title: The differential effect of intrathecal Nav1.8 blockers on the induction and maintenance of capsaicin- and peripheral ischemia-induced mechanical allodynia and thermal hyperalgesia.
abstract: BACKGROUND
  It has been reported that the selective blockade of Nav1.8 sodium channels could be a possible target for the development of analgesics without unwanted side effects. However, the precise role of spinal Nav1.8 in the induction and maintenance of persistent pain, e.g., mechanical allodynia (MA) and thermal hyperalgesia (TH), is not clear. We designed this study to investigate whether spinal Nav1.8 contributes to capsaicin-induced and peripheral ischemia-induced MA and TH.
  
  
  METHODS
  The Nav1.8 blockers, A-803467 or ambroxol, were injected intrathecally either before or after intraplantar capsaicin injection. To evaluate capsaicin-induced neuronal activation in the spinal cord, we quantified the number of Fos-immunoreactive cells in the dorsal horn. In the thrombus-induced ischemic pain model, we determined the differential effect of A-803467 on the induction phase or maintenance phase of MA.
  
  
  RESULTS
  Intrathecal injection of A-803467 (10, 30, 100 nmol) or ambroxol (241, 724, 2410 nmol) before intraplantar injection of capsaicin dose dependently prevented the induction of both MA and TH. However, posttreatment with A-803467 (100 nmol) and ambroxol (2410 nmol) did not reduce the MA that had already developed, but did significantly suppress capsaicin-induced TH. Moreover, the capsaicin-induced increase of spinal Fos-immunoreactive cells was significantly diminished by pretreatment, but not posttreatment with Nav1.8 blockers. In thrombus-induced ischemic pain rats, repetitive treatments of A-803467 during the induction period also prevented the development of MA, whereas A-803467 treatments during the maintenance period were ineffective in preventing or reducing MA.
  
  
  CONCLUSIONS
  These results demonstrate that spinal activation of Nav1.8 mediates the early induction of MA, but not the maintenance of MA. However, both the induction and maintenance of TH are modulated by the intrathecal injection of Nav1.8 blockers. These findings suggest that early treatment with a Nav1.8 blocker can be an important factor in the clinical management of chronic MA associated with inflammatory and ischemic pain.
authors: Department of Veterinary Physiology, College of Veterinary Medicine and Research Institute for Veterinary Science, Seoul National University, South Korea.
authors: Ji-Young
authors: JY
authors: Moon
authors: Sunok
authors: S
authors: Song
authors: Seo-Yeon
authors: SY
authors: Yoon
authors: Dae-Hyun
authors: DH
authors: Roh
authors: Suk-Yun
authors: SY
authors: Kang
authors: Ji-Ho
authors: JH
authors: Park
authors: Alvin J
authors: AJ
authors: Beitz
authors: Jang-Hern
authors: JH
authors: Lee
mesh_terms: D000551:Ambroxol / Q000008:administration & dosage*; D000814:Aniline Compounds / Q000008:administration & dosage*; D000818:Animals; D002211:Capsaicin; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005663:Furans / Q000008:administration & dosage*; D006358:Hot Temperature; D006930:Hyperalgesia / Q000139:chemically induced / Q000209:etiology* / Q000378:metabolism / Q000503:physiopathology; D007278:Injections, Spinal; D007511:Ischemia / Q000150:complications* / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D062559:NAV1.8 Voltage-Gated Sodium Channel; D010146:Pain / Q000139:chemically induced / Q000209:etiology* / Q000378:metabolism / Q000503:physiopathology; D010147:Pain Measurement; D017288:Pain Threshold / Q000187:drug effects; D010812:Physical Stimulation; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D026941:Sodium Channel Blockers / Q000008:administration & dosage*; D015222:Sodium Channels / Q000187:drug effects* / Q000378:metabolism; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism; D013997:Time Factors
chemical_list: C520740:A 803467; D000814:Aniline Compounds; D005663:Furans; D062559:NAV1.8 Voltage-Gated Sodium Channel; D016760:Proto-Oncogene Proteins c-fos; C568319:Scn10a protein, rat; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D000551:Ambroxol; D002211:Capsaicin