title: Trifluoperazine, an orally available clinically used drug, disrupts opioid antinociceptive tolerance.
abstract: Calcium/calmodulin dependent protein kinase II (CaMKII) has been shown to play an important role in the generation and maintenance of opioid tolerance. In this study, trifluoperazine was studied for its effect on morphine tolerance in mice. Acute treatment with trifluoperazine (0.5 mg/kg, i.p.) completely reversed the established antinociceptive tolerance to morphine. Pretreatment with trifluoperazine also significantly attenuated the development of antinociceptive tolerance (p<0.01). Morphine induced a significant up-regulation of supraspinal and spinal CaMKII activity in tolerant mice, which was abolished after the pretreatment or acute treatment with trifluoperazine. These data suggested that trifluoperazine was capable of suppressing opioid tolerance, possibly by the mechanism of inhibiting CaMKII. Since trifluoperazine has been safely used as an antipsychotic drug, we propose that the drug should be studied in humans for the prevention and treatment of opioid tolerance and addiction.
authors.affiliation: Department of Biopharmaceutical Sciences, College of Pharmacy, University of Illinois, 833 South Woods Street, Chicago, IL 60612, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Tang
authors.forename: Pradeep K
authors.initials: PK
authors.lastname: Shukla
authors.forename: Zaijie Jim
authors.initials: ZJ
authors.lastname: Wang
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D015153:Blotting, Western / Q000379:methods; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D004347:Drug Interactions; D004361:Drug Tolerance; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009020:Morphine / Q000009:adverse effects*; D009021:Morphine Dependence / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control; D009294:Narcotics / Q000009:adverse effects*; D010147:Pain Measurement / Q000379:methods; D011930:Reaction Time / Q000187:drug effects; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism; D014268:Trifluoperazine / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D009294:Narcotics; D014268:Trifluoperazine; D009020:Morphine; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases