Sustained sensitization and recruitment of rat cutaneous nociceptors by bradykinin and a novel theory of its excitatory action.

Excitation and sensitization to heat of nociceptors by bradykinin (BK) were examined using an isolated rat skin-saphenous nerve preparation. A total of 52 C-fibres was tested: 42 were mechano-heat sensitive (CMH) and 40% of them were excited and sensitized to heat by BK superfusion (10-5 M, 5 min) of their receptive fields; heat responses were augmented by more than five times and heat thresholds dropped to 36.4 degrees C, on average. Sixty per cent of the CMH did not respond to BK itself, but 3/4 of these units showed an increase in their heat responses by more than 100% following BK exposure. Ten high-threshold mechanosensitive C-fibres did not discharge upon BK application but following this five of them responded to heat in a well-graded manner. In all fibres, the sensitizing effect of BK was abolished within 9 min or less of wash-out, and it could be reproduced several times at equal magnitude, whereas the excitatory effect of BK regularly showed profound tachyphylaxis. Sustained superfusion (20 min) of BK induced a desensitizing excitatory response while superimposed heat responses showed constant degrees of sensitization. The large extent and high prevalence of BK-induced sensitization (almost 80% of all fibres tested) and de novo recruitment of heat sensitivity suggest a prominent role of BK not only in hyperalgesia but also in sustained inflammatory pain which may be driven by body or even lower local temperatures acting on sensitized nociceptors. Based on the latter assumption, a hypothesis is put forward that excludes a direct excitatory effect of BK on nociceptors, but assumes a temperature-controlled activation as a result of rapid and profound sensitization.