Exogenous NT-3 and NGF differentially modulate PACAP expression in adult sensory neurons, suggesting distinct roles in injury and inflammation

Expression of pituitary adenylate cyclase-activating polypeptide in sensory neurons varies with injury or inflammation. The neurotrophins NGF and NT-3 are profound regulators of neuronal peptidergic phenotype in intact and in jured sensory neurons. This study examined their potential for modulation o f PACAP expression in adult rat with intact and injured L4-L6 spinal nerves with or without immediate or delayed intrathecal infusion of NT-3 or NGF. Results indicate that in L5 DRG, few trkC neurons express high levels of PA CAP mRNA in the intact state, but many do following injury. The elevated ex pression in injured neurons is mitigated by NT-3 infusion, suggesting a rol e for NT-3 in returning the 'injured phenotype' back towards an 'Intact phe notype'. NGF dramatically up-regulated PACAP expression in trkA-positive ne urons in both intact and injured DRGs, implicating NGF as a positive regula tor of PACAP expression in nociceptive neurons. Surprisingly, NT-3 modulate s PACAP expression in an antagonistic fashion to NGF in intact neurons, an effect most evident in the trkA neurons not expressing trkC. Both NT-3 and NGF infusion results in decreased detection of PACAP protein in the region of the gracile nuclei, where central axons of the peripherally axotomized l arge sensory fibers terminate. NGF infusion also greatly increased the amou nt of PACAP protein detected in the portion of the dorsal horn innervated b y small-medium size DRG neurons, while both neurotrophins appear able to pr event the decrease in PACAP expression observed in these afferents with inj ury. These results provide the first insights into the potential molecules implicated in the complex regulation of PACAP expression in sensory neurons .