Abstract
Numerous studies have shown functional links between the cannabinoid and opioid systems. The goal of this study was to evaluate whether acute treatments by endogenous cannabinoid agonist, selective CB] or CB2 receptor antagonists modulate the expression of μ- (MOR) and δ- (DOR) opioid receptor mRNA levels and functional activity in the cerebellum of transgenic mice deficient in the CB1 type of cannabis receptors. We examined the effect of noladin ether (endogenous cannabinoid agonist) pretreatment on MOR and DOR mRNA expression by using reverse transcription and real-time polimerase chain reaction (PCR) and the ability of subsequent application of the opioid agonists to activate G-proteins, as measured by [35S]GTPγS binding, in wild-type (CB1+/+) and CB1 cannabinoid receptor deficient (CB1, ‘knockout’, K.O.) mice. The acute administration of noladin ether markedly reduced MOR-mediated G-protein activation and caused a significant increase in the level of MOR mRNAs in the cerebella of wild-type, but not in the CB1-/- mice. No significant differences were observed in DOR functional activity and mRNA expression in wild-type animals. In CB-/- mice the expression of DOR mRNA increased after noladin ether treatment, but no changes were found in DOR functional activity. In addition, Rimonabant (selective central cannabinoid CB] receptor antagonist) and SR144528 (selective peripheral cannabinoid CB2 receptor antagonist) caused significant potentiation in MOR functional activity in the wild-type animals, whereas DOR mediated G-protein activation was increased in the CB-/- mice. In contrast, Rimonabant and SR144528 decreased the MOR and DOR mRNA expressions in both CB1+/+ and CB-/- -mice. Taken together, these results indicate that acute treatment with cannabinoids causes alterations in MOR and DOR mRNA expression and functional activity in the cerebella of wild-type and CB1 knockout mice indicating indirect interactions between these two signaling systems.
Article PDF
Similar content being viewed by others
Avoid common mistakes on your manuscript.
References
Abeyta, A., Dettmer, T. S., Barnes, A., Vega, D., Carta, M., Gallegos, N., Raymond-Stintz, M., Savage, D. D., Valenzuela, C. F., Saland, L. C. (2002) Delta opioid receptor localization in the rat cerebellum. Brain Res. 931, 100–105.
Benyhe, S., Farkas, J., Toth, G., Wollemann, M. (1997) Met-enkephalin-Arg6-Phe7, an endogenous neuropeptide, binds to multiple opioid and nonopioid sites in rat brain. J. Neurosci. Res. 48, 249–258.
Benyhe, S., Sziics, M., Borsodi, A., Wollemann, M. (1992) Species differences in the stereoselectivity of kappa opioid binding sites for [3H]U-69593 and [3H]ethylketocyclazocine. Life Sci. 51, 1647–1655.
Benyhe, S., Farkas, J., Toth, G, Wollemann, M. (1999) Characterization of [3H]Met-enkephalin-Arg6-Phe7 binding to multiple sites in rat and guinea pig cerebellum. Life Sci. 64, 1189–1196.
Blackburn, T. R, Cross, A. J., Hille, C., Slater, P. (1988) Autoradiographic localization of delta opiate receptors in rat and human brain. Neuroscience 27, 497–506.
Childers, S. R., Fleming, L., Konkoy, C., Marckel, D., Pacheco, M., Sexton, T., Ward, S. (1992) Opioid and cannabinoid receptor inhibition of adenylyl cyclase in brain. Ann. NY Acad. Sci. 654, 33–51.
Clarke, S., Kitchen, I. (1999) Opioid analgesia: new information from gene knockout studies. Curr. Opin. Anaesthesiol. 5, 609–614.
Corchero, J., Avila, M. A., Fuentes, J. A., Manzanares, J. (1997a) Delta-9-Tetrahydrocannabinol increases prodynorphin and proenkephalin gene expression in the spinal cord of the rat. Life Sci. 61, 39–43.
Corchero, J., Fuentes, J. A., Manzanares, J. (1997b) Delta-9-Tetrahydrocannabinol increases proopiomelanocortin gene expression in the arcuate nucleus of the rat hypothalamus. Eur. J. Pharmacol. 323, 193–195.
De Petrocellis, L., Di Marzo, V. (2005) Lipids as regulators of the activity of transient receptor potential type VI (TRPV1) channels. Life Sci. 77, 1651–1666.
Delfs, J. M., Kong, H., Mestek, A., Chen, Y., Yu, L., Reisine, T., Chesselet, M. F. (1994) Expression of mu opioid receptor mRNA in rat brain: an in situ hybridization study at the single cell level. J. Comp. Neurol. 345, 46–68.
Demuth, D. G., Molleman, A. (2006) Cannabinoid signaling. Life Sci. 78, 549–563.
Devane, W. A., Hanus, L., Breuer, A., Pertwee, R. G., Stevenson, L. A., Griffin, G., Gibson, D., Mandelbaum, A., Etinger, A., Mechoulam, R. (1992) Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science 258, 1946–1949.
Dhawan, B. N., Cesselin, F., Raghubir, R., Reisine, T., Bradley, P. B., Portoghese, P. S., Hamon, M. (1996) International Union of Pharmacology. XII. Classification of opioid receptors. Pharmacol. Rev. 48, 567–592.
Facci, L., Dal Toso, R., Romanello, S., Buriani, A., Skaper, S. D., Leona, A. (1995) Mast cells express a peripheral cannabinoid receptor with differential sensitivity to anandamide and palmi-toylethanolamide. Proc. Natl. Acad. Sci. USA 92, 3376–3380.
Fields, H. L, Meng, I. D. (1998) Watching the pot boil. Nat. Med. 4, 1008–1009.
Galiegue, S., Mary, S., Marhand, J., Dussossoy, D., Carriere, D., Carayon, R., Bouaboula, M., Shire, D., Le Fur, G., Casellas, P. (1995) Expression of central and peripheral cannabinoid receptors in human tissues and leukocytes subpopulations. Eur. J. Biochem. 232, 54–61.
Gong, J.-R, Onaivi, E. S., Ishiguro, H., Liu, Q.-R., Tagliaferro, P. A., Brusco, A., Uhl, G. R. (2006) Cannabinoid CB2 receptors: Immunohistochemical localization in rat brain. BrainRes. 1071, 10–23.
Hanus, L., Abu-Lafi, S., Fride, E., Breuer, A., Vogel, Z., Shalev, D. E., Kustanovich, I., Mechoulam, R. (2001) 2-Arachidonyl glyceryl ether, an endogenous agonist of the cannabinoid CB1 receptor. Proc. Natl. Acad. Sci. USA 98, 3662–3665.
Hajos, N., Ledent, C., Freund, T. F. (2001) Novel cannabinoid-sensitive receptor mediates inhibition of glutamatergic synaptic transmission in the hippocampus. Neuroscience 106, X.
Herraez-Baranda, L., Carretero, J., Gonzalez-Sarmiento, R., Rodriguez, R. E. (2005) Kappa opioid receptor is expressed in the rat cerebellar cortex. Cell Tissue Res. 320, 223–228.
Howlett, A. C. (1995) Pharmacology of cannabinoid receptors. Ann. Rev. Pharmacol. Toxicol. 35, 607–634.
Howlett, A. C., Barth, E., Bonner, T. I., Cabral, G., Casellas, P., Devane, W. A., Felder, C. C, Herkenham, M., Mackie, K., Martin, B. R., Mechoulam, R., Pertwee, R. G. (2002) International Union of Pharmacology. XXVII. Classification of cannabinoid receptors. Pharmacol. Rev. 54, 161–202.
Ibrahim, M. M., Porreca, F., Lai, J., Albrecht, P. J., Rice, F. L., Khodorova, A., Davar, G., Makriyannis, A., Vanderah, T. W., Mata, H. P., Malan, T. P. Jr (2005) CB2 cannabinoid receptor activation produces antinociception by stimulating peripheral release of endogenous opioids. Proc. Natl. Acad. Sci. USA 102, 3093–3098.
Kieffer, B. L. (1999) Opioids: first lessons from knockout mice. Trends Pharmacol. Sci. 20, 19–26.
Ledent, C., Valverde, O., Cossu, G., Petitet, F., Aubert, J. F., Beslot F., Böhme, G. A., Imperato, A., Pedrazzini, T., Roques, B. P., Vassart, G., Fratta, W., Parmentier, M. (1999) Unresponsiveness to cannabinoids and reduced addictive effects of opiates in CB1 receptor knockout mice. Science 283, 401–404.
Maldonado, R., Rodriguez de Fonseca, F (2002) Cannabinoid addiction: behavioral models and neuronal correlates. J. Neurosci. 22, 3326–3331.
Mansour, A., Fox, C. A., Akil, H., Watson, S. J. (1995) Opioid-receptor mRNA expression in the rat CNS: anatomical and functional implications. Trends Neurosci. 18, 22–29.
Mansour, A., Khachaturian, A., Lewis, M. E., Akil, H., Watson, S. J. (1988) Anatomy of CNS opioid receptors Trends Neurosci. 11, 308–314.
Manzanares, J., Corchero, J., Romero, J. J., Fernandez-Ruiz, J. J., Ramos, J. A., Fuentes, J. A. (1999) Pharmacological and biochemical interactions between opioids and cannabinoids. Trends Pharmacol. Sci. 20, 287–293.
Manzanares, J., Ortiz, S., Oliva, J. M., Perez-Rial, S., Palomo, T. (2005) Interactions between cannabinoid and opioid receptor systems in the mediation of ethanol effects. Alcohol Alcohol. 40, 25–34.
Matsuda, L. A., Lolait, S. J., Brownstein, B. J., Young, A. C., Bonner, T. L. (1990) Structure of a cannabinoid receptor and functional expression of the cloned cDNA. Nature 346, 561–564.
Matthes, H. W., Smadja, C., Valverde, O., Vonesch, J. L., Foutz, A. S., Boudinot, E., Denavit-Saubie, M., Severini, C., Negri, L., Roques, B. P., Maldonado, R., Kieffer, B. L. (1998) Activity of the delta-opioid receptor is partially reduced, whereas activity of the kappa-receptor is maintained in mice lacking the mu-receptor. J. Neurosci. 18, 7285–7295.
Meunier, J. C., Kouakou, Y., Puget, A., Moisand, C. (1983) Multiple opiate binding sites in the central nervous system of the rabbit: Large predominance of a mu subtype in the cerebellum and characterization of a kappa subtype in the thalamus. Mol. Pharmacol. 24, 23–29.
Memory, K., Tzavara, E. Th., Lexime, J., Ledent, C., Parmentier, M., Borsodi, A., Hanoune, J. (2002) Novel, not adenylyl cyclase-coupled cannabinoid binding site in cerebellum of mice. Biochem. Biophys. Res. Commun. 292, 231–235.
Mrkusich, E. M., Kivell, B. M., Miller, J. H., Day, D. J. (2004) Abundant expression of mu and delta opioid receptor mRNA and protein in the cerebellum of the fetal, neonatal, and adult rat. Develop. Brain Res. 148, 213–222.
Munro, S., Thomas, K. L., Abu-Shaar, M. (1993) Molecular characterization of a peripheral receptor for cannabinoids. Nature 365, 61–65.
Pfaffl, M. W. (2001) A new mathematical model for relative quantification in real-time RT-PCR. Nucl. Acids Res. 29, e45.
Peckys, D., Landwehrmeyer, G. B. (1999) Expression of mu, kappa, and delta opioid receptor messenger RNA in the human CNS: a 33P in situ hybridization study. Neuroscience 88, 1093–1135.
Platzer, S., Winkler, A., Schadrack, J., Dworzak D., Tolle, T.R., Zieglgansberger, W., Spanagel R. (2000) Autoradiographic distribution of μ-, δ- and κK-opioid stimulated [35S]guanylyl-5’-0-(y-thio)-triphosphate binding in human frontal cortex and cerebellum. Neuroscience Letters 283, 212–216.
Puskas, L. G., Bereczki, E., Santha, M., Vigh, L., Csanadi, G., Spener, F., Ferdinandy, P., Onody, A. and others (2005) Cholesterol and cholesterol plus DHA diet-induced gene expression and fatty acid changes in mouse eye and brain. Biochimie 87, 817–824.
Reisine, T., Law, S. F., Blake, A., Tallent, M. (1996) Molecular mechanisms of opiate receptor coupling to G proteins and effector systems. Ann. NY Acad. Sci. 780, 168–175.
Rinaldi-Carmona, M., Barth, F., Heaulme, M., Shire D., Calandra, B., Congy, C., Martinez, S., Maruani, J., Neliat, G., Caput, D., Ferrara, P., Soubrie, P., Breliere, J. C., LeFur, G. (1994) SR141716A, a potent and selective antagonist of the brain cannabinoid receptor. FEBS Letters 350, 240–244.
Robson, L. E., Foote, R. W., Mauer, R., Kosterlitz, H. W. (1984) Opioid binding sites of the kappa-type in guinea-pig cerebellum. Neuroscience 12, 621–627.
Rodriguez, J. J., Mackie, K., Pickel, V. M. (2001) Ultrastructural localization of the CB1 cannabinoid receptor in i-opioid receptor patches of the rat caudate putamen nucleus. J. Neurosci. 21, 823–833.
Saab, C. Y., Willis, W. D. (2003) The cerebellum: organization, functions and its role in nociception. Brain Res. Rev. 42, 85–95.
Saland, L. C., Abeyta, A., Frausto, S., Raymond-Stintz, M., Hastings, C. M., Carta, M. Valenzuela, C. F., Savage, D. D. (2004) Chronic ethanol consumption reduces delta-and mu-opioid receptor-stimulated G-protein coupling in rat brain. Alcohol Clin. Exp. Res. 28, 98–104.
Samson, M. T., Small-Howard, A., Shimoda, L M. N., Koblan-Huberson, M., Stokes, A. J., Turner, H. (2003) Differential roles of CB1 and CB2 cannabinoid receptors in mast cells. J. Immunol. 170, 4953–4962.
Shapira, M., Vogel, Z., Same, Y. (2000) Opioid and cannabinoid receptors share a common pool of GTP-binding proteins in cotransfected cells, but not in cells with endogenously coexpress the receptors. Cell. Mol. Neurobiol. 20, 291–304.
Sim, L. J., Childers, S. R. (1997) Anatomical distribution of Mu, delta, and kappa opioid- and noci-ception/orphanin FQ-stimulated [S-35]guanylyl-5’-0-(gamma-thio)-triphosphate binding in guinea pig brain. J. Comp. Neurol. 386, 562–572.
Sim, L. J., Selley, D. E., Childers, S. R. (1995) In vitro autoradiography of receptor-activated G proteins in rat brain by agonist-stimulated guanylyl 5’-[gamma-[35S]thio]-triphosphate binding. Proc. Natl. Acad. Sci. USA 92, 7242–7246.
Skaper, S. D., Buriani, A., Dal Toso, R., Petrelli, L., Romanello, S, Facci, L., Leon, A. (1996) The ALIAmide palmitoylethanolamide, are protective in a delayed postglutamate paradigm of excitotox-ic death in cerebral granule neurons. Proc. Natl. Acad Sci. USA 93, 3984–3989.
Traynor, J. R., Nahorski, S. R. (1995) Modulation by mu-opioid agonists of guanosine-5’-0-(3-[35S](thio)triphosphate binding to membranes from human neuroblastoma SH-SY5Y cells. Mol. Pharm. 47, 848–854.
Van Sickle, M. D., Duncan, M., Kingsley, P. J., Mouihate, A., Urbani, P., Mackie, K., Stella, N., Makriyannis, L. J., Piomelly, D., Davison, J. S., Marnett, L. J., Di Marzo, V., Pittman, Q. J., Patel, K. D., Sharkey, K. A. (2005) Identification and functional characterization of brainstem cannabinoin CB2 receptors. Science 310, 329–332.
Vasques, C., Lewis, L. D. (1999) The CB1 cananbinoid receptor can sequester G proteins, making them unavailable to couple to other receptors. J. Neurosci. 19, 9271–9280.
Vigano, D., Grazia Cascio, M., Rubino, T., Fezza, R., Vaccani, A., DiMarzo, V., Parolaro, D. (2003) Chronic morphine modulates the contents of the endocannabinoid, 2-arachidonoyl glycerol, in rat brain. Neuropsychopharmacology 28, 1160–1167.
Zhang, Y., Pan, Y. X., Kolesnikov, Y., Pasternak, G. W. (2006) Immunohistochemical labeling of the mu opioid receptor carboxy terminal splice variant mMOR-lB4 in the mouse central nervous system. Brain Res. 1099, 33–43.
Zimmer, A., Zimmer, A. G., Hohmann, A. G., Herkenham, M., Bonner, T. I. (1999) Increased mortality, hypoactivity, and hypoalgesia in cannabinoid CB1 receptor knockout mice. Proc. Natl. Acad. Sci. USA 96, 5780–5785.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
About this article
Cite this article
Páldyová, E., Bereczki, E., Sántha, M. et al. Altered Gene Expression and Functional Activity of Opioid Receptors in the Cerebellum of CB1 Cannabinoid Receptor Knockout Mice After Acute Treatments with Cannabinoids. BIOLOGIA FUTURA 58 (Suppl 1), 113–129 (2007). https://doi.org/10.1556/ABiol.58.2007.Suppl.9
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1556/ABiol.58.2007.Suppl.9