title: Regulation of cannabinoid CB2receptor constitutive activity in vivo: repeated treatments with inverse agonists reverse the acute activation of JNK and associated apoptotic signaling in mouse brain.
abstract: CB2receptors express constitutive activity and inverse agonists regulate receptor basal activity, which might be involved in death mechanisms. This study assessed the effects of a selective CB2agonist (JWH133) and different CB2inverse agonists (AM630, JTE907, raloxifene) on death pathways in brain.
  
  
  
  The acute (JWH13) and the acute/chronic effects (AM630, JTE907, raloxifene) of CB2ligands regulating pro-apoptotic c-Jun NH2-terminal kinase (p-JNK/JNK ratio) and associated signaling of extrinsic (Fas receptor, Fas-Associated death domain protein, FADD) and intrinsic (Bax, cytochrome c) death pathways (nuclear poly (ADP-ribose) polymerase PARP) were investigated in mouse brain.
  
  
  
  Mice were treated with CB2drugs and target protein contents were assessed by western blot analysis.
  
  
  
  JWH133 reduced cortical JNK (-27-45%) whereas AM630 acutely increased JNK in cortex (+61-148%), cerebellum (+34-40%), and striatum (+33-42%). JTE907 and raloxifene also increased cortical JNK (+31%-57%). Acute AM630, but not JWH133, increased cortical FADD, Bax, cytochrome c, and PARP cleavage. Repeated treatments with the three CB2inverse agonists were associated with a reversal of the acute effects resulting in decreases in cortical JNK (AM630: -36%; JTE907: -25%; raloxifene: -11%). Chronic treatments also induced a reversal with down-regulation (AM630) or only tolerance (JTE907 and raloxifene) on other apoptotic markers (FADD, Bax, cytochrome c, PARP).
  
  
  
  AM630 and JTE907 are CB2protean ligands. Thus, chronic inverse agonists abolished CB2constitutive activity and then the ligands behaved as agonists reducing (like JWH133) JNK activity. Acute and chronic treatments with CB2inverse agonists regulate in opposite directions brain death markers.
authors.affiliation: Laboratori de Neurofarmacologia, Institut Universitari d'Investigació en Ciències de la Salut (IUNICS/IdisPa), Universitat de les Illes Balears, Cra. Valldemossa km 7.5, E-07122, Palma de Mallorca, Spain.|Redes Temáticas de Investigación Cooperativa en Salud-Red de Trastornos Adictivos (RETICS-RTA), ISCIII, Madrid, Spain.
authors.forename: Glòria
authors.initials: G
authors.lastname: Salort
authors.affiliation: Laboratori de Neurofarmacologia, Institut Universitari d'Investigació en Ciències de la Salut (IUNICS/IdisPa), Universitat de les Illes Balears, Cra. Valldemossa km 7.5, E-07122, Palma de Mallorca, Spain.|Redes Temáticas de Investigación Cooperativa en Salud-Red de Trastornos Adictivos (RETICS-RTA), ISCIII, Madrid, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Álvaro-Bartolomé
authors.affiliation: Laboratori de Neurofarmacologia, Institut Universitari d'Investigació en Ciències de la Salut (IUNICS/IdisPa), Universitat de les Illes Balears, Cra. Valldemossa km 7.5, E-07122, Palma de Mallorca, Spain. jesus.garcia-sevilla@uib.es.|Redes Temáticas de Investigación Cooperativa en Salud-Red de Trastornos Adictivos (RETICS-RTA), ISCIII, Madrid, Spain. jesus.garcia-sevilla@uib.es.
authors.forename: Jesús A
authors.initials: JA
authors.lastname: García-Sevilla
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D063386:Cannabinoid Receptor Agonists / Q000494:pharmacology*; D002186:Cannabinoids / Q000494:pharmacology; D004149:Dioxoles / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects; D054314:Drug Inverse Agonism; D007211:Indoles / Q000494:pharmacology; D008024:Ligands; D048670:MAP Kinase Kinase 4 / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D015363:Quinolones / Q000494:pharmacology; D020849:Raloxifene Hydrochloride / Q000494:pharmacology; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists / Q000187:drug effects* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D063386:Cannabinoid Receptor Agonists; D002186:Cannabinoids; D004149:Dioxoles; D007211:Indoles; C422645:JTE 907; D008024:Ligands; D015363:Quinolones; D043885:Receptor, Cannabinoid, CB2; D020849:Raloxifene Hydrochloride; D048670:MAP Kinase Kinase 4; C432747:1,1-dimethylbutyl-1-deoxy-Delta(9)-THC; C094023:iodopravadoline
keywords: AM630; Cannabinoid CB2 receptors; Constitutive activity; Inverse agonists; JTE907; Raloxifene