title: Chronic morphine modulates the contents of the endocannabinoid, 2-arachidonoyl glycerol, in rat brain.
abstract: Opioids and cannabinoids are among the most widely consumed drugs of abuse in humans and the phenomena of cross-tolerance or mutual potentiation have been demonstrated between the two drugs. Several authors have suggested that both drugs share common links in their molecular mechanisms of action, although this has been a matter of controversy. Furthermore, no data exist on the possible adaptive changes in the contents of arachidonoylethanolamide (anandamide, AEA) and 2-arachidonoylglycerol (2-AG), the two major endogenous ligands for cannabinoid receptors, in morphine-tolerant rats. In the present work, we investigated the alterations in cannabinoid receptor functionality and endocannabinoid levels in rats chronically treated with morphine (5 mg/kg, s.c., twice a day for 5 days). Autoradiographic-binding studies using [(3)H]CP-55 940 revealed a slight but significant reduction in cannabinoid receptor level in the cerebellum and hippocampus of morphine-tolerant rats, while CP-55 940-stimulated [(35)S]GTPgammaS binding showed a strong decrease (40%) in receptor/G protein coupling in the limbic area of these animals. Moreover, in the same brain regions we measured, by isotope-dilution gas chromatography/mass spectrometry, the contents of AEA and 2-AG. Chronic morphine exposure produced a strong reduction in 2-AG contents without changes in AEA levels in several brain regions (ie striatum, cortex, hippocampus, limbic area, and hypothalamus). These findings clearly demonstrate that prolonged activation of opioid receptors could alter the cannabinoid system, in terms of both receptor functionality and endocannabinoid levels, and suggest the involvement of this system, alone or in combination with other mediators, in the phenomenon of morphine tolerance.
authors.affiliation: DBSF, Pharmacology Unit, University of Insubria, Busto Arsizio (VA), Italy. daniela.parolaro@uninsubria.it
authors.forename: Daniela
authors.initials: D
authors.lastname: Viganò
authors.forename: Maria
authors.initials: M
authors.lastname: Grazia Cascio
authors.forename: Tiziana
authors.initials: T
authors.lastname: Rubino
authors.forename: Filomena
authors.initials: F
authors.lastname: Fezza
authors.forename: Angelo
authors.initials: A
authors.lastname: Vaccani
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Di Marzo
authors.forename: Daniela
authors.initials: D
authors.lastname: Parolaro
mesh_terms: D000818:Animals; D001095:Arachidonic Acids; D001921:Brain / Q000187:drug effects* / Q000378:metabolism*; D063385:Cannabinoid Receptor Modulators; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D063388:Endocannabinoids; D005231:Fatty Acids, Unsaturated / Q000378:metabolism*; D005989:Glycerides / Q000378:metabolism*; D007279:Injections, Subcutaneous; D008297:Male; D009020:Morphine / Q000008:administration & dosage*; D018377:Neurotransmitter Agents / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D001095:Arachidonic Acids; D063385:Cannabinoid Receptor Modulators; D063388:Endocannabinoids; D005231:Fatty Acids, Unsaturated; D005989:Glycerides; D018377:Neurotransmitter Agents; D009020:Morphine; C094503:glyceryl 2-arachidonate