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The Effect of Optogenetic Inhibition of the Anterior Cingulate Cortex in Neuropathic Pain Following Sciatic Nerve Injury

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Abstract

Cortical disinhibition is the underlying pathological alteration contributing to neuropathic pain associated with peripheral nerve injury. Nerve injury resulting in disinhibition of the anterior cingulate cortex has been reported. However, the effect of optogenetic inhibition of the anterior cingulate cortex (ACC) on the sensory component of nerve injury–induced neuropathic pain has not been well studied. To investigate the feasibility of optogenetic ACC modulation, we injected an optogenetic virus or a null virus into the ACC of a nerve injury–induced neuropathic pain model. The unilateral ACC was modulated, and the optogenetic effect was measured by mechanical and thermal sensitivity tests. The assessment was performed in “pre—light off,” “stimulation—yellow light on,” and “post—light off” states. Optogenetic inhibition of the ACC in injury models revealed improved mechanical and thermal latencies with profound pain-relieving effects against nerve injury–induced neuropathic pain. The sensory thalamic discharge in electrophysiological in vivo recordings was also altered during laser stimulation. This finding indicates that hyperactivity of the ACC in nerve injury increases output to the spinothalamic tract through direct or indirect pathways. The direct photoinhibition of ACC neurons could play a vital role in restoring equilibrium and provide novel insight into techniques that can assuage peripheral nerve injury–induced neuropathic pain.

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Funding

This work was supported by the National Research Foundation of Korea (NRF 2016H1D5A1908909, NRF 2015H1D3A1066175, NRF 2014K1A3A1A21001372, and NRF 2019R1I1A1A0159554). This work was financially supported by the Research Year of Chungbuk National University in 2018.

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Authors and Affiliations

  1. Department of Neuroscience, College of Medicine, Chungbuk National University, Cheongju, South Korea

    K. C. Elina, Hyeong Cheol Moon, Jaisan Islam & Young Seok Park

  2. Department of Neurosurgery, Chungbuk National University Hospital, 776, 1 Sunhwanro, Seowon-gu, Cheongju-Si, Chungbuk, 28644, South Korea

    Hyeong Cheol Moon & Young Seok Park

  3. Department of Medical and Microbiology, College of Medicine, Cheongju, South Korea

    Hyong Kyu Kim

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  1. K. C. Elina
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  2. Hyeong Cheol Moon
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  5. Young Seok Park
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Contributions

Conception and design: YSP, ELINA, and HCM. Acquisition of data: ELINA and JAISAN. Analysis and interpretation: HCM and ELINA. Writing article: YSP, ELINA, and HCM. Critical review of article: YSP and HKK. Final approval for publication: YSP. Agreement to be accountable for all aspects of the work: ELINA, HCM, and YSP.

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Correspondence to Young Seok Park.

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Animal experiments were performed according to the national guidelines and with approval from the Institutional Animal Care Committee of Chungbuk National University (CBNUR-1072-17).

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The authors declare that they have no conflict of interest.

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This work was conducted during the 2018–2019 research year at Chungbuk National University.

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Supplementary Figure 1.

Experimental timeline and design. (A) Study timeline in weeks. (B) Induction of neuropathic pain by sciatic nerve constriction. (C) Schematic diagram of optogenetic virus injection into the anterior cingulate cortex. (PNG 385 kb)

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Supplementary Figure 2.

Transfection efficiency and quantification. (A) Schematic coronal section of anterior cingulate cortex with EYFP transfection. (B) Comparison of transfection efficiency among CCI-NpHr and sham groups expressed on percentage. No significant differences were found {n=3 per group, Ordinary one-way analysis of variance (ANOVA)}. (C) Quantification of EYFP/DAPI positive cells between groups {(insignificant differences were found, n=3 per group, Ordinary one-way analysis of variance (ANOVA)}. (D) Quantification of c-Fos/DAPI-positive cells. CCI rats showed increased c-Fos expression in ACC compared to sham controls. **** P < 0.0001. n = 3 rats per group. Ordinary one-way analysis of variance (ANOVA). Values represent mean ± SD. (PNG 194 kb)

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Elina, K.C., Moon, H.C., Islam, J. et al. The Effect of Optogenetic Inhibition of the Anterior Cingulate Cortex in Neuropathic Pain Following Sciatic Nerve Injury. J Mol Neurosci 71, 638–650 (2021). https://doi.org/10.1007/s12031-020-01685-7

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