D-Baclofen Is an Antagonist at Baclofen Receptors Mediating Antinociception in the Spinal Cord

Abstract

The antagonistic action of D-baclofen at baclofen receptors mediating antinociception in the spinal cord was examined. Drugs were administered intrathecally to rats and effects on nociceptive threshold evaluated in the tail flick test. L-Baclofen, D-baclofen and the racemate produced dose-related increases in tail flick latency, with L-baclofen being twice as potent as the racemate and approximately 100 times more potent than D-baclofen. When D-baclofen was injected 15 min prior to L-baclofen, it produced a dose-related inhibition of the effect of L-baclofen. Concomitant administration produced a more ambiguous effect. Antagonism appeared specific for baclofen receptors because analogues with full and partial agonist activity as well as an agonist dose of D-baclofen, but not morphine or noradrenaline, were inhibited by pretreatment with D-baclofen. γ-Aminobutyric acid (GABA) did not increase tail flick latency either alone or following pretreatment with an uptake inhibitor or a GABA-transaminase inhibitor. Antinociception produced by intrathecal administration of Baclofen appears to result from activation of a receptor which is stereoselective for the L-isomer and can be blocked by D-baclofen in doses which have initial agonist activity. This receptor may not be a GABA subtype because GABA does not mimic the effect of baclofen and the rank order of potency of analogues differs from established GABAB systems.

CGP 35348, a new GABAB antagonist, prevents antinociception and muscle‐relaxant effect induced by baclofen

“…administration supports the contention that (±)-baclofen-induced antinociception is centrally mediated (Liebman & Pastor, 1980;Sawynok, 1987 reported to antagonize partially the effects of (-)-baclofen, when injected intrathecally at high doses (10pg) (Sawynok & Dickson, 1985a;Sawynok 1986 (Olpe et al, 1990). However, in our study, phaclofen injected intracerebroventricularly was unable to prevent (±)baclofen-induced antinociception.…”

“…Although some compounds, namely (+ )-baclofen, 6-aminovaleric acid and phaclofen have been reported to prevent (±)-baclofen-induced antinociception, their lack of brain penetration and low potency have hampered in vivo studies (Bowery, 1989). In fact, (+ )-baclofen and 6-aminovaleric acid only inhibit the antinociception if injected intrathecally at doses at least 20 times higher than those of (-)-baclofen (Sawynok & Dickson, 1985a;Sawynok, 1986).…”

The Pharmacology of Pain

“…In the rat, intrathecal administration of baclofen increases response latencies in the tail-flick and hot-plate tests in a dose-dependent and stereospecific manner (ARAN and HAMMOND 1991;HAMMOND and DROWER 1984;SAWYNOK and DICKSON 1985;WILSON and Y AKSH 1978) and suppresses both phase 1 and phase 2 responses to injection of formalin in the hindpaw (DIRIG and Y AKSH 1995). In the rat, intrathecal administration of baclofen increases response latencies in the tail-flick and hot-plate tests in a dose-dependent and stereospecific manner (ARAN and HAMMOND 1991;HAMMOND and DROWER 1984;SAWYNOK and DICKSON 1985;WILSON and Y AKSH 1978) and suppresses both phase 1 and phase 2 responses to injection of formalin in the hindpaw (DIRIG and Y AKSH 1995).…”

The Neuropharmacology of Baclofen

“…In a number of behavioral studies and electrophysiological investigations in vivo, it has been shown that the (-)isomer of baclofen is more potent than the (H-)isomer [4,52,53,80,81,107] It was reported by various authors that the (-h)isomer can antagonize the actions of the (-)isomer [94,104,105] (see also Yaksh, this volume). In recent electrophysiological experiments in which intracellular recording techniques were employed however, no such antagonism could be demonstrated [4,58].…”