Gamma-aminobutyric acidB, but not gamma-aminobutyric acidA 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 afferent neurons involved in nociception. Because baclofen alters nociception at the level of the spinal cord and the receptor it activates (gamma-aminobutyric acidB; GABAB) 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 microM) and (-)-baclofen (IC50, 0.8 +/- 0.2 microM) in a dose-dependent manner. The effect of baclofen was stereospecific, (+)-baclofen being approximately 1000 times weaker then the (-)-isomer. The GABAA agonist, isoguvacine (10-100 microM), did not reduce SP release but, if anything, tended to increase SP release. GABA- and (-)-baclofen-induced inhibition of electrically evoked SP release was antagonized by the GABAB antagonists, CGP 35348 and CGP 36742 (10-100 microM). Bicuculline (300 microM) did not affect GABA-inhibition of SP release. These observations suggest that GABAB receptors are likely to mediate the effect of GABA and baclofen on primary afferent terminals. In view of the presence of GABAB receptors in the dorsal horn of the rat spinal 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 spinal cord.
Malcangio
M
M
Department of Pharmacology, School of Pharmacy, London, United Kingdom.
Bowery
N G
NG
D000818:Animals; D001418:Baclofen / Q000494:pharmacology; D004558:Electric Stimulation; D018756:GABA Antagonists; D066298:In Vitro Techniques; D014179:Neurotransmitter Uptake Inhibitors / Q000494:pharmacology; D009943:Organophosphorus Compounds / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000187:drug effects / Q000502:physiology*; D013116:Spinal Cord / Q000187:drug effects* / Q000378:metabolism*; D013373:Substance P / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism*; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology*
D018756:GABA Antagonists; D014179:Neurotransmitter Uptake Inhibitors; D009943:Organophosphorus Compounds; D011963:Receptors, GABA-A; C079148:(3-aminopropyl)(n-butyl)phosphinic acid; D013373:Substance P; D005680:gamma-Aminobutyric Acid; D001418:Baclofen