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

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

  • Biochem Pharmacol. 2014 Jun 15;89(4):536-44. doi: 10.1016/j.bcp.2014.03.015.
Michael F Jarvis 1 Victoria E Scott 2 Steve McGaraughty 2 Katharine L Chu 2 Jun Xu 2 Wende Niforatos 2 Ivan Milicic 2 Shailen Joshi 2 Qingwei Zhang 2 Zhiren Xia 2
Affiliations

Affiliations

  • 1 Neuroscience Research, AbbVie, R4M4, AP4A-3, 1 North Waukegan Rd., North Chicago, IL 60064, USA. Electronic address: [email protected].
  • 2 Neuroscience Research, AbbVie, R4M4, AP4A-3, 1 North Waukegan Rd., North Chicago, IL 60064, USA.
Abstract

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.

Keywords

Dorsal root ganglion; Neuropathic pain; Nociceptive pain; T-type Ca(2+) channels.

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