Reversal of neuropathic pain by alpha-hydroxyphenylamide: a novel sodium channel antagonist.
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.
Ko
Seong-Hoon
SH
Department of Anesthesiology, University of Virginia Health System, 1 Hospital Drive, Box 800710, Charlottesville, VA 22908-0710, USA.
Jochnowitz
Nina
N
Lenkowski
Paul W
PW
Batts
Timothy W
TW
Davis
Gary C
GC
Martin
William J
WJ
Brown
Milton L
ML
Patel
Manoj K
MK
D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000577:Amides / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D005727:Ganglia, Spinal / Q000187:drug effects / Q000502:physiology; D008297:Male; D010146:Pain / Q000188:drug therapy* / Q000503:physiopathology; D010672:Phenytoin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D020426:Sciatic Neuropathy / Q000188:drug therapy* / Q000503:physiopathology; D026941:Sodium Channel Blockers / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D015222:Sodium Channels / Q000502:physiology*
C119075:2-hydroxy-2-phenylnonanamide; D000577:Amides; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D010672:Phenytoin