Study on the inflammatory mediators and intracellular signal transmission involved in the peripheral sensitization of nociceptors

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Hyperalgesia is commonly observed in the inflamed region. One mechanism of the hyperalgesia is considered to be sensitization of peripheral nociceptors. The aim of this project is to clarify this sensitizing mechanism by studying 1) release of inflammatory mediators into the lightly burned (55ﾟC or 66ﾟC for 30s) air pouch, 2) effects of inflammatory mediators, especially of histamine, on the polymodal receptor, a type of nociceptor. In addition, histamine receptor subtypes and intracellular signal transmission were studied. Following results were obtained : 1) Bradykinin content in the exudate of the burned rat air pouch measured by ELISA tended to increase at 20 min after burn, peaked at 40 min, and then decreased. 2) The heat response of polymodal receptors recorded from canine in vitro superiorspermatic nerve preparations was sensitized by histamine >= 10 muM concentration-dependently. This effects was mediated through H1 receptor. To clarify involvement of protein kinase C,which is known to be activated through H1 receptor, in the histamine-induced sensitization of the heat response, effects of phorbol 12,13-dibutyrate (PDBu), a phorbol ester, was studied. PDBu excited a part of polymodal receptors >= 100 nM,and sensitized their heat response >= 10 nM concentration dependently. This sensitizing effect was blocked by treatment of staurosporine, a protein kinase inhibitor. Thus, it is highly possible that activation of protein kinase C induces sensitization of the heat response. The bradykinin response was, however, suppressed by pretreating PDBu 0.1 muM,but facilitated by simultaneously applying PDBu with bradykinin. In addition, the bradykinin response was suppressed by staurosporine. These results suggest that protein kinase C activation is implicated in the bradykinin response, and there also exist a process which is desensitized by protein kinase C.