Endogenous opioid system in developing normal and jimpy oligodendrocytes: μ and κ opioid receptors mediate differential mitogenic and growth responses

Abstract

The early development of both neurons and neuroglia may be modulated by signaling through opioid mediated pathways. Neurons and astroglia not only express specific types of opiate receptors, but also respond functionally 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 oligodendrocyte (OL). Using well-characterized polyclonal antibodies specific for δ-, κ-, and μ-opiate receptors, OLs grown in vitro were shown to express μ-receptors at a very immature stage prior to expression of κ-receptors. This developmentally regulated sequence differs from the pattern of expression in neurons and astroglia. δ-receptors are apparently absent from cultured OLs. OLs also have physiologic responses to selective μ-and κ-receptor agonists and antagonists. Exposure of relatively immature O4+ OLs to the μ-receptor agonist PL017 [H-Tyr-Pro-Phe(N-Me)-D-Pro-NH2] resulted in a significant enhancement in the rate of DNA synthesis. This effect, which was not observed in more mature MBP+ OLs, was entirely blocked by the antagonist naloxone. Although the κ-receptor pathway appeared to be uninvolved in controlling proliferation, the κ-receptor antagonist nor-binaltorphimine significantly increased the size of myelin-like membranes produced 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 κ-opiate receptors. Our findings clearly show that OLs not only express specific opiate receptors, but also respond to changes in their level of stimulation in ways that could profoundly impact nervous system morphology and function. If opiate receptors are expressed by OLs in vivo, their pharmacological manipulation might provide a novel pathway for modulating OL and myelin production both during development and in demyelinated conditions.