PGE(2) selectively blocks inhibitory glycinergic neurotransmission onto rat superficial dorsal horn neurons.
Despite the crucial role that prostaglandins (PGs) have in the sensitization of the central nervous system to pain, their cellular and molecular targets leading to increased pain perception have remained elusive. Here we investigated the effects of PGE(2) on fast synaptic transmission onto neurons in the rat spinal cord dorsal horn, the first site of synaptic integration in the pain pathway. We identified the inhibitory (strychnine-sensitive) glycine receptor as a specific target of PGE(2). PGE(2), but not PGF(2 alpha), PGD(2) or PGI(2), reduced inhibitory glycinergic synaptic transmission in low nanomolar concentrations, whereas GABAA, AMPA and NMDA receptor-mediated transmission remained unaffected. Inhibition of glycine receptors occurred via a postsynaptic mechanism involving the activation of EP2 receptors, cholera-toxin-sensitive G-proteins and cAMP-dependent protein kinase. Via this mechanism, PGE(2) may facilitate the transmission of nociceptive input through the spinal cord dorsal horn to higher brain areas where pain becomes conscious.
Ahmadi
Seifollah
S
Institut für Experimentelle und Klinische Pharmakologie und Toxikologie, Emil-Fischer-Zentrum, Fahrstrasse 17, D-91054 Erlangen, Germany.
Lippross
Sebastian
S
Neuhuber
Winfried L
WL
Zeilhofer
Hanns U
HU
D000818:Animals; D002772:Cholera Toxin / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D015232:Dinoprostone / Q000494:pharmacology / Q000502:physiology*; D004594:Electrophysiology; D005260:Female; D005998:Glycine / Q000378:metabolism; D020962:Heterotrimeric GTP-Binding Proteins / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D016202:N-Methylaspartate / Q000378:metabolism; D010146:Pain / Q000378:metabolism / Q000503:physiopathology; D020671:Posterior Horn Cells / Q000187:drug effects / Q000378:metabolism*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018009:Receptors, Glycine / Q000378:metabolism*; D011982:Receptors, Prostaglandin / Q000819:agonists / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects*; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D018009:Receptors, Glycine; D011982:Receptors, Prostaglandin; D005680:gamma-Aminobutyric Acid; D016202:N-Methylaspartate; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; D002772:Cholera Toxin; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; D020962:Heterotrimeric GTP-Binding Proteins; D015232:Dinoprostone; D005998:Glycine