Pivotal role reelin signaling pathway in the development of tolerance to morphine-induced antinociception

Bambang Subakti Zulkarnanin, Junaidi Khotib


The huge endogenous macromolecule protein responsible for controlling migration and dendritic growth of developing neurons, reelin, has recently been proposed that its signaling pathway modulates synaptic plasticity in the adult rodent brain. This study was carried out to investigate the pivotal role of the reelin signaling pathway in the development of tolerance to morphine induced antinociception. There was evidence that repeated intracerebroventricular administration of reelin’s monoclonal antibody, the competitive inhibitor to reelin – apolipoprotein receptor E2 recombinant, and disabled1 (Dab1) protein inhibitor – MG132, resulted in the inhibition to the development of antinociception tolerance to morphine administration. Furthermore, chronic in vivo administration with morphine caused significance increase of the immunoreactivity (IR) for phosphorylated-Dab1 in the thalamus. These data suggested that persistent activation of reelin signaling pathway due to chronic administration of morphine may be responsible for the development of tolerance to morphine-induced antinociception.

Key words: Morphine tolerance, Neuronal plasticity, Opioid receptor, Reelin signalling pathway


Ballif B. A, Arnaud L, Cooper J. A., 2003, Tyrosine phosphorylation of Disabled-1 is essential for Reelin-stimulated activation of Akt and Src family kinases. Brain Res. Mol. Brain Res. 117:152-159.

Beffert U, Weeber E. J, Morfini G, Ko J, Brady S. T, Tsai L. H, Sweatt J. D, Herz J, 2004, Reelin and cyclin-dependent kinase 5-dependent signal cooperate in regulating neuronal migration and synaptic transmission. J. Neurosci. 24: 1897-1906.

Besse D, Lombard M. C, Zajac J. M, Roques B. P, Besson J. M., 1990, Pre- and postsynaptic distribution of m, d and k opioid receptors in the superficial layers of the cervical dorsal horn of the rat spinal cord. Brain Res. 521, 15-22.

Bock H. H, Jossin Y, May P, Berger O, Herz J, 2004, Apolipoprotein E receptor are required for reelin-induced proteasomal degradation of the neuronal adaptor protein disabled-1. J. Biol. Chem. 279: 33471-33479.

Caruncho H. J, Dopeso-reyes I. G, Loza M. I, Rodriquez M. A, 2004, GABA reelin, and the neurodevelopmental hypothesis of schizophrenia. Critical Rev. Neurobiol. 16: 25-32.

Chen Y, Beffert U, Ertunc M, Tang TS, Kavalali ET, Bezprozvanny I, Herz J., 2005, Reelin modulates NMDA receptor activity in cortical neurons. J. Neurosci. 25: 8209-8216.

D’Arcangelo G, Miao G, Chen SC, Soares H. D, Morgan J. I, Curran T, 1995, A protein related to extracelluler matrix proteins deleted in the mouse mutant reeler. Nature 374: 719-723.

D’Arcangelo G, Homayouni R, Keshvara L, Rice DS, Sheldon M, Curran T , 1999, Reelin is a ligand for lipoprotein receptors. Neuron 24: 471-479.

Fatemi S. H, Stary JM, Earle JA, Agaghi-Niknam M, Eagan E, 2005, GABAergic dysfunction in schizophrenia and mood disorder as reflected by decreased levels of glutamic acid decarboxylase 65 and 67 kDa and reelin proteins in cerebellum. Schizophrenia Res. 72: 109-122

Goffinet A. M., 1984, Event governing organization of postmigratory neurons: study on brain development in normal and reeler mice. Brain Res. 319: 261-296

Goffinet AM., 1995, A real gene for reeler. Nature 374: 675-677.

Haley M. J, McCormick WG, 1957, Pharmacological effects produced by intracerebral injections of drugs in the conscious mouse. Br. J. Pharmacol. 12: 12-15.

Hartfuss E, Foster E, Bock HH, Hack MA, Leprince P, Luque JM, Herz J, Frostcher M, Gotz M,2003, Reelin signaling directly affects radial glia morphology and biochemical maturation. Development 130: 4597-4608.

Kubasak M. D Brooks R, Chen S, Villeda S. A, Phelps P. E., 2004, Developmental distribution positive cell and their secreted product in the rodent spinal cord. J. Comp. Neurol. 468: 165-178.

Lacor P. N, Grayson DR, Auta J, Sugaya I, Costa E, Gidotti A., 2000, Reelin secretion from glutamatergic neurons in culture is dependent from neurotransmitter regulation. Proc. Nat. Acad. Sci. 97: 3556-3561.

Luque J. M., 2004, Integrin and the reelin-DAB1 pathway: a sticky affair? Dev. Brain Res. 152: 269-271.

Mahley R. W., 1998, Apolipoprotein E: cholesterol transport protein with expanding role in cell biology. Science 240: 622-630.

Morimura T, Hattori M, Ogawa M, Mikoshiba K., 2005, Disabled-1 regulates the intracellular trafficking of reelin receptor. J. Biol. Chem. (in press).

Narita M, Makimura M, Feng Y, Hoskins B, Ho I. K., 1994, Influence of chronic morphine treatment on protein kinase C activity: comparison with butorphanol and implication for opioid tolerance. Brain Res. 650, 175-179.

Narita M, Ioka M, Suzuki M, Narita M, Suzuki T., 2002, Effect of repeated administration of morphine on the activity of extracellular signal regulated kinase in the mouse brain. Neurosci. Lett. 324, 97-100.

Ohshima T, Ogawa M, Veeranna, Hirasawa M, Longenecker G, Ishiguro K, Pant H. C, Brady R. O, Kulkarni A. B, Mikoshiba K.,2001, Synergistic contributions of cyclin-dependant kinase 5/p35 and reelin/dab1 to the positioning of cortical neurons in the developing mouse brain. Proc. Nat. Acad. Sci. 98: 2764-2769.

Ohshima T, Ogawa M, Takeuchi K, Takahashi S, Kulkarni A. B, Mikoshiba K., 2002, Cyclindependent kinase 5/p35 contributes synergistically with Reelin/Dab1 to the positioning of facial branchiomotor and inferior olive neurons in the developing mouse hindbrain. J. Neurosci. 22:4036-4044.

Ohshima T, Mikoshiba K., 2002, Reelin signaling and Cdk5 in the control of neuronal positioning. Mol. Neurobiol. 26:153-166.

Pramatarova A, Ochalski P. G, Chen K, Gropman A, Myers S, Min K. T, Howell B. W., 2003, Nck interacts with tyrosine-phosphorilated disabled 1 and redistributes in reelinstimulated neurons. Mol. Cell. Biol. 23: 7210-7221.

Quattrocchi CC, Wannenes F, Persico A. M, Ciafre S. A, D’Arcangelo G, Farece M. G, Keller F.,

, Reelin is a serine protease of the extracellular matrix. J. Biol. Chem. 277: 303-309.

Rice D. S, Curran T., 2001, Role of the reelin signaling pathway in central nerves system development. Annu. Rev. Neurosci. 24: 1005-1039.

Rice D. S., Sheldon M, D’Arngelo G, Nakajima K, Goldowitz D, Curran T., 1998, Disabled-1 acts downstream of reelin in a signaling pathway that control laminar organization in the mammalian brain. Development 125: 3719-3729.

Sanada K, Gupta A, Tsai L. H., 2004, Disabled-1-regulated adhesion of migrating neurons to radial glial fiber contributes to neuronal positioning during early corticogenesis. Neuron 42: 197-211.

Sinagra M, Verrier D, Frankova D, Korwek K. M, Blahos J, Weeber EJ, Manzoni O. J, Chavis P., 2005, Reelin, very-low-density lipoprotein receptor, and apolipoprotein E receptor 2 control somatic NMDA receptor composition during hippocampal maturation in vitro. J. Neurosci. 25: 6127-6136.

Smith F. L., Javed R. R., Elzey M. J. and Dewey W. L., 2003, The expression of a high level of morphine antinociceptive tolerance in mice involves both PKC and PKA. Brain Res. 985, 78-88.

Tesseur I, Van Dorpe J, Spittael K, Van den Haute C, Moechars D van Leuven, 2000, Expression of human apolipoprotein E4 in neurons causes hyperphosphorylation of protein tau in the brain of transgenic mice Am. J. pathol. 150: 951-964.

Trommsdorff M, Borg J. P, Margolis B, Her J., 1998, Internalization of cytosolic adaptor proteins with neuronal apolipoprotein E receptor and amyloid precursor protein. J. Biol. Chem 273: 33556-33560.

Trujillo K. A, Akil H., 1991, Inhibition of morphine tolerance and dependence by the NMDA receptor antagonist MK-801. Science 251: 85-87.

Zhang J, Krishnamurthy P. K, Johnson G. V., 2002, Cdk5 phosphorylates p53 and regulates its activity. J Neurochem. 81: 307-313.

Zukerberg L. R, Patrick G. N, Nikolic M, Humbert S, Wu C. L, Lanier L. M, Gertler F. B, Vidal M, Van Etten RA, Tsai L. H., 2000, Cables links Cdk5 and c-Abl and facilitates Cdk5 tyrosine phosphorylation, kinase upregulation, and neurite outgrowth. Neuron. 26: 633-646.

DOI: http://dx.doi.org/10.14499/indonesianjpharm0iss0pp157-164


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