Block by gabapentin of the facilitation of glutamate release from rat trigeminal nucleus following activation of protein kinase C or adenylyl cyclase.
The effect of activation of protein kinase C (PKC) or adenylyl cyclase on release of glutamate has been investigated in a perfused slice preparation from the rat caudal trigeminal nucleus. Stimulation of PKC by phorbol 12-myristate 13-acetate (PMA) produced a concentration-dependent increase in K(+)-evoked release of [(2)H]-glutamate (maximum increase 45%, EC(50) 11.8 nM), but in the presence of gabapentin (30 microM) the facilitation of release was blocked. The adenylyl cyclase activator forskolin (FSK) also induced a concentration-dependent increase in K(+)-evoked release of [(3)H]-glutamate (maximum increase 36%, EC(50) 2.4 microM), and again this facilitatory effect was blocked by gabapentin (30 microM). We suggest that these results may be of relevance to the antihyperalgesic properties of gabapentin, in conditions where concomitant release of substance P and CGRP produces activation of PKC and adenylyl cyclase respectively.
Maneuf
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Pfizer Global R&D, Cambridge Laboratories, University of Cambridge Forvie Site, Robinson Way, Cambridge CB2 2QB. yann.helen@virgin.net
McKnight
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D000085:Acetates / Q000494:pharmacology*; D000262:Adenylyl Cyclases / Q000378:metabolism*; D000588:Amines; D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D005576:Colforsin / Q000494:pharmacology; D003509:Cyclohexanecarboxylic Acids; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D000077206:Gabapentin; D018698:Glutamic Acid / Q000187:drug effects* / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D011188:Potassium / Q000494:pharmacology; D011493:Protein Kinase C / Q000378:metabolism*; D051381:Rats; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014278:Trigeminal Nuclei / Q000187:drug effects* / Q000378:metabolism; D014316:Tritium; D005680:gamma-Aminobutyric Acid
D000085:Acetates; D000588:Amines; D000700:Analgesics; D003509:Cyclohexanecarboxylic Acids; D014316:Tritium; D005576:Colforsin; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin; D011493:Protein Kinase C; D000262:Adenylyl Cyclases; D013755:Tetradecanoylphorbol Acetate; D011188:Potassium