title: Effects of bupivacaine and tetrodotoxin on carrageenan-induced hind paw inflammation in rats (Part 1): hyperalgesia, edema, and systemic cytokines.
abstract: BACKGROUND
  Local anesthetics exert antiinflammatory actions. To elucidate potential mechanisms, the authors examined effects of bupivacaine or tetrodotoxin, administered to rats by ipsilateral or contralateral sciatic blockade or systemically, on carrageenan-induced hind paw hyperalgesia, edema, and stimulated cytokine production in circulating blood cells.
  
  
  METHODS
  Twelve groups of rats (n = 9-12) received injections in three sites: (1) right or left hind paw (carrageenan or saline), (2) left sciatic block, and (3) systemically (subcutaneously in the upper back). Sciatic and systemic injections were performed with epinephrine plus bupivacaine, tetrodotoxin, or saline; injections were repeated 6 h later. Fifteen hours later, hyperalgesia and/or sensory and motor block were assessed behaviorally, and paw edema was quantified by magnetic resonance imaging. Stimulated production of tumor necrosis factor alpha, interleukin 10, and interleukin 1beta in whole blood cultures was measured by enzyme-linked immunosorbent assay.
  
  
  RESULTS
  Either ipsilateral or contralateral sciatic blocks using either bupivacaine or tetrodotoxin reduced carrageenan-induced edema and hyperalgesia. Systemic bupivacaine and tetrodotoxin were ineffective in preventing edema and hyperalgesia. Bupivacaine was effective in suppressing systemic tumor necrosis factor alpha and interleukin 1beta by all three routes, whereas tetrodotoxin was ineffective by all three routes.
  
  
  CONCLUSIONS
  Bupivacaine and tetrodotoxin, via a contralateral or ipsilateral sciatic block, attenuate local inflammatory edema and hyperalgesia induced by hind paw injection of carrageenan in rats. Mechanisms underlying contralateral effects of sciatic blockade remain unexplained. Bupivacaine inhibits carrageenan-evoked systemic cytokine production by a mechanism not shared by tetrodotoxin; this action may involve tetrodotoxin-resistant sodium channels or a variety of non-sodium-channel targets.
authors.affiliation: Department of Anesthesiology, Perioperative and Pain Medicine, Children's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Hélène
authors.initials: H
authors.lastname: Beloeil
authors.forename: Zaid
authors.initials: Z
authors.lastname: Ababneh
authors.forename: Richard
authors.initials: R
authors.lastname: Chung
authors.forename: David
authors.initials: D
authors.lastname: Zurakowski
authors.forename: Robert V
authors.initials: RV
authors.lastname: Mulkern
authors.forename: Charles B
authors.initials: CB
authors.lastname: Berde
mesh_terms: D000818:Animals; D002045:Bupivacaine / Q000008:administration & dosage*; D002351:Carrageenan / Q000633:toxicity*; D004359:Drug Therapy, Combination; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D006614:Hindlimb / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D013779:Tetrodotoxin / Q000008:administration & dosage*
chemical_list: D013779:Tetrodotoxin; D002351:Carrageenan; D002045:Bupivacaine