Pregabalin Exerts Oppositional Effects on Different Inhibitory Circuits in Human Motor Cortex: A Double‐blind, Placebo‐controlled Transcranial Magnetic Stimulation Study

Abstract

Summary:Purpose: To explore acute effects of pregabalin (PGB) on human motor cortex excitability with transcranial magnetic stimulation (TMS).Methods: PGB, 600 mg/day, was orally administered in 19 healthy subjects twice daily in a randomized, double-blind, placebo-controlled crossover design. Several measures of motor cortex excitability were tested with single-and paired-pulse TMS.Results: Mean short-interval intracortical inhibition (SICI) was reduced after PGB (74 ± 7% of unconditioned response) compared with placebo (60 ± 6% of unconditioned response). In contrast, mean long-interval intracortical inhibition (LICI) was increased by PGB (26 ± 4% of unconditioned response) compared with placebo (45 ± 8% of unconditioned response), and mean cortical silent period (CSP) showed an increase from 139 ± 8 ms or 145 ± 8 ms after placebo to 162 ± 7 ms or 161 ± 10 ms after PGB. Motor thresholds, intracortical facilitation, and corticospinal excitability were unaffected.Conclusions: The observed excitability changes with oppositional effects on SICI and LICI or CSP suggest γ -aminobutyric acid (GABA) B -receptor activation. They are markedly distinct from those induced by gabapentin, although both PGB and gabapentin are thought to mediate their function by binding to the α(2)-δ subunit of voltage-gated calcium channels. Conversely, the TMS profile of PGB shows striking similarities with the pattern evoked by the GABA-reuptake inhibitor tiagabine.

New Perspectives in Transcranial Magnetic Stimulation: Epilepsy, Consciousness and the Perturbational Approach

“…In fact, the observation by Werhahn et al [80] that tiagabine decreases SICI is in line with this finding on the basis of drug auto-inhibition of inhibitory neurons, and an analogous mechanism has also been proposed for pregabalin [84].…”

“…This mechanism was proposed based on the observation that tiagabine [80] and pregabalin [84] lengthen CSP. An indirect effect on the same receptor is believed to explain the effect induced by levetriracetam [70].…”

GABAergic Contributions to the Pathophysiology of Depression and the Mechanism of Antidepressant Action

“…However, the pregabalin's effect on TMS measures of SICI and LICI or CSP suggests GABAB activation, and the drug generates an excitability pattern similar to that seen for tiagabine [237]. Early preliminary data suggests pregabalin, an analogue of gabapentin, is effective and safe in the short-term as therapy for generalized anxiety disorder [238,239].…”

Changes in corticospinal excitability during an acute bout of resistance exercise in the elbow flexors

“…The initial portion of the silent period (50-75 ms) is primarily due to spinal inhibitory mechanism such as after-hyperpolarization and recurrent inhibition of motoneurons, whilst the later part represents cortical inhibition (Fuhr et al 1991;Inghilleri et al 1993;Ziemann et al 1993). Excitability changes during the later part of the silent period are suggested to be caused by GABA B mediated inhibition and more precisely linked to cortical glutamate levels (Lang et al 2006;Tremblay et al 2012). The Current finding of an increase in the silent period duration is consistent with earlier reports of muscle fatigue during sustained MVC ) and intermittent MVC (Taylor et al 2000).…”