Pharmacological and histopathological characterization of a hyperalgesia model induced by freeze lesion.
Induction of a freeze lesion in human skin is an experimental model of hyperalgesia that allows assessing the antihyperalgesic effects of traditional non-steroidal anti-inflammatory drugs (NSAIDs). We have investigated whether this model is also sensitive to selective cyclooxygenase (COX)-2 inhibitors and have characterized morphological substrates of the generated hyperalgesia in the skin. In eight healthy subjects, a freeze lesion was induced and mechanical pain thresholds (MPT) were tested for 5h following administration of the non-selective COX inhibitor diclofenac (75mg), the COX-2-selective inhibitor parecoxib (40mg) or placebo in a randomized, double-blind cross-over study. In five additional healthy subjects, biopsies were taken from normal skin and the area of freezing injury. Induction of the freeze lesion resulted in hyperalgesia expressed by a decrease of MPT after 24h. Diclofenac and parecoxib, but not placebo, statistically significantly elevated MPT. Histochemical and Western blot analyses of skin biopsies revealed a strong upregulation of COX-2, a slight decrease of COX-1 and activation of nuclear factor kappa B (NF-kappaB) in the area of the freezing injury. These findings indicate that the freeze lesion model is sensitive to NSAIDs including selective COX-2 inhibitors, and that NF-kappaB-dependent COX-2 upregulation contributes to the hyperalgesia in this model.
Schmidtko
Achim
A
pharmazentrum frankfurt/ZAFES, Institute of Clinical Pharmacology, Johann Wolfgang Goethe-University, Theodor Stern Kai 7, D-60590, Frankfurt/Main, Germany Department of Dermatology/ZAFES, Johann Wolfgang Goethe-University, Theodor Stern Kai 7, D-60590, Frankfurt/Main, Germany.
Burian
Maria
M
Altis
Kosta
K
Hardt
Katja
K
Angioni
Carlo
C
Schmidt
Ronald
R
Podda
Maurizio
M
Geisslinger
Gerd
G
D000328:Adult; D018592:Cross-Over Studies; D052246:Cyclooxygenase 2 Inhibitors / Q000008:administration & dosage*; D004311:Double-Blind Method; D005260:Female; D005615:Freezing; D006801:Humans; D006930:Hyperalgesia / Q000188:drug therapy / Q000209:etiology / Q000473:pathology* / Q000503:physiopathology*; D008297:Male; D015990:Placebo Effect; D012867:Skin / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology*
D052246:Cyclooxygenase 2 Inhibitors