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  • 1.
    Kononenko, Olga
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Key State Laboratory, Bogomoletz Institute of Physiology, Kiev, Ukraine.
    Galatenko, Vladimir
    Moscow State University.
    Andersson, Malin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Bazov, Igor
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Watanabe, Hiroyuki
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Zhou, Xingwu
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Iatsyshyna, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Department of Human Genetics, Institute of Molecular Biology and Genetics, Kiev, Ukraine.
    Mityakina, Irina
    Moscow State University.
    Yakovleva, Tatiana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Sarkisyan, Daniil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Ponomarev, Igor
    University of Texas.
    Krishtal, Oleg
    Bogomoletz Institute of Physiology, Kiev..
    Marklund, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Tonevitsky, Alex
    Moscow State University.
    Adkins, DeAnna L.
    Medical University of South Carolina.
    Bakalkin, Georgy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Intra- and interregional coregulation of opioid genes: broken symmetry in spinal circuits2017In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 31, no 5, p. 1953-1963Article in journal (Refereed)
    Abstract [en]

    Regulation of the formation and rewiring of neural circuits by neuropeptides may require coordinated production of these signaling molecules and their receptors that may be established at the transcriptional level. Here, we address this hypothesis by comparing absolute expression levels of opioid peptides with their receptors, the largest neuropeptide family, and by characterizing coexpression (transcriptionally coordinated) patterns of these genes. We demonstrated that expression patterns of opioid genes highly correlate within and across functionally and anatomically different areas. Opioid peptide genes, compared with their receptor genes, are transcribed at much greater absolute levels, which suggests formation of a neuropeptide cloud that covers the receptor-expressed circuits. Surprisingly, we found that both expression levels and the proportion of opioid receptors are strongly lateralized in the spinal cord, interregional coexpression patterns are side specific, and intraregional coexpression profiles are affected differently by left-and right-side unilateral body injury. We propose that opioid genes are regulated as interconnected components of the same molecular system distributed between distinct anatomic regions. The striking feature of this system is its asymmetric coexpression patterns, which suggest side-specific regulation of selective neural circuits by opioid neurohormones.

  • 2.
    Kononenko, Olga
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Mityakina, Irina
    Moscow MV Lomonosov State Univ, Moscow, Russia..
    Galatenko, Vladimir
    Moscow MV Lomonosov State Univ, Moscow, Russia.;Univ Haifa, Tauber Bioinformat Res Ctr, Haifa, Israel..
    Watanabe, Hiroyuki
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. ..
    Bazov, Igor
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Gerashchenko, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Inst Mol Biol & Genet, Dept Mol Oncogenet, Kiev, Ukraine..
    Sarkisyan, Daniil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Iatsyshyna, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Inst Mol Biol & Genet, Dept Human Genet, Kiev, Ukraine..
    Yakovleva, Tatiana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Tonevitsky, Alex
    Moscow MV Lomonosov State Univ, Moscow, Russia.;Higher Sch Econ, Moscow, Russia..
    Marklund, Niklas
    Lund Univ, Univ Hosp Southern Sweden, Div Neurosurg, Dept Clin Sci, Lund, Sweden..
    Ossipov, Michael H.
    Univ Arizona, Hlth Sci Ctr, Dept Pharmacol, Tucson, AZ USA..
    Bakalkin, Georgy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Differential effects of left and right neuropathy on opioid gene expression in lumbar spinal cord2018In: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 1695, p. 78-83Article in journal (Refereed)
    Abstract [en]

    The endogenous opioid system (EOS) controls the processing of nociceptive stimuli and is a pharmacological target for opioids. Alterations in expression of the EOS genes under neuropathic pain condition may account for low efficacy of opioid drugs. We here examined whether EOS expression patterns are altered in the lumbar spinal cord of the rats with spinal nerve ligation (SNL) as a neuropathic pain model. Effects of the left- and right-side SNL on expression of EOS genes in the ipsi- and contralateral spinal domains were analysed. The SNL-induced changes were complex and different between the genes; between the dorsal and ventral spinal domains; and between the left and right sides of the spinal cord. Prodynorphin (Pdyn) expression was upregulated in the ipsilateral dorsal domains by each the left and right-side SNL, while changes in expression mu-opioid receptor (Oprm I) and proenkephalin (Penk) genes were dependent on the SNL side. Changes in expression of the Pdyn and kappa-opioid receptor (Oprk1) genes were coordinated between the ipsi- and contralateral sides. Withdrawal response thresholds, indicators of mechanical allodynia correlated negatively with Pdyn expression in the right ventral domain after right side SNL. These findings suggest multiple roles of the EOS gene products in spinal sensitization and changes in motor reflexes, which may differ between the left and right sides. (C) 2018 Elsevier B.V. All rights reserved.

  • 3.
    Watanabe, Hiroyuki
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Fitting, Sylvia
    Hussain, Muhammad
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Kononenko, Olga
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Iatsyshyna, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Yoshitake, Takashi
    Kehr, Jan
    Alkass, Kanar
    Druid, Henrik
    Wadensten, Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Andren, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Nylander, Ingrid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Wedell, Douglas
    Krishtal, Oleg
    Hauser, Kurt
    Nyberg, Fred
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Karpyak, Victor
    Yakovleva, Tatjana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Bakalkin, Georgy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Asymmetry of the Endogenous Opioid System in the Human Anterior Cingulate: a Putative Molecular Basis for Lateralization of Emotions and Pain2015In: Cerebral Cortex, ISSN 1047-3211, E-ISSN 1460-2199, Vol. 25, no 1, p. 97-108Article in journal (Refereed)
    Abstract [en]

    Lateralization of processing of positive and negative emotions and pain suggests an asymmetric distribution of the neurotransmitter systems regulating these functions between the left and right brain hemispheres. By virtue of their ability to selectively mediate euphoria, dysphoria and pain, the m-, d- and k-opioid receptors and their endogenous ligands may subserve these lateralized functions. We addressed this hypothesis by comparing the levels of the opioid receptors and peptides in the left and right anterior cingulate cortex (ACC), a key area for emotion and pain processing. Opioid mRNAs and peptides and five “classical” neurotransmitters were analyzed in postmortem tissues from 20 human subjects. Leu-enkephalin-Arg and Met-enkephalin-Arg-Phe, preferential d-/m- and k-/m-opioid agonists demonstrated marked lateralization to the left and right ACC, respectively. Dynorphin B strongly correlated with Leu-enkephalin-Arg in the left but not right ACC suggesting different mechanisms of conversion of this k-opioid agonist to d-/m-opioid ligand in the two hemispheres; in the right ACC dynorphin B may be cleaved by PACE4, a proprotein convertase regulating left-right asymmetry formation. These findings suggest that region-specific lateralization of neuronal networks expressing opioid peptides underlyes in part lateralization of higher functions including positive and negative emotions and pain in the human brain.

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