Isolated desheathed rat sciatic nerves express capsaicin, heat and proton sensitivity and respond to stimulation with a Ca²⁺dependent graded iCGRP release. There is morphological evidence for TRPV1 expression and capsaicin-stimulated vesicular exocytosis of CGRP in the axolemma of unmyelinated nerve fibers. In sensory terminals, noxious heat-induced CGRP release is facilitated by activation of G-protein coupled receptors, which is a mechanism of inflammatory pain and hyperalgesia. Here we present evidence that also isolated mouse sciatic nerve axons are functionally equipped with GPCRs and related proteinkinase A and C transduction mechanisms. Prostaglandin E₂ and bradykinin as well as direct PKA and PKC activators sensitized the axonal heat response, although inhibition of the protein kinases did not induce a desensitization. PGE₂ and BK in combination showed a major sensitizing effect that was completely abolished in TRPV1 knockout mice, whereas the basal heat response was largely retained as in wildtypes. In this respect the isolated nerve appears as a better model of its nerve endings than cultured DRG neurons that show no retained heat responsiveness in TRPV1 knockouts.Acknowledgement: TRPV1 +/- mice were kindly supplied by Dr. John B. Davis (GSK, Harlow, UK).