The antihyperalgesic effects of the T-type calcium channel blockers ethosuximide, trimethadione, and mibefradil

Barton, Matthew E.; Eberle, Elizabeth L.; Shannon, Harlan E.

doi:10.1016/j.ejphar.2005.08.017

Cited by 60 publications

(36 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Hyperfunction of both channel subtypes has been linked to the development of hyperalgesia and allodynia in various animal models of pain (Ikeda et al, 2003;Barton et al, 2005;Cummins et al, 2007). Conversely, knockout or inhibition of Ttype or Na v channels mediates analgesia (Bourinet et al, 2005;Choi et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

Common Mechanisms of Drug Interactions with Sodium and T-Type Calcium Channels

Bladen¹,

Zamponi²

2012

Mol Pharmacol

View full text Add to dashboard Cite

Voltage-gated sodium (Na v ) and calcium (Ca v ) channels play important roles in physiological processes, including neuronal and cardiac pacemaker activity, vascular smooth muscle contraction, and nociception. They are thought to share a common ancestry, and, in particular, T-type calcium (T-type) channels share structural similarities with Na v channels, both with regard to membrane topology and with regard to gating kinetics, including rapid inactivation. We thus reasoned that certain drugs acting on Na v channels may also modulate the activities of T-type channels. Here we show that the specific Na v 1.8 blocker 5-(4-chlorophenyl-N-(3,5-dimethoxyphenyl)furan-2-carboxamide (A803467) tonically blocks T-type channels in the low micromolar range. Similarly to Na v 1.8, this compound causes a significant hyperpolarizing shift in the voltage dependence of inactivation and seems to promote a slow inactivation-like phenotype. We further hypothesized that the structural similarity between T-type and Na v channels may extend to structurally similar drug-binding sites. Sequence alignment revealed several highly conserved regions between T-type and Na v channels that corresponded to drug-binding sites known to alter voltage-dependent gating kinetics. Mutation of amino acid residues in this regions within human Ca v 3.2 T-type channels altered A803467 blocking affinity severalfold, suggesting that these sites may be exploited for the design of mixed T-type and Na v channel blockers that could potentially act synergistically to normalize aberrant neuronal activity.

show abstract

Section: Discussionmentioning

confidence: 99%

Common Mechanisms of Drug Interactions with Sodium and T-Type Calcium Channels

Bladen¹,

Zamponi²

2012

Mol Pharmacol

View full text Add to dashboard Cite

show abstract

“…39 Of relevance to this review, the antinociceptive effects of several anticonvulsants have been evaluated in the rodent formalin pain model (Table I). While both phases 1 and 2 formalin-induced nociception were shown to be reduced by ethosuximide 40,41 and vigabatrin, 42 only phase 2 was reduced by carbamazepine, 43 gabapentin, 44 lamotrigine, 45 oxcarbazepine 46 and pregabalin. 44 Equivocal results were reported for tiagabine 41,45 and valproic acid, 41,47 possibly due to species differences.…”

Section: Preclinical Evidence Of Analgesic Efficacymentioning

confidence: 99%

Review article: The role of anticonvulsant drugs in postoperative pain management: a bench-to-bedside perspective

Gilron

2006

Can J Anesth/J Can Anesth

View full text Add to dashboard Cite

Purpose: Anticonvulsant drugs are effective in the treatment of chronic neuropathic pain but were not, until recently, thought to be useful in more acute conditions such as postoperative pain. However, similar to nerve injury, surgical tissue injury is known to produce neuroplastic changes leading to spinal sensitization and the expression of stimulus-evoked hyperalgesia and allodynia. Pharmacological effects of anticonvulsant drugs which may be important in the modulation of these postoperative neural changes include suppression of sodium channel, calcium channel and glutamate receptor activity at peripheral, spinal and supraspinal sites. The purpose of this article is to review preclinical evidence and clinical trial data describing the efficacy and safety of anticonvulsant drugs in the setting of postoperative pain management. Source: A Medline search was performed to retrieve available literature on the basic and clinical pharmacology of anticonvulsant drugs as they pertain to postoperative pain management. Principal findings: Numerous laboratory studies have described analgesic effects of different anticonvulsant drugs in experimental pain models. Furthermore, several recent clinical trials have shown that anticonvulsants may reduce spontaneous and movement-evoked pain, as well as decrease opioid requirements postoperatively. Some early findings suggest further that anticonvulsant drugs may alleviate postoperative anxiety, accelerate postoperative functional recovery and reduce chronic postsurgical pain. Conclusion: Given the incomplete efficacy of currently available non-opioid analgesics, and the identified benefits of opioid sparing, anticonvulsant medications may be useful adjuncts for postoperative analgesia. Further research in this field is warranted. Objectif

show abstract

“…Intraperitoneal administration has also been shown to reverse capsaicin-induced mechanical hyperalgesia and provide significant analgesic effects in both early-and late-phase formalin-induced behaviors [74]. A clinical trial search yielded a trial on ethosuximide for the treatment of complex regional pain syndrome (CRPS), which was registered in May 2008 and is currently ongoing.…”

Section: T-type Channelsmentioning

confidence: 99%

Targeting voltage-gated calcium channels for the treatment of neuropathic pain: a review of drug development

Pexton

Moeller-Bertram

Schilling

et al. 2011

Expert Opinion on Investigational Drugs

View full text Add to dashboard Cite

There is real hope that new drugs targeting calcium channels will soon be available. This hope is based on advancing technologies for peptide synthesis, more efficient drug screening and orally available, use-dependent compounds. Some form of direct VGCC blockade or modulation will always have a place in the treatment of neuropathic pain, but given the complexity and neuroplasticity of pain transmission, polypharmacy will likely be required for many chronic pain sufferers for the foreseeable future.

show abstract

The antihyperalgesic effects of the T-type calcium channel blockers ethosuximide, trimethadione, and mibefradil

Cited by 60 publications

References 37 publications

Common Mechanisms of Drug Interactions with Sodium and T-Type Calcium Channels

Common Mechanisms of Drug Interactions with Sodium and T-Type Calcium Channels

Review article: The role of anticonvulsant drugs in postoperative pain management: a bench-to-bedside perspective

Targeting voltage-gated calcium channels for the treatment of neuropathic pain: a review of drug development

Contact Info

Product

Resources

About