Dopamine secreted from hypophysial hypothalamic neurons is a principal inhibitory regulator of pituitary hormone secretion. Mice with a disrupted D2 dopamine receptor gene had chronic hyperprolactinemia and developed anterior lobe lactotroph hyperplasia without evidence of adenomatous transformation. Unexpectedly, the mutant mice had no hyperplasia of the intermediate lobe melanotrophs. Aged female D2 receptor -/- mice developed uterine adenomyosis in response to prolonged prolactin exposure. These data reveal a critical role of hypothalamic dopamine in controlling pituitary growth and support a multistep mechanism for the induction and perpetuation of lactotroph hyperplasia, involving the lack of dopamine signaling, a low androgen/estrogen ratio, and a final autocrine or paracrine "feed-forward" stimulation of mitogenesis, probably by prolactin itself.
Endogenous opioid peptides subserve a wide range of physiological adaptations to stress. Prominent among these functions are inhibition of reproduction (1), modulation of the hypothalamic-pituitary-adrenal (HPA) axis (2), and maintenance of homeostasis in response to autonomic challenge (3). Opioids, together with neurotransmitters in parallel nonopioid neural circuits, also mediate stress-induced analgesia (4). The existence of an intrinsic pain-inhibition system was first demonstrated by the induction of analgesia by electrical stimulation in periventricular, periaqueductal, and medial brainstem loci (5, 6). A possible opioid mechanism for central pain modulation was suggested by the ability of opioid antagonists to block (7) (19)(20)(21). Of the three classes of opioids, 3-endorphin is particularly noteworthy because of its high potency and a nearly one-to-one correspondence between sites supporting electrical stimulation-produced analgesia and high concentrations of endorphinergic fibers in the human brain (22).To further investigate the physiological roles of P-endorphin, we used a genetic approach of homologous recombination in embryonic stem cells to produce mice that are unable to synthesize 13-endorphin. Because 3-endorphin is posttranslationally processed from a larger multifunctional precursor, we introduced a point mutation into the proopiomelanocortin (POMC) gene that translates to a truncated prohormone lacking the entire C-terminal amino acid region encoding /3-endorphin.
Mammalian cell lines (BSC-40, NG108-15, and GH4C1) that cannot process the murine neuroendocrine peptide precursor prepro-opiomelanocortin (mPOMC) when its synthesis is directed by a vaccinia virus vector were coinfected with a second recombinant vaccinia virus carrying the yeast KEX2 gene, which encodes an endopeptidase that cleaves at pairs of basic amino acid residues. mPOMC was cleaved intracellularly to a set of product peptides normally found in vivo, including mature gamma-lipotropin and beta-endorphin1-31. In GH4C1 cells (a rat pituitary line), product peptides were incorporated into stored secretory granules. These results suggest that the inability of any particular cell line to process a prohormone precursor is due to the absence of a suitable endogenous processing enzyme.
The expression of opioid genes was examined in isolated populations of glial cells in primary culture. Northern blot analysis of purified type I astrocytes, oligodendrocytes and mixed oligodendrocyte‐type‐2‐astrocyte lineage cells derived from cerebral cortex demonstrated robust expression of proenkephalin mRNA exclusively in type I astrocytes. The expression of proenkephalin mRNA was stimulated by the beta‐adrenergic agonist isoproterenol, and 8‐(4‐chlorophenyl thio)adenosine 3′‐5′‐cyclic monophosphate (cpt‐cAMP). Both of these compounds regulated a proenkephalin‐chloramphenicol acetyltransferase fusion gene transiently transfected into type I astrocytes. HPLC and immunoassay of the cell culture media revealed significant levels of unprocessed proenkephalin secreted by the cell and this secretion was stimulated by isoproterenol and cpt‐cAMP. The relatively high levels of proenkephalin expressed suggest that enhanced expression in astrocytes may be important during neural development, in trauma‐induced gliosis and in neuroimmune interactions.
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