title: Nociceptor-selective peripheral nerve block induces delayed mechanical hypersensitivity and neurotoxicity in rats.
abstract: BACKGROUND
  Long-lasting, sensory-specific peripheral nerve blockade would advance perioperative analgesia. Perineural injection of a combination of transient receptor potential vanilloid 1 channel agonists and lidocaine or its hydrophilic derivative, QX-314, produces prolonged sensory or nociceptor-selective nerve block in rodents. In this study, the authors tested the efficacy of these combinations in peripheral nerve block after incisional surgery in rats.
  
  
  METHODS
  The authors administered perisciatic lidocaine (2%), QX-314 (0.2%) followed by dilute capsaicin (0.05%, 10 min later), or vehicle in rats and the duration of motor and sensory block to thermal and mechanical stimuli assessed in normal animals and those after incisional surgery to the hind paw. Other animals receiving these injections were evaluated 7 weeks later by behavior and histology for potential neurotoxicity.
  
  
  RESULTS
  Perineural injection of the combination not only attenuated mechanical hypersensitivity for 72 h after incision but also resulted in delayed onset mechanical hypersensitivity several weeks later, accompanied by degeneration of central terminals of isolectin B4 (nonpeptidergic) and calcitonin gene-related peptide-containing (peptidergic) afferents in the ipsilateral spinal cord. Dorsal root ganglia ipsilateral to injection of the combination showed increased expression of activating transcription factor-3 and satellite cell activation.
  
  
  CONCLUSIONS
  Combined administration of local anesthetics with the transient receptor potential vanilloid 1 agonist capsaicin induced a near complete blockade of incision-induced hypersensitivity for several days. However, the same combination induced delayed mechanical hypersensitivity and neurotoxicity in naïve rats. Combination of these drugs in these concentrations is likely to result in neurotoxicity, and the safety of other concentrations warrants further study.
authors.affiliation: From the Department of Anesthesiology, Wake Forest University School of Medicine, Winston-Salem, North Carolina (C.M.P., T.T.H., and C.A.A.); Department of Anesthesiology-Pediatric Anesthesia, Wake Forest University School of Medicine, Winston-Salem, North Carolina (D.R.); and Department of Anesthesiology and Physiology and Pharmacology, Wake Forest University School of Medicine, Winston-Salem, North Carolina (J.C.E.).
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Peters
authors.forename: Douglas
authors.initials: D
authors.lastname: Ririe
authors.forename: Timothy T
authors.initials: TT
authors.lastname: Houle
authors.forename: Carol A
authors.initials: CA
authors.lastname: Aschenbrenner
authors.forename: James C
authors.initials: JC
authors.lastname: Eisenach
mesh_terms: D019162:Anesthetics, Combined / Q000009:adverse effects*; D000779:Anesthetics, Local / Q000008:administration & dosage; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002211:Capsaicin / Q000009:adverse effects*; D004195:Disease Models, Animal; D006930:Hyperalgesia / Q000188:drug therapy; D006968:Hypersensitivity, Delayed / Q000209:etiology*; D008012:Lidocaine / Q000009:adverse effects* / Q000031:analogs & derivatives*; D008297:Male; D009407:Nerve Block / Q000009:adverse effects* / Q000379:methods; D009412:Nerve Fibers / Q000187:drug effects; D009431:Neural Conduction / Q000187:drug effects; D020258:Neurotoxicity Syndromes / Q000209:etiology*; D009619:Nociceptors / Q000187:drug effects; D010149:Postoperative Pain / Q000188:drug therapy; D010812:Physical Stimulation / Q000379:methods; D051381:Rats; D017207:Rats, Sprague-Dawley; D018689:Sensory System Agents / Q000008:administration & dosage / Q000009:adverse effects; D050916:TRPV Cation Channels / Q000819:agonists
chemical_list: D019162:Anesthetics, Combined; D000779:Anesthetics, Local; D018689:Sensory System Agents; D050916:TRPV Cation Channels; C494484:TRPV1 receptor; C012647:QX-314; D008012:Lidocaine; D002211:Capsaicin