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.

The e ects of the synthetic cannabinoid WIN 55,212-2 on forskolin-stimulated and basal adenosine 3' : 5'-cyclic monophosphate (cyclic AMP) accumulation in globus pallidus slices were investigated. WIN 55,212-2 caused a concentration-dependent decrease in forskolin-stimulated cyclic AMP accumulation in globus pallidus slices (maximum inhibition 36% for 30 mM). This e ect was blocked by the cannabinoid receptor antagonist SR 141716A (100 mM). WIN 55,212-2 alone caused a concentration-dependent increase in cyclic AMP levels in unstimulated slices (maximum increase 52.6% for 100 mM). This e ect was also blocked by SR 141716A (100 mM). In either forskolin-stimulated or unstimulated conditions SR 1417161A (100 mM) did not a ect cyclic AMP levels.

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The e ect 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 mM) 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 mM), and again this facilitatory e ect was blocked by gabapentin (30 mM). 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.