A peripherally acting, selective T-type calcium channel blocker, ABT-639, effectively reduces nociceptive and neuropathic pain in rats

作者：Jarvis Michael F^*; Scott Victoria E; McGaraughty Steve; Chu Katharine L; Xu Jun; Niforatos Wende; Milicic Ivan; Joshi Shailen; Zhang Qingwei; Xia Zhiren

来源：Biochemical Pharmacology, 2014, 89(4): 536-544.

DOI：10.1016/j.bcp.2014.03.015

• T-type Ca2+ channels
• Dorsal root ganglion
• Neuropathic pain
• Nociceptive pain

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 (Cav3.2) Ca2+ channels in a voltage-dependent fashion (IC50 =2 mu M) and attenuates LVA currents in rat DRG neurons (IC50 = 8 mu M). ABT-639 was significantly less active at other Ca2+ channels (e.g. Ca(v)1.2 and Cav2.2) (IC50 > 30 mu M). 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, and capsaicin secondary hypersensitivity). 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.

• 出版日期2014-6-15