High opioid doses inhibit whereas low doses enhance neuritogenesis in PC12 cells.

Exposure to opiates affects brain development, cell growth as well as in vitro cell differentiation [33,34]. Perinatal treatment with morphine has been reported to impair neuronal plasticity after neonatal lesion with 5,7-dihydroxytryptamine (5,7-DHT) [8]. This study has investigated the use of mu, delta and kappa opioid receptor ligands to examine the selective receptor mediated inhibition of PC12 neurite formation. Morphine and D-Ala2,D-Leu5-enkephalin (DADLE) had a comparable inhibitory potency with a maximal effect at 1 mM concentration, while both naltrexone and naltrindole antagonized their effect at only 10 nM. D-Ala2-MePhe4,Gly-ol5-enkephalin (DAMGO) showed only a transient inhibitory effect. The administration of 10 nM guanosine 5'-O-(3-thiotriphosphate) (GTP-gamma-S) prevented morphine inhibition. It is suggested that opiate inhibition of neuritogenesis may be mediated by a receptor with delta-like characteristics coupled to G proteins. On the other hand, the activation of this receptor with morphine at a very low concentration (1 pM) actually enhanced nerve growth factor (NGF) neurite promoting activity.