title: Chronic Delta9-tetrahydrocannabinol treatment produces antinociceptive tolerance in mice without altering protein kinase A activity in mouse brain and spinal cord.
abstract: The present study investigated the effect of different levels of Delta-9-tetrahydrocannabinol (Delta(9)-THC) antinociceptive tolerance on Protein Kinase A (PKA) activity in mouse brain and spinal cord. To strengthen this investigation, a positive control was developed to demonstrate the assay utilized in this study was sensitive enough to detect an increase in PKA activity in the anatomical regions utilized in this study. The membrane-permeant and phosphodiesterase-resistant cAMP analog 8-Bromoadenosine-3',5'-cyclic monophosphorothioate, Sp-isomer (Sp-8-Br-cAMPS) was utilized for the development of this positive control and this compound produced an increase in PKA activity in several mouse brain regions (i.c.v.) and lumbar spinal cord (i.t.) following its administration. Models were then developed in which mice expressed either a 13-fold or 49-fold level of Delta(9)-THC antinociceptive tolerance following chronic treatment with 10mg/kg Delta(9)-THC or 80mg/kg Delta(9)-THC for 6.5 days. Basal and total cytosolic and particulate PKA activities were measured directly in homogenates from the striatum, hippocampus, cerebellum, cortex and lumbar spinal cord. Results from this study indicate that chronic exposure to Delta(9)-THC does not produce an increase in PKA activity in these mouse brain regions or spinal cord. Future work is needed to determine the role of PKA in cannabinoid tolerance in mice.
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University Medical Center, 1112 E. Clay Street McGuire Hall, Box 980613, Richmond, VA 23298, USA. gddalton@hsc.vcu.edu <gddalton@hsc.vcu.edu>
authors.forename: George D
authors.initials: GD
authors.lastname: Dalton
authors.forename: Forrest L
authors.initials: FL
authors.lastname: Smith
authors.forename: Paul A
authors.initials: PA
authors.lastname: Smith
authors.forename: William L
authors.initials: WL
authors.lastname: Dewey
mesh_terms: D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D001921:Brain / Q000201:enzymology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D013759:Dronabinol / Q000494:pharmacology*; D004361:Drug Tolerance; D004789:Enzyme Activation; D008297:Male; D051379:Mice; D013116:Spinal Cord / Q000201:enzymology*; D013873:Thionucleotides / Q000008:administration & dosage / Q000494:pharmacology
chemical_list: C105593:8-bromoadenosine-3',5'-cyclic monophosphorothioate; D000700:Analgesics; D013873:Thionucleotides; D015124:8-Bromo Cyclic Adenosine Monophosphate; D013759:Dronabinol; D017868:Cyclic AMP-Dependent Protein Kinases