title: Molecular mechanisms involved in the asymmetric interaction between cannabinoid and opioid systems.
abstract: The aim of this work was to study the mechanism of cross-modulation between cannabinoid and opioid systems for analgesia during acute and chronic exposure. Acute coadministration of ineffectual subanalgesic doses of the synthetic cannabinoid CP-55,940 (0.2 mg/kg i.p.) and morphine (2.5 mg/kg i.p.) resulted in significant antinociception. In chronic studies, a low dose of CP-55,940 (0.2 mg/kg, i.p.) that per se did not induce analgesia in naive animals produced a significant degree of antinociception in rats made tolerant to morphine, whereas in rats made tolerant to CP-55,940, morphine challenge did not produce any analgesic response. To identify the mechanism of these asymmetric interactions during chronic treatment, we investigated the functional activity of cannabinoid and mu opioid receptors and their effects on the cyclic AMP (cAMP) cascade. Autoradiographic-binding studies indicated a slight but significant reduction in cannabinoid receptor levels in the hippocampus and cerebellum of morphine-tolerant rats, whereas CP-55,940-stimulated [35S]GTPgammaS binding showed a significant decrease in receptor/G protein coupling in the limbic area. In CP-55,940 exposed rats, mu opioid receptor binding was significantly raised in the lateral thalamus and periaqueductal gray (PAG), with an increase in DAMGO-stimulated [35S]GTPgammaS binding in the nucleus accumbens. Finally, we tested the cAMP system's responsiveness to the cannabinoid and opioid in the striatum and dorsal mesencephalon. In vivo chronic morphine did not affect CP-55,940's ability to inhibit forskolin-stimulated cAMP production in vitro and actually induced sensitization in striatal membranes. In contrast, in vivo chronic CP-55,940 desensitized DAMGO's efficacy in inhibiting forskolin-stimulated cAMP production in vitro. The alterations to the cAMP system seem to mirror the behavioral responses, indicating that the two systems may interact at the postreceptor level. This might open up new therapeutic opportunities for relief of chronic pain through cannabinoid-opioid coadministration.
authors.affiliation: DBSF, Pharmacology Section and Neuroscience Center, University of Insubria, via A. da Giussano 10, 21052, Busto Arsizio, VA, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Viganò
authors.forename: Tiziana
authors.initials: T
authors.lastname: Rubino
authors.forename: Angelo
authors.initials: A
authors.lastname: Vaccani
authors.forename: Silvia
authors.initials: S
authors.lastname: Bianchessi
authors.forename: Patrick
authors.initials: P
authors.lastname: Marmorato
authors.forename: Chiara
authors.initials: C
authors.lastname: Castiglioni
authors.forename: Daniela
authors.initials: D
authors.lastname: Parolaro
mesh_terms: D000818:Animals; D019540:Area Under Curve; D001522:Behavior, Animal / Q000187:drug effects*; D001921:Brain / Q000033:anatomy & histology / Q000187:drug effects; D001923:Brain Chemistry / Q000187:drug effects*; D002186:Cannabinoids / Q000494:pharmacology*; D000242:Cyclic AMP / Q000378:metabolism; D003511:Cyclohexanols / Q000493:pharmacokinetics / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004347:Drug Interactions; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000493:pharmacokinetics / Q000494:pharmacology; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000493:pharmacokinetics; D008297:Male; D009294:Narcotics / Q000494:pharmacology*; D010147:Pain Measurement / Q000187:drug effects; D011869:Radioligand Assay / Q000379:methods; D051381:Rats; D017207:Rats, Sprague-Dawley; D043882:Receptors, Cannabinoid / Q000502:physiology*; D011957:Receptors, Opioid / Q000502:physiology*; D013460:Sulfur Isotopes / Q000493:pharmacokinetics; D014316:Tritium / Q000493:pharmacokinetics
chemical_list: D002186:Cannabinoids; D003511:Cyclohexanols; D009294:Narcotics; D043882:Receptors, Cannabinoid; D011957:Receptors, Opioid; D013460:Sulfur Isotopes; D014316:Tritium; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D016244:Guanosine 5'-O-(3-Thiotriphosphate); C054649:3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol; D000242:Cyclic AMP