatergic neurons in the thalamic ventral posterolateral nucleus (VPLGlu) exhibited significantly elevated burst firing accompanied by upregulation of Cav3.1 T-type calcium channel expression and function in RIH model mice. In addition, we identified a glutamatergic neuronal thalamocortical circuit in the VPL projecting to hindlimb primary somatosensory cortex glutamatergic neurons (S1HLGlu) that mediated RIH. In vivo calcium imaging and multi-tetrode recordings revealed heightened S1HLGlu neuronal activity during RIH. Moreover, preoperative suppression of Cav3.1-dependent burst firing in VPLGlu neurons or chemogenetic inhibition of VPLGlu neuronal terminals in the S1HL abolished the increased S1HLGlu neuronal excitability while alleviating RIH. Our findings suggest that remifentanil induces postoperative hyperalgesia by upregulating T-type calcium channel-dependent burst firing in VPLGlu neurons to activate S1HLGlu neurons, thus revealing an ion channel–mediated neural circuit basis for RIH that can guide analgesic development.

Authors

Yan Jin, Yu Mao, Danyang Chen, Yingju Tai, Rui Hu, Chen-Ling Yang, Jing Zhou, Lijian Chen, Xuesheng Liu, Erwei Gu, Chunhui Jia, Zhi Zhang, Wenjuan Tao

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Figure 7

The VPLGlu

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The VPLGlu

→ S1HLGlu circuit controls allodynia in RIH mice. (A) Schema...
→ S1HLGlu circuit controls allodynia in RIH mice. (A) Schematic of the experimental procedure. (B) c-Fos expression in ipsilateral S1HL. Scale bars: 200 μm. (C) Colocalization of c-Fos+ neurons with tdTomato+. Scale bars: 20 μm. (D) The percentage of c-Fos+ and glutamate expression (left, t(14) = 0.4611, P = 0.6518; right, t(14) = 17.61, P < 0.0001) in the ipsilateral S1HL (n = 8 slices from 5 mice per group). (E–G) Representative traces (E) and quantitative data of the firing rate (F, F(1,348.99) = 67.193, P < 0.0001) and rheobase (G, t(33) = 4.207, P = 0.0002) of action potentials from ipsilateral S1HLGlu neurons (n = 20 neurons from 8 ACSF mice; n = 15 neurons from 7 Mibe mice). (H) Virus injection and optrode implantation in RIH mice. (I and J) Example traces (I) and quantitative data (J) for spike firing (n = 25–49 neurons from 8 mice per group; F(1,270.918) = 18.013, P = 0.0002). (K) Schematic of microinjection. (L) Viral expression within the VPL. Scale bars: 200 μm (left) and 20 μm (right). (M) The percentage of glutamate+ neurons expressing GFP signals (n = 8 slices from 5 mice). (N) GFP+ fibers in the S1HL. Scale bars: 200 μm. (O) Effects of CNO on VPLGlu neurons (n = 5 neurons from 5 mice per group; F(1,188) = 118.596, P < 0.0001). (P–R) Representative traces (P) and quantitative data of the firing rate (Q, F(1,460.808) = 39.677, P < 0.0001) and rheobase (R, t(13) = 4.954, P = 0.0003) of action potentials from ipsilateral S1HLGlu neurons (n = 23 neurons from 7 GFP mice or 8 GFP-hM4Di mice).(S) Mechanical pain thresholds in RIH mice injected with CNO in the S1HL (n = 9 mice per group; F(1,16) = 64.69, P < 0.0001). (T and U) Heatmaps (T) and summary data (U, GFP, n = 10 mice; hM4Di-GFP, n = 9 mice; t(17) = 1.242, P = 0.231) for RT-PEAP tests of RIH mice. Data are presented as mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001. Unpaired 2-tailed Student’s t test in D and U, linear mixed models with post hoc Bonferroni’s test in F, J, O and Q, nested2-tailed t test in G and R; 2-way repeated measures ANOVA with post hoc Bonferroni’s test in S.

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