Abstract
Several agents that are preferential T-type calcium (T-channel) blockers have shown promise as being effective in alleviating acute and chronic pain, suggesting an urgent need to identify even more selective and potent T-channel antagonists. We used small, acutely dissociated dorsal root ganglion (DRG) cells of adult rats to study the in vitro effects of 3,5-dichloro-N-[1-(2,2-dimethyl-tetrahydro-pyran-4-ylmethyl)-4-fluoro-piperidin-4-ylmethyl]-benzamide (TTA-P2), a derivative of 4-aminomethyl-4-fluoropiperdine, on T currents, as well as other currents known to modulate pain transmission. We found that TTA-P2 potently and reversibly blocked DRG T currents with an IC50 of 100 nM and stabilized channel in the inactive state, whereas high-voltage-activated calcium and sodium currents were 100- to 1000-fold less sensitive to channel blocking effects. In in vivo studies, we found that intraperitoneal injections of 5 or 7.5 mg/kg TTA-P2 reduced pain responses in mice in phases 1 and 2 of the formalin test. Furthermore, TTA-P2, at 10 mg/kg i.p., selectively and completely reversed thermal hyperalgesia in diabetic rats treated with streptozocin but had no effect on the nociceptive response of healthy animals. The antihyperalgesic effects of TTA-P2 in diabetic rats were completely abolished by administration of oligonucleotide antisense for CaV3.2 isoform of T channels. Thus, TTA-P2 is not only the most potent and selective blocker of T channels in sensory neurons yet described, but it also demonstrates the potential for the pharmacological effectiveness of this approach in addressing altered nociceptive responses in animal models of both inflammatory and neuropathic pain.
Footnotes
This work was supported by The National Institutes of Health National Institute on Drug Abuse [Grant R21-DA029342]; the Harold Carron Endowment Fund; the American Diabetes Association [Basic Research Grant 7-09-BS-190]; the Department of Anesthesiology at the University of Virginia, InJe University; and a gift from Joseph C. Palumbo and Sandra C. Palumbo.
Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.
doi:10.1124/mol.111.073205.
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ABBREVIATIONS:
- HVA
- high-voltage-activated
- DRG
- dorsal root ganglion
- HEK
- human embryonic kidney
- PWL
- paw withdrawal latency
- STZ
- streptozocin
- TTX
- tetrodotoxin
- TTA-P2
- 3,5-dichloro-N-[1-(2,2-dimethyl-tetrahydro-pyran-4-ylmethyl)-4-fluoro-piperidin-4-ylmethyl]-benzamide)
- ECN
- [(3β, 5α, 17β)-17-hydroxyestrane-3-carbonitrile]
- CNS
- central nervous system
- P1
- phase 1
- P2
- phase 2
- AS
- antisense-CaV3.2
- MIS
- Mismatch-CaV3.2
- I-V
- current-voltage.
- Received April 21, 2011.
- Accepted August 5, 2011.
- Copyright © 2011 The American Society for Pharmacology and Experimental Therapeutics
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