title: Paradoxical enhancement of bupivacaine anesthesia in mice by drugs that open sodium channels.
abstract: Sodium channel drugs were used to modulate the anesthetic effects of bupivacaine in mice. Anesthesia was measured following perisciatic injection of bupivacaine with vehicle or neurotoxin in the popliteal region. The site 1 Na(+) channel blocker tetrodotoxin alone was inactive, but increased the anesthetic effects of bupivacaine. We hypothesized that the site 2 and site 3 Na(+) channel openers veratridine and anemone toxin II (ATXII), respectively, would antagonize bupivacaine. Paradoxically, both drugs enhanced bupivacaine. In bupivacaine-treated mice, a significant correlation was observed between limb weakness scores and paw withdrawal latencies. The correlation coefficients were higher when tetrodotoxin, veratridine, or ATXII was coadministered with bupivacaine. In conclusion, veratridine and ATXII may have increased the stimulus-dependent binding of bupivacaine to Na(+) channels, thereby increasing the anesthetic effects of bupivacaine.
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University School of Medicine, Richmond, Va 23298-0613, USA. flsmith@hsc.vcu.edu
authors.forename: Forrest L
authors.initials: FL
authors.lastname: Smith
authors.forename: Raymond J
authors.initials: RJ
authors.lastname: Lindsay
mesh_terms: D000277:Adjuvants, Pharmaceutic / Q000494:pharmacology; D000779:Anesthetics, Local / Q000494:pharmacology*; D000818:Animals; D002045:Bupivacaine / Q000494:pharmacology*; D003064:Cnidarian Venoms / Q000494:pharmacology; D004357:Drug Synergism; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D010147:Pain Measurement / Q000187:drug effects; D026941:Sodium Channel Blockers / Q000494:pharmacology*; D015222:Sodium Channels / Q000502:physiology*; D013779:Tetrodotoxin / Q000494:pharmacology; D014701:Veratridine / Q000494:pharmacology
chemical_list: D000277:Adjuvants, Pharmaceutic; D000779:Anesthetics, Local; D003064:Cnidarian Venoms; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D013779:Tetrodotoxin; C028800:toxin II (Anemonia sulcata); D014701:Veratridine; D002045:Bupivacaine