Actions of the GABA_B agonist, (−)‐baclofen, on neurones in deep dorsal horn of the rat spinal cord in vitro

Abstract

1 The electrophysiological actions of the GABAB agonist, (-)-baclofen, on deep dorsal horn neurones were studied using an in vitro preparation of the spinal cord of 9-16 day old rat.2 On all neurones tested, (-)-baclofen (100nM-30.uM) had a hyperpolarizing action which was associated with a reduction in apparent membrane input resistance. The increase in membrane conductance was dose-dependent and had a Hill coefficient of 1.0.3 The (-)-baclofen-activated hyperpolarization persisted in the presence of bicuculline (50 gM) and Mg2+ (20mM). 4 The reversal potential of the hyperpolarizing event was estimated at 102 mV and was made less negative by increasing the external concentration of potassium ions. 5 Over the same concentration range, (--baclofen also depressed the polysynaptic composite excitatory postsynaptic potentials (e.p.s.ps) evoked in these neurones by electrical stimulation of the dorsal root entry zone. 6 The potassium channel blockers caesium, applied intracellularly, and barium, applied extracellularly, depressed the postsynaptic response to baclofen but not its effect on e.p.s.ps. 7 We propose that (--baclofen has more than one mechanism of action in spinal dorsal horn: a postsynaptic action mediated via an increase in potassium conductance and a presynaptic action that is not associated with potassium channels and may be mediated via calcium channels. Since previous studies have demonstrated little effect of (-)-baclofen on transmitter release in spinal cord, it is possible that the postsynaptic hyperpolarizing action of (-)-baclofen may account for its clinical potency as an anti-spastic agent.

Omega-conotoxin sensitivity and presynaptic inhibition of glutamatergic sensory neurotransmission in vitro

“…The present experiments did not reveal a peptide-mediated EPSP, EPSPs were consistently and completely blocked by CNQX, and a prolonged EPSP was never observed, even after high-frequency presynaptic stimulation. Our finding that baclofen had no postsynaptic effect on spinal cord neurons is consistent with some, but not all previous reports (Lev-Tov et al, 1988;Peng and Frank, 1989; but see also Allerton et al, 1989;Kangrga et al, 199 1). Differences between the present findings and these previous reports may be due to our use of a dissociated cell preparation, or may reflect the use of embryonic tjssue.…”

“…GABA, receptors on neurons in the spinal cord (Allerton et al, 1989;Wang and Dun, 1990;Kangrga et al, 1991) and brain (Newberry and Nicoll, 1984;Gahwiler and Brown, 1985;Howe et al, 1987;Connors et al, 1988) are coupled to the activation of a potassium conductance. Interestingly, GABAergic inputs onto hippocampal CA1 pyramidal neurons are presynaptically inhibited via this potassium conductance .…”

Inhibitory control of plateau properties in dorsal horn neurones in the turtle spinal cord in vitro

“…Second, baclofen also had a prominent postsynaptic effect. As described previously in the hippocampus (Newberry & Nicoll, 1984) and rat dorsal horn (Allerton et al 1989), the hyperpolarization induced by baclofen in plateau neurones in the turtle was associated with decreased input resistance. In hippocampal pyramidal neurones, the baclofen-induced hyperpolarization is produced by a K¤ conductance (Newberry & Nicoll, 1984) which is blocked by low concentrations of Ba¥ (G ahwiler & Brown, 1985).…”

“…In the hippocampus (G ahwiler & Brown, 1985) and spinal cord (Allerton, Boden & Hill, 1989) the hyperpolarization mediated by GABAB receptors is sensitive to low concentrations of Ba¥. In agreement, extracellular Ba¥ (1-2 mÒ, n = 7) decreased the baclofen-induced hyperpolarization (not illustrated) and shunt (Fig.…”

Inhibition of the centrally induced increases in myocardial oxygen demand in rabbits by chronic treatment with baclofen, a selective GABAB agonist

“…It has already been demonstrated that baclofen selectively inhibits the release of excitatory amino acids like aspartate and glutamate (Johnston et al, 1980;Davies, 1981;Lanthorn & Cotman, 1981). In fact, the activation of GABAB receptors, which are also located on nerve terminals, leads to the inhibition of neurotransmitter release via the opening of K+ channels and consequent neuronal hyperpolarization (Bowery et al, 1980;Newberry & Nicoll, 1984;1985;Raiteri et al, 1989;Potier & Dutar, 1993) or inhibition of calcium currents (Zhu & Chuang, 1987;Allerton et al, 1989;Maguire et al, 1989). Furthermore, the neuronal inhibitory effects of low doses of systemically administered baclofen, which correspond to the dose-range used in this study, on the synaptic excitatory transmission in the CNS, is mediated by a presynaptic action (Pierau & Zimmerman, 1973;Fox et al, 1978;Davies, 1981).…”