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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References
Bennett GJ, Xie Y-K (1988) A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man. Pain 33:87–107
Blom SM, Pfister J-P, Santello M, Senn W, Nevian T (2014a) Nerve injury-induced neuropathic pain causes disinhibition of the anterior cingulate cortex. J Neurosci 34:5754–5764
Blom SM, Pfister JP, Santello M, Senn W, Nevian T (2014b) Nerve injury-induced neuropathic pain causes disinhibition of the anterior cingulate cortex. J Neurosci 34:5754–5764. https://doi.org/10.1523/JNEUROSCI.3667-13.2014
Cai YQ, Wang W, Hou YY, Pan ZZ (2014) Optogenetic activation of brainstem serotonergic neurons induces persistent pain sensitization. Mol Pain 10:70. https://doi.org/10.1186/1744-8069-10-70
Chen T et al (2014) Postsynaptic potentiation of corticospinal projecting neurons in the anterior cingulate cortex after nerve injury. Mol Pain 10:33
Chen T et al (2018) Top-down descending facilitation of spinal sensory excitatory transmission from the anterior cingulate cortex. Nat Commun 9:1–17
Chiou C-S, Chen C-C, Tsai T-C, Huang C-C, Chou D, Hsu K-S (2016) Alleviating bone cancer–induced mechanical hypersensitivity by inhibiting neuronal activity in the anterior cingulate cortex anesthesiology. J Am Soc Anesthesiol 125:779–792
Daou I, Tuttle AH, Longo G, Wieskopf JS, Bonin RP, Ase AR, Wood JN, de Koninck Y, Ribeiro-da-Silva A, Mogil JS, Seguela P (2013) Remote optogenetic activation and sensitization of pain pathways in freely moving mice. J Neurosci 33:18631–18640
De Vry J, Kuhl E, Franken-Kunkel P, Eckel G (2004) Pharmacological characterization of the chronic constriction injury model of neuropathic pain. Eur J Pharmacol 491:137–148
Decosterd I, Woolf CJ (2000) Spared nerve injury: an animal model of persistent peripheral neuropathic pain. Pain 87:149–158. https://doi.org/10.1016/S0304-3959(00)00276-1
Deuis JR, Vetter I (2016) The thermal probe test: a novel behavioral assay to quantify thermal paw withdrawal thresholds in mice. Temperature (Austin) 3:199–207. https://doi.org/10.1080/23328940.2016.1157668
Ding Z et al (2018) Resveratrol promotes nerve regeneration via activation of p300 acetyltransferase-mediated VEGF signaling in a rat model of sciatic nerve crush injury. Front Neurosci 12:341–341. https://doi.org/10.3389/fnins.2018.00341
Dodla MC, Alvarado-Velez M, Mukhatyar VJ, Bellamkonda RV (2019) Peripheral nerve regeneration. In: Principles of regenerative medicine. Elsevier, pp 1223-1236
Fuchs PN, Peng YB, Boyette-Davis JA, Uhelski ML (2014a) The anterior cingulate cortex and pain processing. Front Integr Neurosci 8:35
Fuchs PN, Peng YB, Boyette-Davis JA, Uhelski ML (2014b) The anterior cingulate cortex and pain processing. Front Integr Neurosci 8:35. https://doi.org/10.3389/fnint.2014.00035
Gage GJ, Kipke DR, Shain W (2012) Whole animal perfusion fixation for rodents. J Visual Exp:JoVE. https://doi.org/10.3791/3564
Gradinaru V, Thompson KR, Deisseroth K (2008) eNpHR: a Natronomonas halorhodopsin enhanced for optogenetic applications. Brain Cell Biol 36:129–139
Gu L, Uhelski ML, Anand S, Romero-Ortega M, Kim YT, Fuchs PN, Mohanty SK (2015) Pain inhibition by optogenetic activation of specific anterior cingulate cortical neurons. PLoS One 10:e0117746. https://doi.org/10.1371/journal.pone.0117746
Guru A, Post RJ, Ho Y-Y, Warden MR (2015) Making sense of optogenetics. Int J Neuropsychopharmacol 18:pyv079. https://doi.org/10.1093/ijnp/pyv079
Harte SE, Spuz CA, Borszcz GS (2011) Functional interaction between medial thalamus and rostral anterior cingulate cortex in the suppression of pain affect. Neuroscience 172:460–473
Hsieh J-C, Stone-Elander S, Ingvar M (1999) Anticipatory coping of pain expressed in the human anterior cingulate cortex: a positron emission tomography study. Neurosci Lett 262:61–64
Hsu MM, Shyu BC (1997) Electrophysiological study of the connection between medial thalamus and anterior cingulate cortex in the rat. Neuroreport 8:2701–2707. https://doi.org/10.1097/00001756-199708180-00013
Huh Y, Bhatt R, Jung D, Shin H-S, Cho J (2012) Interactive responses of a thalamic neuron to formalin induced lasting pain in behaving mice. PLoS One 7:e30699
Hutchison WD, Davis KD, Lozano AM, Tasker RR, Dostrovsky JO (1999) Pain-related neurons in the human cingulate cortex. Nat Neurosci 2:403–405
Im K, Mareninov S, Diaz MFP, Yong WH (2019) An introduction to performing immunofluorescence staining. Methods Molec Biol (Clifton NJ) 1897:299–311. https://doi.org/10.1007/978-1-4939-8935-5_26
Iwata M, LeBlanc BW, Kadasi LM, Zerah ML, Cosgrove RG, Saab CY (2011) High-frequency stimulation in the ventral posterolateral thalamus reverses electrophysiologic changes and hyperalgesia in a rat model of peripheral neuropathic pain. PAIN 152:2505–2513. https://doi.org/10.1016/j.pain.2011.07.011
Iyer SM et al (2016) Optogenetic and chemogenetic strategies for sustained inhibition of pain. Sci Rep 6:30570
Jagodic MM, Pathirathna S, Joksovic PM, Lee WY, Nelson MT, Naik AK, Su P, Jevtovic-Todorovic V, Todorovic SM (2008) Upregulation of the T-type calcium current in small rat sensory neurons after chronic constrictive injury of the sciatic nerve. J Neurophysiol 99:3151–3156
Kang SJ et al (2015a) Bidirectional modulation of hyperalgesia via the specific control of excitatory and inhibitory neuronal activity in the ACC. Molec Brain 8:81
Kang SJ et al (2015b) Bidirectional modulation of hyperalgesia via the specific control of excitatory and inhibitory neuronal activity in the ACC. Molec Brain 8:1–11
KC E, Moon HC, Kim S, Kim HK, Won SY, Hyun SH, Park YS (2020) Optical modulation on the nucleus accumbens core in the alleviation of neuropathic pain in chronic dorsal root ganglion compression rat model. Neuromodulation 23:167–176
Kim JG, Lim DW, Cho S, Han D, Kim YT (2014) The edible brown seaweed Ecklonia cava reduces hypersensitivity in postoperative and neuropathic pain models in rats. Molecules 19:7669–7678. https://doi.org/10.3390/molecules19067669
Kim KH, Byeon GJ, Kim HY, Baek SH, Shin SW, Koo ST (2015) Mechanical antiallodynic effect of intrathecal nefopam in a rat neuropathic pain model. J Korean Med Sci 30:1189–1196. https://doi.org/10.3346/jkms.2015.30.8.1189
Kugler S, Kilic E, Bahr M (2003) Human synapsin 1 gene promoter confers highly neuron-specific long-term transgene expression from an adenoviral vector in the adult rat brain depending on the transduced area. Gene Ther 10:337–347. https://doi.org/10.1038/sj.gt.3301905
Kügler S, Kilic E, Bähr M (2003) Human synapsin 1 gene promoter confers highly neuron-specific long-term transgene expression from an adenoviral vector in the adult rat brain depending on the transduced area. Gene Ther 10:337–347. https://doi.org/10.1038/sj.gt.3301905
LaBuda CJ, Fuchs PN (2005) Attenuation of negative pain affect produced by unilateral spinal nerve injury in the rat following anterior cingulate cortex activation. Neuroscience 136:311–322
LaGraize SC, Labuda CJ, Rutledge MA, Jackson RL, Fuchs PN (2004) Differential effect of anterior cingulate cortex lesion on mechanical hypersensitivity and escape/avoidance behavior in an animal model of neuropathic pain. Exp Neurol 188:139–148
Lee GH, Kim SS (2016) Therapeutic strategies for neuropathic pain: potential application of pharmacosynthetics and optogenetics. Mediat Inflamm 2016:5808215
Liu J et al (2015) Frequency-selective control of cortical and subcortical networks by central thalamus. Elife 4:e09215
Liu S, Tang Y, Xing Y, Kramer P, Bellinger L, Tao F (2019) Potential application of optogenetic stimulation in the treatment of pain and migraine headache: a perspective from animal studies. Brain Sci 9. https://doi.org/10.3390/brainsci9020026
Luo F, Yang C, Chen Y, Shukla P, Tang L, Wang LX, Wang ZJ (2008) Reversal of chronic inflammatory pain by acute inhibition of Ca2+/calmodulin-dependent protein kinase II. J Pharmacol Exp Ther 325:267–275
McCutcheon JE et al (2014) Optical suppression of drug-evoked phasic dopamine release. Front Neural Circuits 8:114. https://doi.org/10.3389/fncir.2014.00114
Moisset X, Bouhassira D (2007) Brain imaging of neuropathic pain. Neuroimage 37:S80–S88
Moon HC et al (2017) Optical inactivation of the anterior cingulate cortex modulate descending pain pathway in a rat model of trigeminal neuropathic pain created via chronic constriction injury of the infraorbital nerve. J Pain Res 10:2355
Navratilova E et al (2015) Endogenous opioid activity in the anterior cingulate cortex is required for relief of pain. J Neurosci 35:7264–7271. https://doi.org/10.1523/JNEUROSCI.3862-14.2015
Nazeri M, Chamani G, Abareghi F, Mohammadi F, Talebizadeh M-H, Zarei M-R, Shabani M (2019) Sensory and affective dimensions of pain and anxiety like behaviors are altered in an animal model of pain empathy. Iran J Psychiatry 14:221
Nirogi R, Goura V, Shanmuganathan D, Jayarajan P, Abraham R (2012) Comparison of manual and automated filaments for evaluation of neuropathic pain behavior in rats. J Pharmacol Toxicol Methods 66:8–13
Osaka N, Osaka M, Morishita M, Kondo H, Fukuyama H (2004) A word expressing affective pain activates the anterior cingulate cortex in the human brain: an fMRI study. Behav Brain Res 153:123–127
Saab CY (2012) Pain-related changes in the brain: diagnostic and therapeutic potentials. Trends Neurosci 35:629–637
Seifert F, Maihöfner C (2009) Central mechanisms of experimental and chronic neuropathic pain: findings from functional imaging studies. Cell Mol Life Sci 66:375
Shen F-Y et al (2015) Alleviation of neuropathic pain by regulating T-type calcium channels in rat anterior cingulate cortex. Mol Pain 11:s12990-12015-10008-12993
Shevtsova Z, Malik JMI, Michel U, Bähr M, Kügler S (2005) Promoters and serotypes: targeting of adeno-associated virus vectors for gene transfer in the rat central nervous system in vitro and in vivo. Exp Physiol 90:53–59. https://doi.org/10.1113/expphysiol.2004.028159
Shyu BC, Lin CY, Sun JJ, Chen SL, Chang C (2004) BOLD response to direct thalamic stimulation reveals a functional connection between the medial thalamus and the anterior cingulate cortex in the rat. Magn Reson Med 52:47–55. https://doi.org/10.1002/mrm.20111
Sugimine S, Ogino Y, Kawamichi H, Obata H, Saito S (2016) Brain morphological alternation in chronic pain patients with neuropathic characteristics. Mol Pain 12:1744806916652408. https://doi.org/10.1177/1744806916652408
Tachibana K, Kato R, Tsuruga K, Takita K, Hashimoto T, Morimoto Y (2008) Altered synaptic transmission in rat anterior cingulate cortex following peripheral nerve injury. Brain Res 1238:53–58
Wei F, Zhuo M (2008) Activation of Erk in the anterior cingulate cortex during the induction and expression of chronic pain. Mol Pain 4:1744-8069-1744-1728
Xiao X, Zhang YQ (2018) A new perspective on the anterior cingulate cortex and affective pain. Neurosci Biobehav Rev 90:200–211. https://doi.org/10.1016/j.neubiorev.2018.03.022
Xiao Z et al (2019) Cortical pain processing in the rat anterior cingulate cortex and primary somatosensory cortex. Front Cell Neurosci 13:165
Xu H, Wu LJ, Wang H, Zhang X, Vadakkan KI, Kim SS, Steenland HW, Zhuo M (2008) Presynaptic and postsynaptic amplifications of neuropathic pain in the anterior cingulate cortex. J Neurosci 28:7445–7453
Xu L, Liu Y, Sun Y, Li H, Mi W, Jiang Y (2018) Analgesic effects of TLR4/NF-κB signaling pathway inhibition on chronic neuropathic pain in rats following chronic constriction injury of the sciatic nerve. Biomed Pharmacother 107:526–533
Yizhar O et al (2011) Neocortical excitation/inhibition balance in information processing and social dysfunction. Nature 477:171–178. https://doi.org/10.1038/nature10360
Zachariou V, Carr F (2014) Nociception and pain: lessons from optogenetics. Front Behav Neurosci 8:69
Zhao P, Waxman SG, Hains BC (2006) Sodium channel expression in the ventral posterolateral nucleus of the thalamus after peripheral nerve injury. Mol Pain 2:27
Zhao R, Zhou H, Huang L, Xie Z, Wang J, Gan W-B, Yang G (2018) Neuropathic pain causes pyramidal neuronal hyperactivity in the anterior cingulate cortex. Front Cell Neurosci 12:107
Zhuang X et al. (2019) The anterior cingulate cortex projection to the dorsomedial striatum modulates hyperalgesia in a chronic constriction injury mouse model. Arch Med Sci 15
Zhuo M (2006) Molecular mechanisms of pain in the anterior cingulate cortex. J Neurosci Res 84:927–933
Zhuo M (2008) Cortical excitation and chronic pain. Trends Neurosci 31:199–207
Zhuo M (2014a) Long-term potentiation in the anterior cingulate cortex and chronic pain. Philosoph Transact R Soc B: Biol Sci 369:20130146
Zhuo M (2014b) Long-term potentiation in the anterior cingulate cortex and chronic pain. Philos Trans R Soc Lond Ser B Biol Sci 369:20130146. https://doi.org/10.1098/rstb.2013.0146
Zimmermann M (1986) Ethical considerations in relation to pain in animal experimentation. Acta Physiol Scand Suppl 554:221–233
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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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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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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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)
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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DOI: https://doi.org/10.1007/s12031-020-01685-7