Calcium Channel α2δ1 Subunit Mediates Secondary Orofacial Hyperalgesia Through PKC-TRPA1/Gap Junction Signaling

Cui, Weihong; Chu, Yu‐Xia; Xu, Fei; Chen, Teng; Feng, Yi; Hu, Xue-Ming; Yang, Wei; Du, Lixia; Zhang, Wenwen; Mao-Ying, Qi-Liang; Mi, Wen-Li; Wang, Yan-Qing

doi:10.1016/j.jpain.2019.08.012

Cited by 20 publications

(27 citation statements)

References 50 publications

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“…No treatment was given in the naive group, and animals with emaciation or abnormal movement or mental state were excluded from subsequent experiments. According to our previous work [12], the pT-ION-induced mechanical and cold hypersensitivity is stable for at least 28 days (the longest time period that we observed) and does not spontaneously resolve over time within 28 days after surgery.…”

Section: The Partial Transection Of the Infraorbital Nervesupporting

confidence: 58%

Tacr3 in the lateral habenula differentially regulates orofacial allodynia and anxiety-like behaviors in a mouse model of trigeminal neuralgia

Cui

Zhang

Chen

et al. 2020

acta neuropathol commun

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Trigeminal neuralgia (TN) is debilitating and is usually accompanied by mood disorders. The lateral habenula (LHb) is considered to be involved in the modulation of pain and mood disorders, and the present study aimed to determine if and how the LHb participates in the development of pain and anxiety in TN. To address this issue, a mouse model of partial transection of the infraorbital nerve (pT-ION) was established. pT-ION induced stable and long-lasting primary and secondary orofacial allodynia and anxiety-like behaviors that correlated with the increased excitability of LHb neurons. Adeno-associated virus (AAV)-mediated expression of hM4D(Gi) in glutamatergic neurons of the unilateral LHb followed by clozapine-N-oxide application relieved pT-ION-induced anxiety-like behaviors but not allodynia. Immunofluorescence validated the successful infection of AAV in the LHb, and microarray analysis showed changes in gene expression in the LHb of mice showing allodynia and anxiety-like behaviors after pT-ION. Among these differentially expressed genes was Tacr3, the downregulation of which was validated by RT-qPCR. Rescuing the downregulation of Tacr3 by AAV-mediated Tacr3 overexpression in the unilateral LHb significantly reversed pT-ION-induced anxiety-like behaviors but not allodynia. Whole-cell patch clamp recording showed that Tacr3 overexpression suppressed nerve injury-induced hyperexcitation of LHb neurons, and western blotting showed that the pT-ION-induced upregulation of p-CaMKII was reversed by AAVmediated Tacr3 overexpression or chemicogenetic inhibition of glutamatergic neurons in the LHb. Moreover, not only anxiety-like behaviors, but also allodynia after pT-ION were significantly alleviated by chemicogenetic inhibition of bilateral LHb neurons or by bilateral Tacr3 overexpression in the LHb. In conclusion, Tacr3 in the LHb plays a protective role in treating trigeminal nerve injury-induced allodynia and anxiety-like behaviors by suppressing the

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Section: The Partial Transection Of the Infraorbital Nervesupporting

confidence: 58%

Tacr3 in the lateral habenula differentially regulates orofacial allodynia and anxiety-like behaviors in a mouse model of trigeminal neuralgia

Cui

Zhang

Chen

et al. 2020

acta neuropathol commun

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“…Calcium channels, once activated, permit calcium ions to pass through and elicit changes in nerve membrane potentials and a variety of intracellular responses (Catterall 2011). A large body of evidence shows that calcium channels play important roles in orofacial pain (Li et al 2014; Cui et al 2020). Both N-type calcium channels (encoded by Cacna 1b) and T-type calcium channels (encoded by Cacna 1i) are involved in the regulation of CGRP expression and release (Amrutkar et al 2011).…”

Section: Discussionmentioning

confidence: 99%

CGRP Modulates Orofacial Pain through Mediating Neuron-Glia Crosstalk

Liang

Shan

et al. 2020

J Dent Res

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Calcitonin gene-related peptide (CGRP) plays a crucial role in the modulation of orofacial pain, and we hypothesized that CGRP mediated a neuron-glia crosstalk in orofacial pain. The objective of this study was to elucidate the mechanisms whereby CGRP mediated trigeminal neuron-glia crosstalk in modulating orofacial pain. Orofacial pain was elicited by ligating closed-coil springs between incisors and molars. Trigeminal neurons and satellite glial cells (SGCs) were cultured for mechanistic exploration. Gene and protein expression were determined through immunostaining, polymerase chain reaction, and Western blot. Orofacial pain was evaluated through the rat grimace scale. Our results revealed that the expressions of CGRP were elevated in both trigeminal neurons and SGCs following the induction of orofacial pain. Intraganglionic administration of CGRP and olcegepant exacerbated and alleviated orofacial pain, respectively. The knockdown of CGRP through viral vector-mediated RNA interference was able to downregulate CGRP expressions in both neurons and SGCs and to alleviate orofacial pain. CGRP upregulated the expression of inducible nitric oxide synthase through the p38 signaling pathway in cultured SGCs. In turn, L-arginine (nitric oxide donor) was able to enhance orofacial pain by upregulating CGRP expressions in vivo. In cultured trigeminal neurons, L-arginine upregulated the expression of CGRP, and this effect was diminished by cilnidipine (N-type calcium channel blocker) while not by mibefradil (L-type calcium channel blocker). In conclusion, CGRP modulated orofacial pain through upregulating the expression of nitric oxide through the p38 signaling pathway in SGCs, and the resulting nitric oxide in turn stimulated CGRP expression through N-type calcium channel in neurons, building a CGRP-mediated positive-feedback neuron-glia crosstalk.

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“…It is mainly present in presynaptic terminals and, to a much lower extent, in the cell bodies of neurons in many brain regions under physiological conditions ( Alles and Smith, 2018 ; Bikbaev et al, 2020 ). In the PNS, α2δ1 is strongly expressed in all neuronal cell types of DRG and trigeminal ganglion (TG), such as IB4 + , CGRP + , and NF200 + neurons ( Tachiya et al, 2018 ; Cui et al, 2020 ). It was found that α2δ1 was expressed in most neurons of different sizes after nerve injuries, predominantly in small (less 20 μm) and medium (20–50 μm) neurons in animal models of sciatica neuralgia and trigeminal neuralgia ( Tachiya et al, 2018 ; Cui et al, 2020 ).…”

Section: The α2δ1 Subunit and Its Role In Neuropathic Painmentioning

confidence: 99%

“…In the PNS, α2δ1 is strongly expressed in all neuronal cell types of DRG and trigeminal ganglion (TG), such as IB4 + , CGRP + , and NF200 + neurons ( Tachiya et al, 2018 ; Cui et al, 2020 ). It was found that α2δ1 was expressed in most neurons of different sizes after nerve injuries, predominantly in small (less 20 μm) and medium (20–50 μm) neurons in animal models of sciatica neuralgia and trigeminal neuralgia ( Tachiya et al, 2018 ; Cui et al, 2020 ). In addition, studies using rat models of chronic constriction injury to the infraorbital nerve (CCI-ION) have shown that the number of α2δ1-immunoreactive neurons over 25 μm in diameter was obviously increased ( Li et al, 2014 ).…”

Section: The α2δ1 Subunit and Its Role In Neuropathic Painmentioning

confidence: 99%

“…Several studies have demonstrated that the expression level of α2δ1 was elevated in the TG after partial transection of the infraorbital nerve (pT-ION) ( Cui et al, 2020 ) and CCI-ION ( Li et al, 2014 ). The mechanical and cold hyperalgesia induced by nerve injury could be mimicked by injecting the Cavα2δ1 overexpression adeno-associated virus (AAV) and be reversed by injecting the AAV of Cavα2δ1 downregulation in TG neurons ( Cui et al, 2020 ). These results indicated that the Cavα2δ1 of primary afferent neurons play a vital role in neuropathic pain and that is mainly related to its regulation of Ca 2+ inflow.…”

Section: The α2δ1 Subunit and Its Role In Neuropathic Painmentioning

confidence: 99%

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The Calcium Channel α2δ1 Subunit: Interactional Targets in Primary Sensory Neurons and Role in Neuropathic Pain

Cui

et al. 2021

Front. Cell. Neurosci.

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Neuropathic pain is mainly triggered after nerve injury and associated with plasticity of the nociceptive pathway in primary sensory neurons. Currently, the treatment remains a challenge. In order to identify specific therapeutic targets, it is necessary to clarify the underlying mechanisms of neuropathic pain. It is well established that primary sensory neuron sensitization (peripheral sensitization) is one of the main components of neuropathic pain. Calcium channels act as key mediators in peripheral sensitization. As the target of gabapentin, the calcium channel subunit α2δ1 (Cavα2δ1) is a potential entry point in neuropathic pain research. Numerous studies have demonstrated that the upstream and downstream targets of Cavα2δ1 of the peripheral primary neurons, including thrombospondins, N-methyl-D-aspartate receptors, transient receptor potential ankyrin 1 (TRPA1), transient receptor potential vanilloid family 1 (TRPV1), and protein kinase C (PKC), are involved in neuropathic pain. Thus, we reviewed and discussed the role of Cavα2δ1 and the associated signaling axis in neuropathic pain conditions.

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Calcium Channel α2δ1 Subunit Mediates Secondary Orofacial Hyperalgesia Through PKC-TRPA1/Gap Junction Signaling

Cited by 20 publications

References 50 publications

Tacr3 in the lateral habenula differentially regulates orofacial allodynia and anxiety-like behaviors in a mouse model of trigeminal neuralgia

Tacr3 in the lateral habenula differentially regulates orofacial allodynia and anxiety-like behaviors in a mouse model of trigeminal neuralgia

CGRP Modulates Orofacial Pain through Mediating Neuron-Glia Crosstalk

The Calcium Channel α2δ1 Subunit: Interactional Targets in Primary Sensory Neurons and Role in Neuropathic Pain

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