Chronic intrathecal infusion of mibefradil, ethosuximide and nickel attenuates nerve ligation-induced pain in rats

Chen, Y.L.; Tsaur, Meei‐Ling; Wang, S.W.; Wang, T.Y.; Hung, Yu Chun; Lin, Chao-Shun; Chang, Yu-Cheng; Wang, Y.C.; Shiue, Sheng-Jie; Cheng, Jen-Kun

doi:10.1093/bja/aev198

Cited by 22 publications

(25 citation statements)

References 40 publications

(31 reference statements)

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“…Ethosuximide (Zarontin) is a T‐type calcium channel blocker that is clinically used in the treatment of absence epilepsy (see Zamponi, ). As noted earlier, this compound reverses pain in animal models (Flatters and Bennett, ; Hamidi et al, ; Chen et al, ), but to date, there have been no reports of its efficacy as an analgesic in human studies. There is, however, a currently ongoing clinical trial examining the effects of ethosuximide in non‐diabetic peripheral neuropathy (Kerckhove et al, ).…”

Section: Clinical Stage T‐type Calcium Channel Blockersmentioning

confidence: 86%

Recent advances in the development of T‐type calcium channel blockers for pain intervention

Snutch

Zamponi

2017

British J Pharmacology

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Section: Clinical Stage T‐type Calcium Channel Blockersmentioning

confidence: 86%

Recent advances in the development of T‐type calcium channel blockers for pain intervention

Snutch

Zamponi

2017

British J Pharmacology

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“…Each mini-osmotic pump (ALZET ® micro-osmotic pump, 1007D; Durect Corporation, Cupertino, CA, USA) was attached to a cannula and placed in a subcutaneous pocket. Subsequently, the cannula was implanted into the lateral hippocampus (positions: −4.0 mm posterior to bregma, 3.0 mm bilateral to the midline, and 3.1 mm under the skull surface) with infusion of Mibefradil (1.5 mg/ml in 0.1 M PBS; Sigma-Aldrich) for seven consecutive days (19,20). The cannula was secured with dental acrylic cement.…”

Section: Methodsmentioning

confidence: 99%

Altered axon initial segment in hippocampal newborn neurons, associated with recurrence of temporal lobe epilepsy in rats

Liu

Feng

Liu

et al. 2017

Molecular Medicine Reports

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Hippocampal neurogenesis in temporal lobe epilepsy (TLE) may result in alteration of the excitability of neurons, which contributes to spontaneous recurrent seizures. Axon initial segment (AIS) structural and functional plasticity is important in the control of neuronal excitability. It remains to be elucidated whether the plasticity of AIS occurs in hippocampal newly-generated neurons that are involved in recurrent seizures following pilocarpine-induced status epilepticus (SE). The present study first established a pilocarpine-induced TLE rat model to assess the features of newborn neurons and AIS plasticity alterations using double immunofluorescence staining of Ankyrin G and doublecortin (DCX). AIS plasticity alterations include length and distance from soma in the hippocampal newly-generated neurons post-SE. The results of the present study demonstrated that pilocarpine-induced epileptic rats exhibited aberrant hippocampal neurogenesis and longer DCX-labeled cell dendrites in the dentate gyrus. Pilocarpine-induced epileptic rats demonstrated shortened lengths of AIS and an increased distance from the soma in hippocampal newborn neurons. Mibefradil, a T/L-type calcium blocker, reversed the alterations in length and position of AIS in hippocampal newborn neurons post-SE, accompanied by decreased long-term seizure activity without increased aberrant neurogenesis. These findings indicate that the plasticity of AIS in hippocampal neurogenesis may have profound consequences in epilepsy, at least in animals.

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“…Ca V 3.2 can be upregulated by increased expression of USP5, which interacts with and de-ubiquitinates these channels thereby decreasing their degradation (Garcia-Caballero et al, 2014;Stemkowski et al, 2016). Moreover, treatment with T-type channel blockers results in reduced mechanical hyperalgesia in the spinal nerve ligation model (Dogrul et al, 2003;Chen et al, 2015). Similarly, manipulation of the expression levels of Ca V 3.2, as in the KO mouse model (Choi et al, 2007) or by selective knockdown in DRG neurons using antisense (Bourinet et al, 2005) results in attenuated pain responses, confirming the critical role of Ca V 3.2 in pain transmission.…”

Section: Introductionmentioning

confidence: 99%

“…Similarly, manipulation of the expression levels of Ca V 3.2, as in the KO mouse model (Choi et al, 2007) or by selective knockdown in DRG neurons using antisense (Bourinet et al, 2005) results in attenuated pain responses, confirming the critical role of Ca V 3.2 in pain transmission. Ca V 3.2 are therefore viable pharmacological targets to control pain (Dogrul et al, 2003;Flatters and Bennett, 2004;Okubo et al, 2011;Chen et al, 2015). An alternative strategy to modulate channel function is to target auxiliary or modulatory subunits to indirectly affect channel activity or trafficking to the plasma membrane (Weiss and Zamponi, 2019).…”

Section: Introductionmentioning

confidence: 99%

KLHL1 Controls CaV3.2 Expression in DRG Neurons and Mechanical Sensitivity to Pain

Martínez-Hernández

Zeglin

Almazan

et al. 2020

Front. Mol. Neurosci.

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Dorsal root ganglion (DRG) neurons process pain signaling through specialized nociceptors located in their peripheral endings. It has long been established low voltage-activated (LVA) Ca V 3.2 calcium channels control neuronal excitability during sensory perception in these neurons. Silencing Ca V 3.2 activity with antisense RNA or genetic ablation results in anti-nociceptive, anti-hyperalgesic and anti-allodynic effects. Ca V 3.2 channels are regulated by many proteins (Weiss and Zamponi, 2017), including KLHL1, a neuronal actin-binding protein that stabilizes channel activity by recycling it back to the plasma membrane through the recycling endosome. We explored whether manipulation of KLHL1 levels and thereby function as a Ca V 3.2 modifier can modulate DRG excitability and mechanical pain transmission or sensitivity to pain. We first assessed the mechanical sensitivity threshold and DRG properties in the KLHL1 KO mouse model. KO DRG neurons exhibited smaller T-type current density compared to WT without significant changes in voltage dependence, as expected in the absence of its modulator. Western blot analysis confirmed Ca V 3.2 but not Ca V 3.1, Ca V 3.3, Ca V 2.1, or Ca V 2.2 protein levels were significantly decreased; and reduced neuron excitability and decreased pain sensitivity were also found in the KLHL1 KO model. Analogously, transient down-regulation of KLHL1 levels in WT mice with viral delivery of anti-KLHL1 shRNA also resulted in decreased pain sensitivity. These two experimental approaches confirm KLHL1 as a physiological modulator of excitability and pain sensitivity, providing a novel target to control peripheral pain.

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Chronic intrathecal infusion of mibefradil, ethosuximide and nickel attenuates nerve ligation-induced pain in rats

Cited by 22 publications

References 40 publications

Recent advances in the development of T‐type calcium channel blockers for pain intervention

Recent advances in the development of T‐type calcium channel blockers for pain intervention

Altered axon initial segment in hippocampal newborn neurons, associated with recurrence of temporal lobe epilepsy in rats

KLHL1 Controls CaV3.2 Expression in DRG Neurons and Mechanical Sensitivity to Pain

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