Reversal of neuropathic pain by alpha-hydroxyphenylamide: a novel sodium channel antagonist
| Autor: | Paul W. Lenkowski, Nina Jochnowitz, Milton L. Brown, William J. Martin, Seong-Hoon Ko, Gary C. Davis, Manoj K. Patel, Timothy W. Batts |
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| Rok vydání: | 2005 |
| Předmět: |
Phenytoin
Male Sodium chemistry.chemical_element Action Potentials Pain Pharmacology Sodium Channels Rats Sprague-Dawley Cellular and Molecular Neuroscience Sodium channel blocker Ganglia Spinal medicine Animals heterocyclic compounds Channel blocker Dose-Response Relationship Drug Sodium channel Antagonist Amides Rats chemistry Anesthesia Neuropathic pain Hyperalgesia medicine.symptom Sciatic Neuropathy medicine.drug Sodium Channel Blockers |
| Zdroj: | Neuropharmacology. 50(7) |
| ISSN: | 0028-3908 |
| Popis: | Sodium (Na) channel blockers are known to possess antihyperalgesic properties. We have designed and synthesized a novel Na channel antagonist, alpha-hydroxyphenylamide, and determined its ability to inhibit both TTX-sensitive (TTX-s) and TTX-resistant (TTX-r) Na currents from small dorsal root ganglion (DRG) neurons. alpha-Hydroxyphenylamide tonically inhibited both TTX-s and TTX-r Na currents yielding an IC(50) of 8.2+/-2.2 microM (n=7) and 28.9+/-1.8 microM (n=8), respectively. In comparison, phenytoin was less potent inhibiting TTX-s and TTX-r currents by 26.2+/-4.0% (n=8) and 25.5+/-2.0%, respectively, at 100 microM. alpha-Hydroxyphenylamide (10 microM) also shifted equilibrium gating parameters of TTX-s Na channels to greater hyperpolarized potentials, slowed recovery from inactivation, accelerated the development of inactivation and exhibited use-dependent block. In the chronic constriction injury (CCI) rat model of neuropathic pain, intraperitoneal administration of alpha-hydroxyphenylamide attenuated the hyperalgesia by 53% at 100mg/kg, without affecting motor coordination in the Rotorod test. By contrast, the reduction in pain behavior produced by phenytoin (73%; 100mg/kg) was associated with significant motor impairment. In summary, we report that alpha-hydroxyphenylamide, a sodium channel antagonist, exhibits antihyperalgesic properties in a rat model of neuropathic pain, with favorable sedative and ataxic side effects compared with phenytoin. |
| Databáze: | OpenAIRE |
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