Gabapentin inhibits the substance P-facilitated K+-evoked release of [3H]glutamate from rat caudal 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 [H-3]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 muM. 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 NK1 receptor in mediating the facilitatory effect. On its own, gabapentin at up to 100 muM 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 (EC50 = 6.49 muM). 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 muM 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. (C) 2001 International Association for the Study of Pain. Published by Elsevier Science B.V. All rights reserved.