Involvement of the TTX-resistant sodium channel Nav 1.8 in inflammatory and neuropathic, but not post-operative, pain states.
Antisense (AS) oligodeoxynucleotides (ODNs) targeting the Nav 1.8 sodium channel have been reported to decrease inflammatory hyperalgesia and L5/L6 spinal nerve ligation-induced mechanical allodynia in rats. The present studies were conducted to further characterize Nav 1.8 AS antinociceptive profile in rats to better understand the role of Nav 1.8 in different pain states. Consistent with earlier reports, chronic intrathecal Nav 1.8 AS, but not mismatch (MM), ODN decreased TTX-resistant sodium current density (by 60.5+/-10.2% relative to MM; p<0.05) in neurons from L4 to L5 dorsal root ganglia and significantly attenuated mechanical allodynia following intraplantar complete Freund's adjuvant. In addition, 10 days following chronic constriction injury of the sciatic nerve, Nav 1.8 AS, but not MM, ODN also attenuated mechanical allodynia (54.3+/-8.2% effect, p<0.05 vs. MM) 2 days after initiation of ODN treatment. The anti-allodynic effects remained for the duration of the AS treatment, and CCI rats returned to an allodynic state 4 days after discontinuing AS. In contrast, Nav 1.8 AS ODN failed to reduce mechanical allodynia in the vincristine chemotherapy-induced neuropathic pain model or a skin-incision model of post-operative pain. Finally, Nav 1.8 AS, but not MM, ODN treatment produced a small but significant attenuation of acute noxious mechanical sensitivity in naïve animals (17.6+/-6.2% effect, p<0.05 vs. MM). These data demonstrate a greater involvement of Nav 1.8 in frank nerve injury and inflammatory pain as compared to acute, post-operative or chemotherapy-induced neuropathic pain states.
Abbott Laboratories, Neuroscience Research, Abbott Park, IL 60064, USA. shailen.joshi@abbott.com
S K
SK
Joshi
Joseph P
JP
Mikusa
Gricelda
G
Hernandez
Scott
S
Baker
Char-Chang
CC
Shieh
Torben
T
Neelands
Xu-Feng
XF
Zhang
Wende
W
Niforatos
Karen
K
Kage
Ping
P
Han
Douglas
D
Krafte
Connie
C
Faltynek
James P
JP
Sullivan
Michael F
MF
Jarvis
Prisca
P
Honore
D000818:Animals; D001522:Behavior, Animal; D004353:Drug Evaluation, Preclinical; D005620:Freund's Adjuvant / Q000633:toxicity; D006930:Hyperalgesia / Q000188:drug therapy / Q000209:etiology / Q000503:physiopathology*; D007249:Inflammation / Q000503:physiopathology*; D007278:Injections, Spinal; D017136:Ion Transport; D008026:Ligation; D008297:Male; D062559:NAV1.8 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D009437:Neuralgia / Q000139:chemically induced / Q000503:physiopathology*; D009475:Neurons, Afferent / Q000187:drug effects / Q000502:physiology; D020319:Oligodeoxyribonucleotides, Antisense / Q000494:pharmacology / Q000627:therapeutic use*; D010149:Postoperative Pain / Q000503:physiopathology*; D018408:Patch-Clamp Techniques; D011312:Pressure / Q000009:adverse effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D012584:Sciatic Nerve / Q000293:injuries; D012964:Sodium / Q000502:physiology; D015222:Sodium Channels / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D013127:Spinal Nerves / Q000293:injuries; D013314:Stress, Mechanical; D013779:Tetrodotoxin / Q000494:pharmacology; D014750:Vincristine / Q000633:toxicity*
D062559:NAV1.8 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; D020319:Oligodeoxyribonucleotides, Antisense; C568319:Scn10a protein, rat; D015222:Sodium Channels; D013779:Tetrodotoxin; D014750:Vincristine; D005620:Freund's Adjuvant; D012964:Sodium