ENDOGENOUS OPIOID SYSTEM IN DEVELOPING NORMAL AND JIMPY OLIGODENDROCYTES - MU-OPIOID AND KAPPA-OPIOID RECEPTORS MEDIATE DIFFERENTIAL MITOGENIC AND GROWTH-RESPONSES

The early development of both neurons and neuroglia may be modulated b y signaling through opioid mediated pathways. Neurons and astroglia no t only express specific types of opiate receptors, but also respond fu nctionally to opioids with altered rates of proliferation and growth. The present study was undertaken to determine if opioids also modulate development of the other major CNS macroglial cell, the oligodendrocy te (OL). Using well-characterized polyclonal antibodies specific for d elta-, kappa-, and mu-opiate receptors, OLs grown in vitro were shown to express mu-receptors at a very immature stage prior to expression o f kappa-receptors. This developmentally regulated sequence differs fro m the pattern of expression in neurons and astroglia. delta-receptors are apparently absent from cultured OLs. OLs also have physiologic res ponses to selective mu- and kappa-receptor agonists and antagonists. E xposure of relatively immature O-4+ OLs to the mu-receptor agonist PL0 17 [H-Tyr-Pro-Phe(N-Me)-D-Pro-NH2] resulted in a significant enhanceme nt in the rate of DNA synthesis. This effect, which was not observed i n more mature MBP+ OLs, was entirely blocked by the antagonist naloxon e. Although the kappa-receptor pathway appeared to be uninvolved in co ntrolling proliferation, the kappa-receptor antagonist nor-binaltorphi mine significantly increased the size of myelin-like membranes produce d by the cultured OLs. Interestingly, OLs derived from the jimpy mouse , a mutant characterized by an almost complete lack of CNS myelin and premature death of OLs, were found to be deficient in kappa-opiate rec eptors. Our findings clearly show that OLs not only express specific o piate receptors, but also respond to changes in their level of stimula tion in ways that could profoundly impact nervous system morphology an d function. If opiate receptors are expressed by OLs in vivo, their ph armacological manipulation might provide a novel pathway for modulatin g OL and myelin production both during development and in demyelinated conditions. (C) 1998 Wiley-Liss, Inc.