scholarly journals Novel charged sodium and calcium channel inhibitor active against neurogenic inflammation

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Seungkyu Lee ◽  
Sooyeon Jo ◽  
Sébastien Talbot ◽  
Han-Xiong Bear Zhang ◽  
Masakazu Kotoda ◽  
...  
Keyword(s):  
Calcium Channels ◽  
Calcium Channel ◽  
Sodium Channel ◽  
Dorsal Root Ganglion Neurons ◽  
Channel Blockers ◽  
Potent Inhibition ◽  
Calcitonin Gene ◽  
Peptide Release ◽  
Voltage Dependent ◽  
Ganglion Neurons

Voltage-dependent sodium and calcium channels in pain-initiating nociceptor neurons are attractive targets for new analgesics. We made a permanently charged cationic derivative of an N-type calcium channel-inhibitor. Unlike cationic derivatives of local anesthetic sodium channel blockers like QX-314, this cationic compound inhibited N-type calcium channels more effectively with extracellular than intracellular application. Surprisingly, the compound is also a highly effective sodium channel inhibitor when applied extracellularly, producing more potent inhibition than lidocaine or bupivacaine. The charged inhibitor produced potent and long-lasting analgesia in mouse models of incisional wound and inflammatory pain, inhibited release of the neuropeptide calcitonin gene-related peptide (CGRP) from dorsal root ganglion neurons, and reduced inflammation in a mouse model of allergic asthma, which has a strong neurogenic component. The results show that some cationic molecules applied extracellularly can powerfully inhibit both sodium channels and calcium channels, thereby blocking both nociceptor excitability and pro-inflammatory peptide release.

Calcium channel involvement in GABAB receptor-mediated inhibition of GABA release in area CA1 of the rat hippocampus

1995 ◽  
Vol 74 (1) ◽  
pp. 43-53 ◽  
Author(s):  
V. A. Doze ◽  
G. A. Cohen ◽  
D. V. Madison
Keyword(s):  
Calcium Channels ◽  
Action Potential ◽  
Calcium Channel ◽  
Calcium Channel Blockers ◽  
Gabab Receptor ◽  
Gaba Release ◽  
Extracellular Potassium ◽  
Channel Blockers ◽  
Voltage Dependent ◽  
Subtype Selective

1. Experiments were performed in rat hippocampal slices to examine the nature of GABAergic inhibition of inhibitory synaptic transmission. In these experiments the effects of the gamma-aminobutyric acid-B (GABAB) receptor agonist, baclofen, and of subtype-selective calcium channel blockers were tested with the use of intracellular recordings of evoked inhibitory postsynaptic potentials (IPSPs) and whole cell recordings of spontaneous GABAergic inhibitory postsynaptic currents (IPSCs). 2. Baclofen inhibited evoked and spontaneous (action-potential-dependent) monosynaptic GABAA-mediated IPSPs and IPSCs but had no effect on the frequency of tetrodotoxin-resistant (action-potential-independent) miniature IPSCs recorded in CA1 pyramidal neurons. 3. Depolarizing GABAergic synaptic terminals by raising the extracellular potassium concentration caused an increase in action-potential-independent miniature IPSC frequency that could be inhibited by either baclofen or cadmium, a blocker of voltage-dependent calcium channels. In addition, under these depolarizing conditions, cadmium occluded the baclofen inhibition of miniature IPSCs. These data suggest that baclofen reduces only depolarization-induced, not quantal, GABA release and that it does so by decreasing presynaptic voltage-dependent calcium influx. 4. Experiments with subtype-selective calcium channel blockers demonstrate that the presynaptic action of baclofen was mediated through both omega-conotoxin-GVIA-sensitive and omega-agatoxin-IVA-sensitive, but not dihydropyridine-sensitive calcium channels.

scholarly journals Voltage-gated calcium channel blockers for psychiatric disorders: genomic reappraisal

2019 ◽  
Vol 216 (5) ◽  
pp. 250-253 ◽  
Author(s):  
Paul J. Harrison ◽  
Elizabeth M. Tunbridge ◽  
Annette C. Dolphin ◽  
Jeremy Hall
Keyword(s):  
Calcium Channels ◽  
Calcium Channel ◽  
Psychiatric Disorders ◽  
Calcium Channel Blockers ◽  
Channel Blockers ◽  
Risk Genes ◽  
Voltage Gated ◽  
Voltage Gated Calcium Channels ◽  
Voltage Gated Calcium Channel ◽  
Second Use

SummaryWe reappraise the psychiatric potential of calcium channel blockers (CCBs). First, voltage-gated calcium channels are risk genes for several disorders. Second, use of CCBs is associated with altered psychiatric risks and outcomes. Third, research shows there is an opportunity for brain-selective CCBs, which are better suited to psychiatric indications.

G-proteins are involved in riluzole inhibition of high voltage-activated calcium channels in rat dorsal root ganglion neurons

1997 ◽  
Vol 762 (1-2) ◽  
pp. 235-239 ◽  
Author(s):  
Chao-Sheng Huang ◽  
Jin-Ho Song ◽  
Keiichi Nagata ◽  
Dennis Twombly ◽  
Jay Z Yeh ◽  
...  
Keyword(s):  
Dorsal Root Ganglion ◽  
Calcium Channels ◽  
G Proteins ◽  
High Voltage ◽  
Dorsal Root ◽  
Dorsal Root Ganglion Neurons ◽  
Ganglion Neurons

scholarly journals The terpenes camphene and alpha-bisabolol inhibit inflammatory and neuropathic pain via Cav3.2 T-type calcium channels

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Vinicius M. Gadotti ◽  
Sun Huang ◽  
Gerald W. Zamponi
Keyword(s):  
Neuropathic Pain ◽  
Calcium Channels ◽  
Wide Spectrum ◽  
Thermal Hyperalgesia ◽  
Significant Inhibition ◽  
Dorsal Root Ganglion Neurons ◽  
Intraplantar Injection ◽  
Mouse Dorsal Root Ganglion ◽  
Ganglion Neurons ◽  
Micromolar Range

AbstractT-type calcium channels are known molecular targets of certain phytocannabinoids and endocannabinoids. Here we explored the modulation of Cav3.2 T-type calcium channels by terpenes derived from cannabis plants. A screen of eight commercially available terpenes revealed that camphene and alpha-bisabolol mediated partial, but significant inhibition of Cav3.2 channels expressed in tsA-201 cells, as well as native T-type channels in mouse dorsal root ganglion neurons. Both compounds inhibited peak current amplitude with IC50s in the low micromolar range, and mediated an additional small hyperpolarizing shift in half-inactivation voltage. When delivered intrathecally, both terpenes inhibited nocifensive responses in mice that had received an intraplantar injection of formalin, with alpha-bisabolol showing greater efficacy. Both terpenes reduced thermal hyperalgesia in mice injected with Complete Freund’s adjuvant. This effect was independent of sex, and absent in Cav3.2 null mice, indicating that these compounds mediate their analgesic properties by acting on Cav3.2 channels. Both compounds also inhibited mechanical hypersensitivity in a mouse model of neuropathic pain. Hence, camphene and alpha-bisabolol have a wide spectrum of analgesic action by virtue of inhibiting Cav3.2 T-type calcium channels.

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