Protein kinase A-dependence of the supraspinally mediated analgesic effects of gabapentin on thermal and mechanical hypersensitivity.

Abstract	We have recently shown that gabapentin generates protein kinase A (PKA)-dependent presynaptic inhibition of GABAergic synaptic transmission in locus coeruleus (LC) neurons only under neuropathic states. To verify behaviorally this in vitro electrophysiological finding, the PKA inhibitor H-89 was injected intracerebroventricularly (i.c.v.) before supraspinal application of gabapentin in mice developing thermal and mechanical hypersensitivity after peripheral nerve injury. H-89 dose-dependently attenuated the analgesic effects of i.c.v.-injected gabapentin, suggesting that PKA-dependent removal of GABAergic inhibition of LC neurons is the most plausible synaptic mechanism underlying the supraspinally mediated analgesic effects of gabapentin involving activation of the descending noradrenergic pain-inhibitory system.
Authors	Keiko Takasu, Yu Kinoshita, Hideki Ono, Mitsuo Tanabe
Journal	Journal of pharmacological sciences (J Pharmacol Sci) Vol. 110 Issue 2 Pg. 223-6 (Jun 2009) ISSN: 1347-8613 [Print] Japan
PMID	19498268 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	Amines Analgesics Cyclohexanecarboxylic Acids Isoquinolines Protein Kinase Inhibitors Sulfonamides gamma-Aminobutyric Acid Gabapentin Cyclic AMP-Dependent Protein Kinases N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide
Topics	Amines (pharmacology) Analgesics (pharmacology) Animals Cyclic AMP-Dependent Protein Kinases (drug effects, metabolism) Cyclohexanecarboxylic Acids (pharmacology) Dose-Response Relationship, Drug Gabapentin Injections, Intraventricular Isoquinolines (administration & dosage, pharmacology) Locus Coeruleus (drug effects, metabolism) Male Mice Pain (drug therapy, physiopathology) Pain Measurement Protein Kinase Inhibitors (administration & dosage, pharmacology) Sulfonamides (administration & dosage, pharmacology) gamma-Aminobutyric Acid (metabolism, pharmacology)

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