ACTIVATION OF PROTEIN-KINASE-C AUGMENTS PEPTIDE RELEASE FROM RAT SENSORY NEURONS

To determine whether protein kinase C (PKC) mediates release of peptid es from sensory neurons, we examined; the effects of altering PKC acti vity on resting and evoked release of substance P (SP) and calcitonin gene-related peptide (CGRP). Exposing rat sensory neurons in culture t o 10 or 50 nM phorbol 12,13-dibutyrate (PDBu) significantly increased SP and CGRP release at least 10-fold above resting levels, whereas the inactive 4 alpha-PDBu analogue at 100 nM had no effect on release. Fu rthermore, 100 nM bradykinin increased peptide release approximately f ivefold. Down-regulation of PKC significantly attenuated the release o f peptides evoked by either PDBu or bradykinin. PDBu at 1 nM or 1-oleo yl-2-acetyl-sn-glycerol at 50 mu M did not alter resting release of pe ptides, but augmented potassium; and capsaicin-stimulated release of b oth SP and CGRP approximately twofold. This sensitizing action of PKC activators on peptide release was significantly reduced by PKC down-re gulation or by pretreating cultures with 10 nM staurosporine. These re sults establish that activation of PKC is important in the regulation of peptide release from sensory neurons. The PKC-induced enhancement o f peptide release may be a mechanism underlying the neuronal sensitiza tion that produces hyperalgesia.