Preferencje help
Widoczny [Schowaj] Abstrakt
Liczba wyników
2014 | 74 | 3 |

Tytuł artykułu

Expression and localization of cannabinoid receptor 1 in rats’ brain treated with acute and repeated morphine

Warianty tytułu

Języki publikacji



Morphine induces adaptive changes in gene expression throughout the reward circuitry of brain. Recent research has proven the functional interactions between opioid and endogenous cannabinoid system in the central nervous system (CNS). The cannabinoid receptor 1 (CBj-R) is one of the receptors that mediate the actions of cannabinoids and endocannabinoids in the CNS. Here, we investigated the expression of CBrR in mRNA and protein levels in the brains of rats treated with acute and repeated morphine. Three groups of rats received intraperitoneal injections (ip injections) of saline, acute morphine (10 mg/ kg) and repeated morphine (10 mg/kg, twice daily for 12 consecutive days), and the mRNA levels and protein expressions of CB1-R were examined. RT-PCR and western blot analyses supported that both mRNA and protein levels of CB1-R in cortex, cerebellum and hippocampus were increased by repeated morphine treatment. However, the mRNA level in cerebellum was down-regulated only after acute morphine treatment and would returned to basal levels later. We used immunohistochemistry techniques to determine the functional expression of CB1-R in morphine treated rat's brain. Enzyme- Linked Immunosorbent Assay (ELISA) revealed the significant increase of cytokine (IL-ip, IL-6) levels in the repeated morphine treatment rats' cortex and hippocampus regions, which are both addiction-related brain areas. In addition, the results from RT-PCR and western blot assay indicated that the expression of CB1-R was directly increased by morphine treatment in vitro. All the results indicated that the CB1-R expression could be changed by morphine exposure and it might be involved in neural immune function, which provided a potential target for neurogenic disease treatment.

Słowa kluczowe








Opis fizyczny



  • Department of Neurology, Shanghai Tongji Hospital, Tongji University School of Medicine, Shanghai, China
  • Department of Neurology, Shanghai Tongji Hospital, Tongji University School of Medicine, Shanghai, China
  • Department of Neurology, Shanghai Tongji Hospital, Tongji University School of Medicine, Shanghai, China
  • Department of Biomedicine, China National Center for Biotechnology Development, Beijing, China
  • Department of Neurology, Shanghai Tongji Hospital, Tongji University School of Medicine, Shanghai, China
  • School of Life Science and Technology, Tongji University, Shanghai , China; 3 Department of Biomedicine, China National Center for Biotechnology Development, Beijing, China


  • Abrams DI, Couey P, Shade SB, Kelly ME, Benowitz NL (2011) Cannabinoid-opioid interaction in chronic pain. Clin Pharmacol Ther 90: 844-851.
  • Carlezon WA, Wise RA (1996) Microinjections of phency- clidine (PCP) and related drugs into nucleus accumbens shell potentiate medial forebrain bundle brain stimulation reward. Psychopharmacology 128: 413-420.
  • Castle DJ, Ames FR (1996) Cannabis and the brain. Aust Nz J Psychiat 30: 179-183.
  • Cichewicz DL, McCarthy EA (2003) Antinociceptive syn¬ergy between Delta(9)-tetrahydrocannabinol and opioids after oral administration. J Pharmacol Exp Ther 304: 1010-1015.
  • Commons KG, Aicher SA, Kow LM, Pfaff DW (2000) Presynaptic and postsynaptic relations of mu-opioid receptors to gamma-aminobutyric acid-immunoreactive and medullary-projecting periaqueductal gray neurons. J Comp Neurol 419: 532-542.
  • Connor M, Christie MD (1999) Opioid receptor signalling mechanisms. Clin Exp Pharmacol Physiol 26: 493-499.
  • De Vries TJ, Shippenberg TS (2002) Neural systems under¬lying opiate addiction. J Neurosci 22: 3321-3325.
  • Fattore L, Vigano D, Fadda P, Rubino T, Fratta W, Parolaro D (2007) Bidirectional regulation of mu-opioid and CB1- cannabinoid receptor in rats self-administering heroin or WIN 55,212-2. Eur J Neurosci 25: 2191-2200.
  • Gertsch J, Schoop R, Kuenzle U, Suter A (2004) Echinacea alkylamides modulate TNF-alpha gene expression via cannabinoid receptor CB2 and multiple signal transduc¬tion pathways. FEBS Lett 577: 563-569.
  • Heifets BD, Castillo PE (2009) Endocannabinoid signaling and long-term synaptic plasticity. Annu Rev Physiol 71: 283-306.
  • Herkenham M (1992) Cannabinoid receptor localization in brain: relationship to motor and reward systems. An N Y Acad Sci 654: 19-32.
  • Howlett AC, Barth F, Bonner TI, Cabral G, Casellas P, Devane WA, Felder CC, Herkenham M, Mackie K, Martin BR, Mechoulam R, Pertwee RG (2002) International Union of Pharmacology. XXVII. Classification of cannabinoid receptors. Pharmacol Rev 54: 161-202.
  • Jongenrelo AL, Voorn P, Groenewegen HJ (1994) Immunohistochemical characterization of the shell and core territories of the nucleus-accumbens in the rat. Eur J Neurosci 6: 1255-1264.
  • Kauer JA (2004) Learning mechanisms in addiction: Synaptic plasticity in the ventral tegmental area as a result of expo¬sure to drugs of abuse. Annu Rev Physiol 66: 447-475.
  • Kelley AE, Berridge KC (2002) The neuroscience of natural rewards: Relevance to addictive drugs. J Neurosci 22: 3306-3311.
  • Klein TW, Cabral GA (2006) Cannabinoid-induced immune suppression and modulation of antigen-presenting cells. J Neuroimmune Pharmacol 1: 50-64.
  • Lee RS, Criado JR, Koob GF, Henriksen SJ (1999) Cellular responses of nucleus accumbens neurons to opiate-seek¬ing behavior: I. Sustained responding during heroin self- administration. Synapse 33: 49-58.
  • Lopez-Moreno JA, Lopez-Jimenez A, Gorriti MA, de Fonseca FR (2010) Functional Interactions between Endogenous Cannabinoid and Opioid Systems: Focus on
  • Alcohol, Genetics and Drug-Addicted Behaviors. Curr Drug Targets 11: 406-428.
  • Mackie K (2007) Understanding cannabinoid psychoactivity with mouse genetic models. Plos Biol 5: 2106-2108.
  • Mackie K (2008) Cannabinoid receptors: Where they are and what they do. J Neuroendocrinol 20: 10-14.
  • Mailleux P, Vanderhaeghen JJ (1992) Distribution of neu¬ronal cannabinoid receptor in the adult rat brain: a com¬parative receptor binding radioautography and in situ hybridization histochemistry. Neuroscience 48: 655-668.
  • Meng ID, Johansen JP (2004) Antinociception and modula¬tion of rostral ventromedial medulla neuronal activity by local microinfusion of a cannabinoid receptor agonist. Neuroscience 124: 685-693.
  • Mickiewicz AL, Napier TC (2011) Repeated exposure to morphine alters surface expression of AMPA receptors in the rat medial prefrontal cortex. Eur J Neurosci 33: 259¬265.
  • Mukhopadhyay P, Pan H, Rajesh M, Batkai S, Patel V, Harvey-White J, Mukhopadhyay B, Hasko G, Gao B, Mackie K, Pacher P (2010) CB1 cannabinoid receptors promote oxidative/nitrosative stress, inflammation and cell death in a murine nephropathy model. Br J Pharmacol 160: 657-668.
  • Pacheco DF, Klein A, Perez AC, Pacheco CM, de Francischi JN, Reis GM, Duarte ID (2009) Central antinociception induced by mu-opioid receptor agonist morphine, but not delta- or kappa-, is mediated by cannabinoid CB1 recep¬tor. Br J Pharmacol 158: 225-231.
  • Pugh G, Jr., Smith PB, Dombrowski DS, Welch SP (1996) The role of endogenous opioids in enhancing the anti- nociception produced by the combination of delta 9-tetra- hydrocannabinol and morphine in the spinal cord. J Pharmacol Exp Ther 279: 608-616.
  • Pu L, Bao GB, Xu NJ, Ma L, Pei G (2002) Hippocampal long-term potentiation is reduced by chronic opiate treat¬ment and can be restored by re-exposure to opiates. J Neurosci 22: 1914-1921.
  • Ray AP, Griggs L, Darmani NA (2009) Delta(9)- Tetrahydrocannabinol suppresses vomiting behavior and Fos expression in both acute and delayed phases of cispl- atin-induced emesis in the least shrew. Behav Brain Res 196: 30-36.
  • Schlicker E, Kathmann M (2001) Modulation of transmitter release via presynaptic cannabinoid receptors. Trends Pharmacol Sci 22: 565-572.
  • Sharkey KA, Cristino L, Oland LD, Van Sickle MD, Starowicz K, Pittman QJ, Guglielmotti V, Davison JS, Di Marzo V (2007) Arvanil, anandamide and N-arachidonoyl- dopamine (NADA) inhibit emesis through cannabinoid CB1 and vanilloid TRPV1 receptors in the ferret. Eur J Neurosci 25: 2773-2782.
  • Tanasescu R, Constantinescu CS (2010) Cannabinoids and the immune system: an overview. Immunobiology 215: 588-597.
  • Tsou K, Brown S, Sanudo-Pena MC, Mackie K, Walker JM (1998) Immunohistochemical distribution of cannabinoid CB1 receptors in the rat central nervous system. Neuroscience 83: 393-411
  • Van Sickle MD, Oland LD, Ho W, Hillard CJ, Mackie K, Davison JS, Sharkey KA (2001) Cannabinoids inhibit emesis through CB1 receptors in the brainstem of the fer¬ret. Gastroenterology 121: 767-774.
  • Van Sickle MD, Oland LD, Mackie K, Davison JS, Sharkey KA (2003) Delta9-tetrahydrocannabinol selectively acts on CB1 receptors in specific regions of dorsal vagal com¬plex to inhibit emesis in ferrets. Am J Physiol Gastrointest Liver Physiol 285: 566-576.
  • Vaseghi G, Rabbani M, Hajhashemi V (2012) The CB(1) receptor antagonist, AM281, improves recog¬nition loss induced by naloxone in morphine with¬drawal mice. Basic Clin Pharmacol Toxicol 111: 161-165.
  • Vigano D, Grazia Cascio M, Rubino T, Fezza F, Vaccani A, Di Marzo V, Parolaro D (2003) Chronic morphine modu¬lates the contents of the endocannabinoid, 2-arachidonoyl glycerol, in rat brain. Neuropsychopharmacology 28: 1160-1167.
  • Wang J, Charboneau R, Balasubramanian S, Barke RA, Loh HH, Roy S (2002) The immunosuppressive effects of chronic morphine treatment are partially dependent on corticosterone and mediated by the mu-opioid receptor. J Leukoc Biol 71: 782-790.
  • Wang XM, Zhou Y, Spangler R, Ho A, Han JS, Kreek MJ (1999) Acute intermittent morphine increases prepro- dynorphin and kappa opioid receptor mRNA levels in the rat brain. Mol Brain Res 66: 184-187.
  • Wilson RI, Nicoll RA (2002) Neuroscience - Endocannabinoid signaling in the brain. Science 296: 678-682.
  • Zelek-Molik A, Taracha E, Nawrat D, Bielawski A, Lehner M, Plaznik A, Nalepa I (2010) Effects of morphine and methadone treatment on mRNA expression of G alpha(i) subunits in rat brains. Pharmacol Rep 62: 1197-1203.

Typ dokumentu



Identyfikator YADDA

JavaScript jest wyłączony w Twojej przeglądarce internetowej. Włącz go, a następnie odśwież stronę, aby móc w pełni z niej korzystać.