A peripherally acting, selective T-type calcium channel blocker, ABT-639, effectively reduces nociceptive and neuropathic pain in rats
| Autor: | Zhiren Xia, Wende Niforatos, Qingwei Zhang, Steve McGaraughty, Katharine L. Chu, Jun Xu, Ivan Milicic, Shailen K. Joshi, Victoria E. Scott, Michael F. Jarvis |
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| Rok vydání: | 2014 |
| Předmět: |
Male
Low protein Biological Availability T-type Calcium Channel Blocker ABT-639 Nerve Tissue Proteins Pharmacology Heterocyclic Compounds 2-Ring Biochemistry Nociceptive Pain Rats Sprague-Dawley Calcium Channels T-Type Dorsal root ganglion medicine Animals Humans Channel blocker Peripheral Nerves Cells Cultured Sulfonamides Psychomotor function Behavior Animal Dose-Response Relationship Drug business.industry Chronic pain Calcium Channel Blockers medicine.disease Recombinant Proteins Rats Disease Models Animal medicine.anatomical_structure Blood-Brain Barrier Anesthesia Neuropathic pain Hyperalgesia Neuralgia Chronic Pain medicine.symptom business |
| Zdroj: | Biochemical Pharmacology. 89:536-544 |
| ISSN: | 0006-2952 |
| DOI: | 10.1016/j.bcp.2014.03.015 |
| Popis: | Activation of T-type Ca²⁺ channels contributes to nociceptive signaling by facilitating action potential bursting and modulation of membrane potentials during periods of neuronal hyperexcitability. The role of T-type Ca²⁺ channels in chronic pain is supported by gene knockdown studies showing that decreased Ca(v)3.2 channel expression results in the loss of low voltage-activated (LVA) currents in dorsal root ganglion (DRG) neurons and attenuation of neuropathic pain in the chronic constriction injury (CCI) model. ABT-639 is a novel, peripherally acting, selective T-type Ca²⁺ channel blocker. ABT-639 blocks recombinant human T-type (Ca(v)3.2) Ca²⁺ channels in a voltage-dependent fashion (IC₅₀ = 2 μM) and attenuates LVA currents in rat DRG neurons (IC₅₀ = 8 μM). ABT-639 was significantly less active at other Ca²⁺ channels (e.g. Ca(v)1.2 and Ca(v)2.2) (IC₅₀ > 30 μM). ABT-639 has high oral bioavailability (%F = 73), low protein binding (88.9%) and a low brain:plasma ratio (0.05:1) in rodents. Following oral administration ABT-639 produced dose-dependent antinociception in a rat model of knee joint pain (ED₅₀ = 2 mg/kg, p.o.). ABT-639 (10-100 mg/kg, p.o.) also increased tactile allodynia thresholds in multiple models of neuropathic pain (e.g. spinal nerve ligation, CCI, and vincristine-induced). [corrected]. ABT-639 did not attenuate hyperalgesia in inflammatory pain models induced by complete Freund's adjuvant or carrageenan. At higher doses (e.g. 100-300 mg/kg) ABT-639 did not significantly alter hemodynamic or psychomotor function. The antinociceptive profile of ABT-639 provides novel insights into the role of peripheral T-type (Ca(v)3.2) channels in chronic pain states. |
| Databáze: | OpenAIRE |
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