All
tumor-promoting
phorbol esters induce
inflammation in mouse skin. The correlation between promoting and inflammatory activities is only partial, however, indicating that only some events in
inflammation may be closely coupled to the process of
tumor promotion.
Resiniferatoxin (RTX), an extremely inflammatory
phorbol-related
diterpene, acts as an ultrapotent analog of
capsaicin to stimulate and then to block the neurogenic inflammatory pathway. In CD-1 mice, we have used pretreatment with RTX to show that the
erythema and
edema responses to
phorbol and 12-deoxyphorbol
esters in significant part involve this neurogenic inflammatory pathway. We report here that mouse strains with differing sensitivities to
phorbol-ester-induced promotion displayed marked differences in the effect of pretreating with RTX on the
edema response following phorbol-12-myristate-13-acetate (PMA) application. In the highly promotion-sensitive SENCAR mouse, RTX pretreatment had little inhibitory effect; the
edema response to PMA was similar with or without RTX pretreatment 6 h before PMA application. On the other hand, in C57BL/6J mice, which are resistant to promotion by
phorbol esters under the usual protocols, the
edema response to PMA was totally eliminated by RTX pretreatment during the first 8 h after PMA administration. DBA/2J mice, which are similar to CD-1 mice in their susceptibility to PMA promotion, responded similarly to CD-1: the
edema response was blocked partially by RTX pretreatment during the early phase (up to 8 h) of
inflammation. Our results suggest that the RTX-resistant component of PMA-induced
edema may correlate better with the sensitivity to promoting action than does the overall inflammatory response.