GAMMA-AMINOBUTYRIC ACID(B), BUT NOT GAMMA-AMINOBUTYRIC ACID(A) RECEPTOR ACTIVATION, INHIBITS ELECTRICALLY-EVOKED SUBSTANCE P-LIKE IMMUNOREACTIVITY RELEASE FROM THE RAT SPINAL-CORD IN-VITRO

Substance P (SP) is believed to be a neuromodulator of primary afferen t neurons involved in nociception. Because baclofen alters nociception at the level of the spinal cord and the receptor it activates (gamma- aminobutyric acid(B); GABA(B)) is located on presynaptic terminals, we examined whether this agent and GABA could influence the electrically evoked release of SP from rat spinal cord in vitro. The calcium- and tetrodotoxin-dependent release of SP was inhibited completely by GABA (IC50, 165 +/- 17.8 muM) and (-)-baclofen (IC50, 0.8 +/- 0.2 muM) in a dose-dependent manner. The effect of baclofen was stereospecific, (+) -baclofen being approximately 1000 times weaker then the (-)- isomer. The GABA(A) agonist, isoguvacine (10-100 muM), did not reduce SP relea se but, if anything, tended to increase SP release. GABA- and (-)-bacl ofen-induced inhibition of electrically evoked SP release was antagoni zed by the GABA(B) antagonists, CGP 35348 and CGP 36742 (10-100 muM). Bicuculline (300 muM) did not affect GABA-inhibition of SP release. Th ese observations suggest that GABA(B) receptors are likely to mediate the effect of GABA and baclofen on primary afferent terminals. In view of the presence of GABA(B) receptors in the dorsal horn of the rat sp inal cord on slow conducting primary afferent terminals which contain SP, we suggest that the inhibition of the neuropeptide release may be one mechanism to explain baclofen-induced antinociception within the s pinal cord.