OPPOSING ACTIONS OF THE EGF FAMILY AND OPIOIDS - HEPARIN-BINDING EPIDERMAL GROWTH-FACTOR (HB-EGF) PROTECTS MOUSE CEREBELLAR NEUROBLASTS AGAINST THE ANTIPROLIFERATIVE EFFECT OF MORPHINE

Endogenous opioids and opiate drugs of abuse inhibit the proliferation of cerebellar external granular layer (EGL) neuroblasts by mechanisms that are incompletely understood. Opioids do not act alone, rather mu ltiple extracellular factors regulate granule cell neurogenesis and th ese undoubtedly act in concert with opioids to shape developmental out come. We examined whether, heparin binding-epidermal growth factor-lik e growth factor (HB-EGF), a recently described member of the epidermal growth factor (EGF) family, might compete with an inhibitory opioid s ignal. The results confirmed our ongoing studies that morphine inhibit ed neuroblast proliferation, while HB-EGF enhanced cell replication. H B-EGF not only counteracted the antiproliferative morphine signal, but invariably enhanced DNA synthesis irrespective of morphine treatment. Our findings suggest that regional and temporal differences in the av ailability of endogenous HB-EGF may serve to limit the response of EGL neuroblasts to opioids, and HB-EGF may be neuroprotective in opiate d rug abuse. If similar responses occur in vivo, then the EGF family and the opioid system may represent distinct and contrasting components o f an extracellular signaling system serving to coordinate EGL neurogen esis. (C) 1998 Elsevier Science B.V. All rights reserved.