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      Effects of Loperamide and Other Opioid-Related Substances on the Transcriptional Regulation of the Rat Pro-Opiomelanocortin Gene in AtT20 Cells

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          Although opioid peptides are involved in the regulation of the hypothalamic-pituitary-adrenal axis, their role in pro-opiomelanocortin (POMC) gene expression at the pituitary level is not known. We therefore examined the effects of opioid receptor agonists, including recently discovered endogenous opioid peptides, on POMC gene expression using the AtT20PL cell line, a subclone of AtT20 in which the rat POMC 5′-promoter-luciferase fusion gene was stably incorporated. The endogenous µ-opioid receptor agonists endomorphin 1 and 2 had no effect on either basal or corticotropin-stimulating-hormone-induced POMC expression. This was also the case with the δ-agonist BUBUC, the ĸ-agonist U50488H and the orphan receptor agonist orphanin FQ. In contrast, the synthetic µ-agonist loperamide significantly inhibited basal and yet enhanced cAMP-induced POMC expression. The inhibitory effect of loperamide was mimicked by the calmodulin antagonist W7 and antagonized by the calcium channel blocker nifedipine, whereas neither the inhibitory nor the enhancing effect of loperamide was influenced by the opioid antagonist naloxone. These results suggest that the synthetic µ-agonist loperamide has a modulatory effect on the 5′-promoter activity of the POMC gene. This effect does not seem to be mediated through the classical µ-opioid receptor but rather in part through a calcium/calmodulin-related mechanism.

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          Most cited references 5

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          Localization of orphanin FQ (nociceptin) peptide and messenger RNA in the central nervous system of the rat.

          Orphanin FQ (OFQ) is the endogenous agonist of the opioid receptor-like receptor (ORL-1). It and its precursor, prepro-OFQ, exhibit structural features suggestive of the opioid peptides. A cDNA encoding the OFQ precursor sequence in the rat recently has been cloned, and the authors recently generated a polyclonal antibody directed against the OFQ peptide. In the present study, the authors used in situ hybridization and immunohistochemistry to examine the distribution of OFQ peptide and mRNA in the central nervous system of the adult rat. OFQ immunoreactivity and prepro-OFQ mRNA expression correlated virtually in all brain areas studied. In the forebrain, OFQ peptide and mRNA were prominent in the neocortex endopiriform nucleus, claustrum, lateral septum, ventral forebrain, hypothalamus, mammillary bodies, central and medial nuclei of the amygdala, hippocampal formation, paratenial and reticular nuclei of the thalamus, medial habenula, and zona incerta. No OFQ was observed in the pineal or pituitary glands. In the brainstem, OFQ was prominent in the ventral tegmental area, substantia nigra, nucleus of the posterior commissure, central gray, nucleus of Darkschewitsch, peripeduncular nucleus, interpeduncular nucleus, tegmental nuclei, locus coeruleus, raphe complex, lateral parabrachial nucleus, inferior olivary complex, vestibular nuclear complex, prepositus hypoglossus, solitary nucleus, nucleus ambiguous, caudal spinal trigeminal nucleus, and reticular formation. In the spinal cord, OFQ was observed throughout the dorsal and ventral horns. The wide distribution of this peptide provides support for its role in a multitude of functions, including not only nociception but also motor and balance control, special sensory processing, and various autonomic and physiologic processes.
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            Differential distribution of endomorphin 1- and endomorphin 2-like immunoreactivities in the CNS of the rodent.

            Endomorphins are endogenous peptides that have high affinity and selectivity for the mu-opiate receptor and potent analgesic activity. The distributions of endomorphin 1 (Tyr-Pro-Trp-Phe-NH2; EM1) and endomorphin 2 (Tyr-Pro-Phe-Phe-NH2; EM2) in the rat central nervous system were determined by immunocytochemistry with two antisera, each demonstrating clear preference for the target antigen. Perikarya expressing EM2-like immunoreactivity were present in the posterior hypothalamus, whereas those expressing EM1-like immunoreactivity were present in both the posterior hypothalamus and the nucleus of the solitary tract (NTS). EM1-like immunoreactivity was more widely and densely distributed throughout the brain than was EM2-like immunoreactivity, whereas EM2-like immunoreactivity was more prevalent in the spinal cord than was EM1-like immunoreactivity. The greatest density of EM1-like-immunoreactive fibers was detected in the parabrachial nucleus and the NTS, with notable staining in the septum, diagonal band, bed nucleus of the stria terminalis, organum vasculosum, nucleus of Meynert, paraventricular thalamic nucleus, posterior hypothalamic nucleus, periaqueductal gray, locus coeruleus, nucleus accumbens, and amygdala. The greatest density of EM2-like-immunoreactive fibers was detected in the superficial laminae of the spinal cord dorsal horn and the nucleus of the spinal trigeminal tract. The overall pattern of immunoreactivities was similar in rat, mouse, and guinea pig, but some differences were observed. In many but not in all locations, immunoreactive fibers were prominently present in regions in which mu receptors are reported to be concentrated. The neuroanatomical results suggest that endomorphins participate in modulating nociceptive and autonomic nervous system processes and responsiveness to stress.
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              Anatomy of the CNS opioid systems


                Author and article information

                S. Karger AG
                August 2001
                27 July 2001
                : 74
                : 2
                : 87-94
                aFirst Department of Internal Medicine and bDepartment of Clinical Laboratory Medicine, Nagoya University School of Medicine and Hospital, Nagoya, Japan
                54674 Neuroendocrinology 2001;74:87–94
                © 2001 S. Karger AG, Basel

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                Page count
                Figures: 7, References: 23, Pages: 8
                Regulation of Anterior Pituitary Hormones


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