Alterations in brain Protein Kinase A activity and reversal of morphine tolerance by two fragments of native Protein Kinase A inhibitor peptide (PKI).
Two peptide fragments of native Protein Kinase A inhibitor (PKI), PKI-(6-22)-amide and PKI-(Myr-14-22)-amide, significantly reversed low-level morphine antinociceptive tolerance in mice. The inhibition of Protein Kinase A (PKA) activity by both peptide fragments was then measured in specific brain regions (thalamus, periaqueductal gray (PAG), and medulla) and in lumbar spinal cord (LSC), which in previous studies have been shown to play a role in morphine-induced analgesia. In drug naive animals, cytosolic PKA activity was greater than particulate PKA activity in each region, while cytosolic and particulate PKA activities were greater in thalamus and PAG compared to medulla and LSC. The addition of both peptides to homogenates from each region completely abolished cytosolic and particulate PKA activities in vitro. Following injection into the lateral ventricle of the brain of drug naive mice and morphine-tolerant mice, both peptides inhibited PKA activity in the cytosolic, but not the particulate fraction of LSC. In addition, cytosolic and particulate PKA activities were inhibited by both peptides in thalamus. These results demonstrate that the inhibition of PKA reverses morphine tolerance. Moreover, the inhibition of PKA activity in specific brain regions and LSC from morphine-tolerant mice by PKI analogs administered i.c.v. is evidence that PKA plays a role in morphine tolerance.
Dalton
George D
GD
Department of Pharmacology and Toxicology, Virginia Commonwealth University School of Medicine, Richmond, 3298-0613, USA.
Smith
Forrest L
FL
Smith
Paul A
PA
Dewey
William L
WL
D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000201:enzymology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D007276:Injections, Intraventricular / Q000379:methods; D047908:Intracellular Signaling Peptides and Proteins / Q000494:pharmacology*; D008297:Male; D051379:Mice; D009020:Morphine / Q000008:administration & dosage; D009021:Morphine Dependence / Q000188:drug therapy / Q000201:enzymology*; D009294:Narcotics / Q000008:administration & dosage; D009433:Neural Inhibition / Q000187:drug effects; D010147:Pain Measurement / Q000187:drug effects; D010446:Peptide Fragments / Q000494:pharmacology*; D013116:Spinal Cord / Q000187:drug effects / Q000201:enzymology; D013997:Time Factors
D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D009294:Narcotics; D010446:Peptide Fragments; C094636:protein kinase inhibitor (6-22); D009020:Morphine; D017868:Cyclic AMP-Dependent Protein Kinases