Phosphodiesterase 2A localized in the spinal cord contributes to inflammatory pain processing.
BACKGROUND
Phosphodiesterase 2A (PDE2A) is an evolutionarily conserved enzyme that catalyzes the degradation of the cyclic nucleotides, cyclic adenosine monophosphate, and/or cyclic guanosine monophosphate. Recent studies reported the expression of PDE2A in the dorsal horn of the spinal cord, pointing to a potential contribution to the processing of pain. However, the functions of PDE2A in spinal pain processing in vivo remained elusive.


METHODS
Immunohistochemistry, laser microdissection, and quantitative real-time reverse transcription polymerase chain reaction experiments were performed to characterize the localization and regulation of PDE2A protein and messenger RNA in the mouse spinal cord. Effects of the selective PDE2A inhibitor, BAY 60-7550 (Cayman Chemical, Ann Arbor, MI), in animal models of inflammatory pain (n = 6 to 10), neuropathic pain (n = 5 to 6), and after intrathecal injection of cyclic nucleotides (n = 6 to 8) were examined. Also, cyclic adenosine monophosphate and cyclic guanosine monophosphate levels in spinal cord tissues were measured by liquid chromatography tandem mass spectrometry.


RESULTS
The authors here demonstrate that PDE2A is distinctly expressed in neurons of the superficial dorsal horn of the spinal cord, and that its spinal expression is upregulated in response to hind paw inflammation. Administration of the selective PDE2A inhibitor, BAY 60-7550, increased the nociceptive behavior of mice in animal models of inflammatory pain. Moreover, BAY 60-7550 increased the pain hypersensitivity induced by intrathecal delivery of cyclic adenosine monophosphate, but not of cyclic guanosine monophosphate, and it increased the cyclic adenosine monophosphate levels in spinal cord tissues.


CONCLUSIONS
Our findings indicate that PDE2A contributes to the processing of inflammatory pain in the spinal cord.
From the Pharmazentrum Frankfurt/Zentrum für Arzneimittelforschung, -entwicklung und -sicherheit, Institut für Klinische Pharmakologie, Universitätsklinikum Frankfurt, Frankfurt am Main, Germany (W.K-.G., R.L., A.B., D.T., J.E.L., N.L., N.F., G.G., A.S.); Institut für Pharmakologie und Toxikologie, Zentrum für Biomedizinische Ausbildung und Forschung, Universität Witten/Herdecke, Witten, Germany (R.L., C.I.R., A.S.); and Institut für Klinische Neuroanatomie, Neuroscience Center, Goethe-Universität, Frankfurt am Main, Germany (J.S., D.D.T.). Current address: Institut für Neuroradiologie, Universitätsklinikum Frankfurt, Frankfurt am Main, Germany (A.B.).
Wiebke
W
Kallenborn-Gerhardt
Ruirui
R
Lu
Aaron
A
Bothe
Dominique
D
Thomas
Jessica
J
Schlaudraff
Jana E
JE
Lorenz
Nancy
N
Lippold
Catherine I
CI
Real
Nerea
N
Ferreirós
Gerd
G
Geisslinger
Domenico
D
Del Turco
Achim
A
Schmidtko
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D000242:Cyclic AMP / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D054678:Cyclic Nucleotide Phosphodiesterases, Type 2 / Q000096:biosynthesis / Q000378:metabolism* / Q000502:physiology*; D004342:Drug Hypersensitivity / Q000503:physiopathology; D007093:Imidazoles / Q000008:administration & dosage / Q000494:pharmacology; D007150:Immunohistochemistry; D007249:Inflammation / Q000150:complications / Q000201:enzymology* / Q000503:physiopathology*; D007278:Injections, Spinal; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D042282:Microdissection; D009437:Neuralgia / Q000201:enzymology / Q000503:physiopathology / Q000523:psychology; D010146:Pain / Q000201:enzymology* / Q000209:etiology / Q000503:physiopathology*; D010147:Pain Measurement; D010726:Phosphodiesterase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D020671:Posterior Horn Cells / Q000201:enzymology; D060888:Real-Time Polymerase Chain Reaction; D013116:Spinal Cord / Q000201:enzymology*; D014227:Triazines / Q000008:administration & dosage / Q000494:pharmacology; D015854:Up-Regulation / Q000235:genetics / Q000502:physiology; D015054:Zymosan
C539142:2-(3,4-dimethoxybenzyl)-7-(1-(1-hydroxyethyl)-4-phenylbutyl)-5-methylimidazo(5,1-f)(1,2,4)triazin-4 (3H)-one; D007093:Imidazoles; D010726:Phosphodiesterase Inhibitors; D014227:Triazines; D015054:Zymosan; D000242:Cyclic AMP; D054678:Cyclic Nucleotide Phosphodiesterases, Type 2; D006152:Cyclic GMP