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Upregulation of N-type calcium channels in the soma of uninjured dorsal root ganglion neurons contributes to neuropathic pain by increasing neuronal excitability following peripheral nerve injury.
Brain Behav Immun. 2018 07; 71:52-65.BB

Abstract

N-type voltage-gated calcium (Cav2.2) channels are expressed in the central terminals of dorsal root ganglion (DRG) neurons, and are critical for neurotransmitter release. Cav2.2 channels are also expressed in the soma of DRG neurons, where their function remains largely unknown. Here, we showed that Cav2.2 was upregulated in the soma of uninjured L4 DRG neurons, but downregulated in those of injured L5 DRG neurons following L5 spinal nerve ligation (L5-SNL). Local application of specific Cav2.2 blockers (ω-conotoxin GVIA, 1-100 μM or ZC88, 10-1000 μM) onto L4 and 6 DRGs on the operated side, but not the contralateral side, dose-dependently reversed mechanical allodynia induced by L5-SNL. Patch clamp recordings revealed that both ω-conotoxin GVIA (1 μM) and ZC88 (10 μM) depressed hyperexcitability in L4 but not in L5 DRG neurons of L5-SNL rats. Consistent with this, knockdown of Cav2.2 in L4 DRG neurons with AAV-Cav2.2 shRNA substantially prevented L5-SNL-induced mechanical allodynia and hyperexcitability of L4 DRG neurons. Furthermore, in L5-SNL rats, interleukin-1 beta (IL-1β) and IL-10 were upregulated in L4 DRGs and L5 DRGs, respectively. Intrathecal injection of IL-1β induced mechanical allodynia and Cav2.2 upregulation in bilateral L4-6 DRGs of naïve rats, whereas injection of IL-10 substantially prevented mechanical allodynia and Cav2.2 upregulation in L4 DRGs in L5-SNL rats. Finally, in cultured DRG neurons, Cav2.2 was dose-dependently upregulated by IL-1β and downregulated by IL-10. These data indicate that the upregulation of Cav2.2 in uninjured DRG neurons via IL-1β over-production contributes to neuropathic pain by increasing neuronal excitability following peripheral nerve injury.

Authors+Show Affiliations

Pain Research Center and Department of Physiology, Zhongshan School of Medicine of Sun Yat-sen University, 74 Zhongshan Rd. 2, Guangzhou 510080, China.Department of Anesthesiology, Cancer Center, Sun Yat-sen University, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, East 651 Dongfeng Rd, Guangzhou 510060, China.CAS Key Laboratory of Mental Health, Institute of Psychology, 16 Lincui Rd, Beijing 100101, China; Department of Psychology, University of Chinese Academy of Sciences, Beijing 100049, China.Pain Research Center and Department of Physiology, Zhongshan School of Medicine of Sun Yat-sen University, 74 Zhongshan Rd. 2, Guangzhou 510080, China.Pain Research Center and Department of Physiology, Zhongshan School of Medicine of Sun Yat-sen University, 74 Zhongshan Rd. 2, Guangzhou 510080, China.Pain Research Center and Department of Physiology, Zhongshan School of Medicine of Sun Yat-sen University, 74 Zhongshan Rd. 2, Guangzhou 510080, China.Beijing Key Laboratory of Neuropsychopharmacology, State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, 27th Taiping Road, Beijing 100850, China.Beijing Key Laboratory of Neuropsychopharmacology, State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, 27th Taiping Road, Beijing 100850, China.Beijing Key Laboratory of Neuropsychopharmacology, State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, 27th Taiping Road, Beijing 100850, China.Pain Research Center and Department of Physiology, Zhongshan School of Medicine of Sun Yat-sen University, 74 Zhongshan Rd. 2, Guangzhou 510080, China. Electronic address: pangruip@mail.sysu.edu.cn.Pain Research Center and Department of Physiology, Zhongshan School of Medicine of Sun Yat-sen University, 74 Zhongshan Rd. 2, Guangzhou 510080, China; Guangdong Provincial Key Laboratory of Brain Function and Disease, 74 Zhongshan Rd. 2, Guangzhou 510080, China. Electronic address: liuxg@mail.sysu.edu.cn.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

29709527

Citation

Yang, Jie, et al. "Upregulation of N-type Calcium Channels in the Soma of Uninjured Dorsal Root Ganglion Neurons Contributes to Neuropathic Pain By Increasing Neuronal Excitability Following Peripheral Nerve Injury." Brain, Behavior, and Immunity, vol. 71, 2018, pp. 52-65.
Yang J, Xie MX, Hu L, et al. Upregulation of N-type calcium channels in the soma of uninjured dorsal root ganglion neurons contributes to neuropathic pain by increasing neuronal excitability following peripheral nerve injury. Brain Behav Immun. 2018;71:52-65.
Yang, J., Xie, M. X., Hu, L., Wang, X. F., Mai, J. Z., Li, Y. Y., Wu, N., Zhang, C., Li, J., Pang, R. P., & Liu, X. G. (2018). Upregulation of N-type calcium channels in the soma of uninjured dorsal root ganglion neurons contributes to neuropathic pain by increasing neuronal excitability following peripheral nerve injury. Brain, Behavior, and Immunity, 71, 52-65. https://doi.org/10.1016/j.bbi.2018.04.016
Yang J, et al. Upregulation of N-type Calcium Channels in the Soma of Uninjured Dorsal Root Ganglion Neurons Contributes to Neuropathic Pain By Increasing Neuronal Excitability Following Peripheral Nerve Injury. Brain Behav Immun. 2018;71:52-65. PubMed PMID: 29709527.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Upregulation of N-type calcium channels in the soma of uninjured dorsal root ganglion neurons contributes to neuropathic pain by increasing neuronal excitability following peripheral nerve injury. AU - Yang,Jie, AU - Xie,Man-Xiu, AU - Hu,Li, AU - Wang,Xiao-Fang, AU - Mai,Jie-Zhen, AU - Li,Yong-Yong, AU - Wu,Ning, AU - Zhang,Cheng, AU - Li,Jin, AU - Pang,Rui-Ping, AU - Liu,Xian-Guo, Y1 - 2018/04/27/ PY - 2017/12/05/received PY - 2018/04/24/revised PY - 2018/04/26/accepted PY - 2018/5/2/pubmed PY - 2019/7/16/medline PY - 2018/5/1/entrez KW - Cytokine KW - Dorsal root ganglion KW - Excitability KW - Mechanical allodynia KW - N-type voltage-gated calcium SP - 52 EP - 65 JF - Brain, behavior, and immunity JO - Brain Behav Immun VL - 71 N2 - N-type voltage-gated calcium (Cav2.2) channels are expressed in the central terminals of dorsal root ganglion (DRG) neurons, and are critical for neurotransmitter release. Cav2.2 channels are also expressed in the soma of DRG neurons, where their function remains largely unknown. Here, we showed that Cav2.2 was upregulated in the soma of uninjured L4 DRG neurons, but downregulated in those of injured L5 DRG neurons following L5 spinal nerve ligation (L5-SNL). Local application of specific Cav2.2 blockers (ω-conotoxin GVIA, 1-100 μM or ZC88, 10-1000 μM) onto L4 and 6 DRGs on the operated side, but not the contralateral side, dose-dependently reversed mechanical allodynia induced by L5-SNL. Patch clamp recordings revealed that both ω-conotoxin GVIA (1 μM) and ZC88 (10 μM) depressed hyperexcitability in L4 but not in L5 DRG neurons of L5-SNL rats. Consistent with this, knockdown of Cav2.2 in L4 DRG neurons with AAV-Cav2.2 shRNA substantially prevented L5-SNL-induced mechanical allodynia and hyperexcitability of L4 DRG neurons. Furthermore, in L5-SNL rats, interleukin-1 beta (IL-1β) and IL-10 were upregulated in L4 DRGs and L5 DRGs, respectively. Intrathecal injection of IL-1β induced mechanical allodynia and Cav2.2 upregulation in bilateral L4-6 DRGs of naïve rats, whereas injection of IL-10 substantially prevented mechanical allodynia and Cav2.2 upregulation in L4 DRGs in L5-SNL rats. Finally, in cultured DRG neurons, Cav2.2 was dose-dependently upregulated by IL-1β and downregulated by IL-10. These data indicate that the upregulation of Cav2.2 in uninjured DRG neurons via IL-1β over-production contributes to neuropathic pain by increasing neuronal excitability following peripheral nerve injury. SN - 1090-2139 UR - https://www.unboundmedicine.com/medline/citation/29709527/Upregulation_of_N_type_calcium_channels_in_the_soma_of_uninjured_dorsal_root_ganglion_neurons_contributes_to_neuropathic_pain_by_increasing_neuronal_excitability_following_peripheral_nerve_injury_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0889-1591(18)30168-5 DB - PRIME DP - Unbound Medicine ER -