Vasoactive intestinal polypeptide and neuropeptide Y act indirectly to increase neurite outgrowth of dissociated dorsal root ganglion cells.

Abstract

Recent studies suggest that rearrangement of synaptic circuitry of primary afferent neurons in the spinal cord may contribute, in part, to hyperalgesia that is often associated with peripheral nerve injury. This study of cultured adult rat dorsal root ganglion cells examined whether vasoactive intestinal polypeptide and neuropeptide Y, which are up-regulated in sensory neurons following nerve transection, possibly contribute to the morphological alterations induced by nerve injury. Neurite outgrowth of dissociated dorsal root ganglion cells was examined two weeks following either sciatic nerve transection or intrathecal administration of test agents via osmotic pumps. Dissociated cells taken from rats with transected sciatic nerve or following intrathecal administration of either vasoactive intestinal polypeptide or neuropeptide Y had a significant increase in the percentage of cells with neurites as compared to dorsal root ganglion cells taken from normal animals. Intrathecal administration, into rats with nerve lesion, of the vasoactive intestinal polypeptide and neuropeptide Y antagonists, vasoactive intestinal polypeptide(10-28) and alpha-trinositol, respectively, significantly attenuated the nerve injury-induced increase in neurite outgrowth. Vasoactive intestinal polypeptide and neuropeptide Y had no influence on neurite outgrowth when applied to normal dissociated dorsal root ganglion cells, however, when added to cells co-cultured with spinal cord explants, both peptides significantly increased the percentage of cells with neurites. K252a, a protein kinase inhibitor, attenuated the trophic action of neuropeptide Y, but not that of vasoactive intestinal polypeptide. The action of vasoactive intestinal polypeptide on neurite outgrowth was attenuated by the protein kinase A inhibitor, the Rp-isomer of adenosine-3',5'-cyclic monophosphorothioate. The results suggest that the peptides may contribute, indirectly, to the nerve injury-induced increase in neurite outgrowth of sensory neurons via separate spinally-derived neurotrophic factors and the study provides further insight into the possible mechanisms underlying hyperalgesia associated with nerve injury.