title: Repeated local administration of noradrenaline or saline inhibits thermal hyperalgesia in pain-sensitized human skin.
abstract: OBJECTIVE
  Noradrenaline increases thermal hyperalgesia in skin sensitized to heat by the topical application of capsaicin. The aim of this study was to determine whether desensitization to the hyperalgesic effects of noradrenaline would develop after repeated local administrations of noradrenaline in the skin of the forearm.
  
  
  METHODS
  Noradrenaline and saline were administered to the forearm by iontophoresis (200 microA, 2 min, over a surface area of 3.1 cm(2)) two times per day for 4-10 days in 19 healthy subjects. The adequacy of the desensitization procedure was evaluated by measuring noradrenaline-induced vasoconstriction with laser Doppler fluxmetry. Thresholds and pain ratings to heat were then investigated at treated and control sites before and after the topical application of capsaicin, and after the iontophoresis of noradrenaline.
  
  
  RESULTS
  At previously untreated sites blood flow was 49 +/- 14% (+/- 95% confidence intervals) lower than flow at reference sites after the iontophoresis of noradrenaline. Vascular signs of adrenergic desensitization developed after 4-5 days of repeated local administration of noradrenaline in the majority of subjects. In those whose vessels constricted after the acute administration of noradrenaline, the adrenergic response averaged 23 +/- 15% at the desensitized site compared with 61 +/- 9% at previously untreated sites (P < 0.001). However, similar signs developed after repeated iontophoreses of saline (adrenergic response 7 +/- 16% compared with 58 +/- 15% at previously untreated sites, P < 0.001). Both the noradrenaline and saline treatments inhibited thermal hyperalgesia after the topical application of capsaicin. Heat-pain thresholds averaged 43.2 +/- 2.5 degrees C and 43.0 +/- 2.3 degrees C at the noradrenaline and saline pretreated sites compared with 41.4 +/- 2.7 degrees C at the control site (P < 0.05 and P < 0.06, respectively). On a 0-10 scale, heat-pain ratings to a 7 s, 45 degrees C stimulus averaged 3.8 +/- 1.6 and 3.5 +/- 1.7 at the noradrenaline and saline pretreated sites compared with 5.3 +/- 1.6 at the control site (P < 0.05). After the iontophoresis of noradrenaline heat-pain ratings increased 1.6 +/- 1.4 at the site pretreated with saline (P < 0.05) compared with only 0.4 +/- 1.0 at the site pretreated with noradrenaline (not significant), consistent with local adrenergic desensitization.
  
  
  CONCLUSIONS
  We conclude that repeated iontophoreses of noradrenaline or saline inhibit vasoconstriction to noradrenaline, and also inhibit increases in thermal hyperalgesia evoked by capsaicin. The release of endogenous stores of noradrenaline by iontophoretic currents might contribute to these effects.
authors.affiliation: School of Psychology, Murdoch University, Western Australia. drummond@central.murdoch.edu.au
authors.forename: P D
authors.initials: PD
authors.lastname: Drummond
authors.forename: D M
authors.initials: DM
authors.lastname: Lipnicki
mesh_terms: D000279:Administration, Cutaneous; D000293:Adolescent; D000328:Adult; D002211:Capsaicin / Q000494:pharmacology; D005260:Female; D006801:Humans; D006930:Hyperalgesia / Q000517:prevention & control*; D008297:Male; D009638:Norepinephrine / Q000494:pharmacology*; D010146:Pain / Q000517:prevention & control; D010147:Pain Measurement; D017288:Pain Threshold / Q000187:drug effects; D012039:Regional Blood Flow / Q000187:drug effects; D012867:Skin / Q000098:blood supply / Q000187:drug effects* / Q000503:physiopathology; D012965:Sodium Chloride / Q000494:pharmacology*; D014662:Vasoconstrictor Agents / Q000494:pharmacology*
chemical_list: D014662:Vasoconstrictor Agents; D012965:Sodium Chloride; D002211:Capsaicin; D009638:Norepinephrine