Gabapentin inhibits the substance P-facilitated K(+)-evoked release of [(3)H]glutamate from rat caudial trigeminal nucleus slices.
The effect of gabapentin on the release of the spinal sensory neurotransmitter glutamate has been investigated in an in vitro model using a perfused thin slice preparation from the rat brainstem containing the spinal trigeminal caudal subnucleus (Sp5C) and pre-incubated with [(3)H]glutamate. Addition of excess K(+) to the perfusing solution increased the content of tritium in the perfusate. The prior addition of substance P increased this index of glutamate release in a concentration-dependent manner, with the mean maximum of around 50% increase obtained at 1-3 microM. The action of substance P to increase the evoked release of glutamate was blocked by the antagonist CP-99994, suggesting a specific involvement of the NK(1) receptor in mediating the facilitatory effect. On its own, gabapentin at up to 100 microM did not modify the baseline level of K(+)-evoked release of glutamate; however, gabapentin caused a concentration-dependent decrease of the facilitatory effect of substance P (EC(50)=6.49 microM). The R-(-)- and S-(+)-isomers of 3-isobutylgaba were then tested against the increase in K(+)-evoked release of glutamate by substance P. S-(+)-3-isobutylgaba (pregabalin) at 30 microM acted like gabapentin to reduce the substance P-mediated increase of release almost to the baseline level of K(+)-evoked release, while in contrast the R-(-)-isomer at this concentration produced no reduction, and rather a trend towards a further enhancement of the potentiating effect of substance P. In conclusion, we have found and characterized an effect of gabapentin that is of possible mechanistic relevance to the anti-hyperalgesic/allodynic actions of this compound.
Maneuf
Yannick P
YP
Pfizer Global Research & Development, Cambridge Laboratories, Cambridge University Forvie Site, Robinson Way, Cambridge CB2 2QB, UK.
Hughes
John
J
McKnight
Alexander T
AT
D000085:Acetates / Q000494:pharmacology*; D000588:Amines; D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology; D003509:Cyclohexanecarboxylic Acids; D004305:Dose-Response Relationship, Drug; D000077206:Gabapentin; D018698:Glutamic Acid / Q000493:pharmacokinetics*; D008297:Male; D064729:Neurokinin-1 Receptor Antagonists; D009924:Organ Culture Techniques; D010880:Piperidines / Q000494:pharmacology; D011188:Potassium / Q000494:pharmacology; D000069583:Pregabalin; D051381:Rats; D011919:Rats, Inbred Strains; D013237:Stereoisomerism; D013373:Substance P / Q000494:pharmacology*; D014279:Trigeminal Nucleus, Spinal / Q000187:drug effects / Q000378:metabolism*; D014316:Tritium; D005680:gamma-Aminobutyric Acid / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology
D000085:Acetates; D000588:Amines; D000700:Analgesics; D000927:Anticonvulsants; D003509:Cyclohexanecarboxylic Acids; D064729:Neurokinin-1 Receptor Antagonists; D010880:Piperidines; D014316:Tritium; C080755:3-(2-methoxybenzylamino)-2-phenylpiperidine; D013373:Substance P; D018698:Glutamic Acid; D000069583:Pregabalin; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin; D011188:Potassium