Molecular mechanisms of the antispasticity effects of baclofen on spinal ventral horn neurons

Background Baclofen is a lipophilic gamma-aminobutyric acid (GABA) derivative that exhibits strong intrinsic activity and a high affinity for GABA(B) receptors. Intrathecal baclofen therapy has been used as an antispasticity and muscle relaxant drug in the clinical treatment of patients with severe spasticity. However, the cellular mechanisms of the antispasticity effects of baclofen on the ventral horn neurons of the spinal cord are unknown. Objective We examined the action of baclofen on excitatory synaptic transmission in ventral horn neurons in the rat spinal cord by whole-cell patch-clamp recordings. Results Baclofen significantly reduced the frequency and amplitude of miniature excitatory postsynaptic currents. The reduction in miniature excitatory postsynaptic current frequency was particularly strong, indicating presynaptic inhibition by baclofen. Moreover, baclofen-induced outward currents in all neurons tested. The baclofen-induced outward currents persisted in the presence of tetrodotoxin and glutamate receptor antagonists and were diminished in the presence of the postsynaptic intracellular K+ channel blocker cesium sulfate and the G-protein inhibitor guanosine 5 '-(beta-thio)diphosphate trilithium salt. These results indicate direct postsynaptic depression mediated by G-protein-activated K+ channels by GABA(B) receptors on ventral horn neurons. The baclofen-induced outward currents and the inhibitory effects on spontaneous excitatory postsynaptic currents were blocked by the selective GABA(B) receptor antagonist CGP35348. Conclusion Baclofen may have both presynaptic and postsynaptic capacity to inhibit synaptic transmission in ventral horn neurons by GABA(B) receptors. These cellular mechanisms may induce the antispasticity effects of intrathecal baclofen therapy in the spinal cord. Copyright (c) 2018 Wolters Kluwer Health, Inc. All rights reserved.