Sensitization to heat through G-protein-coupled receptor pathways in the isolated sciatic mouse nerve.
We have previously shown that isolated rat sciatic nerve axons express capsaicin, heat and proton sensitivity and respond to stimulation with a Ca(++)-dependent and graded calcitonin gene related peptide (CGRP) release. There is morphological evidence for stimulated vesicular exocytosis and for capsaicin receptor, transient receptor potential vanilloid type-1 (TRPV1, formerly VR1) translocation in the axolemma of unmyelinated nerve fibres. In sensory nerve terminals CGRP release in response to noxious heat can be sensitized by activation of G-protein-coupled receptors and related protein kinases. We present evidence that also in isolated mouse sciatic nerve axons the intracellular protein kinase A (PKA)- and C (PKC)-dependent transduction pathways modulate heat-induced (45 degrees C) CGRP release. This is demonstrated using the direct activators, forskolin and phorbol 12-myristate 13-acetate (PMA), as well as prostaglandin E2 (PGE(2)) and bradykinin acting through G-protein-coupled receptors. Inhibition at rest of protein kinases A or C left heat-induced CGRP release unchanged. In TRPV1 knockout animals no sensitization to heat was observed using a combined stimulation by prostaglandin E2 and bradykinin. To a surprising degree, peripheral nerve axons resemble peripheral sensory terminals in their common properties of sensory and signal transduction.
Fischer
Michael J M
MJ
Institut für Physiologie und Pathophysiologie, Universität Erlangen/Nürnberg, D-91054 Erlangen, Germany. fischer@physiologie1.uni-erlangen.de
Reeh
Peter W
PW
D000818:Animals; D001920:Bradykinin / Q000494:pharmacology; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism; D005576:Colforsin / Q000494:pharmacology; D015232:Dinoprostone / Q000494:pharmacology; D006358:Hot Temperature; D066298:In Vitro Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010120:Oxytocics / Q000494:pharmacology; D043562:Receptors, G-Protein-Coupled / Q000502:physiology*; D012584:Sciatic Nerve / Q000187:drug effects / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D050916:TRPV Cation Channels / Q000172:deficiency; D013755:Tetradecanoylphorbol Acetate / Q000031:analogs & derivatives / Q000494:pharmacology
D010120:Oxytocics; D043562:Receptors, G-Protein-Coupled; D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse; D005576:Colforsin; C020922:4-O-methyl-12-O-tetradecanoylphorbol 13-acetate; D015740:Calcitonin Gene-Related Peptide; D015232:Dinoprostone; D013755:Tetradecanoylphorbol Acetate; D001920:Bradykinin