Acute modulation of calcium currents and synaptic transmission by gabapentinoids

Abstract

Gabapentin and pregabalin are anticonvulsant drugs that are extensively used for the treatment of several neurological and psychiatric disorders. Gabapentinoids (GBPs) are known to have a high affinity binding to α2δ-1 and α2δ-2 auxiliary subunit of specific voltage-gated calcium channels. Despite the confusing effects reported on Ca (2+) currents, most of the studies showed that GBPs reduced release of various neurotransmitters from synapses in several neuronal tissues. We showed that acute in vitro application of pregabalin can reduce in a dose dependent manner synaptic transmission in both neuromuscular junctions and calyx of Held-MNTB excitatory synapses. Furthermore presynaptic Ca (2+) currents treated with pregabalin are reduced in amplitude, do not show inactivation at a clinically relevant low concentration of 100 μM and activate and deactivate faster. These results suggest novel modulatory role of acute pregabalin that might contribute to better understanding its anticonvulsant/analgesic clinical effects.

In vivo imaging reveals that pregabalin inhibits cortical spreading depression and propagation to subcortical brain structures

“…Gabapentin has been shown to increase the threshold for SD in vivo (38), and we hypothesized that pregabalin also might alter SD. Furthermore, gabapentin and pregabalin are known to bind to the α 2 δ 1/2 auxiliary subunit of Ca V 2.1 calcium channels, and gabapentinoid-mediated inhibition of calcium currents has been reported both acutely (24,30,39) and via chronic effects on channel trafficking (25,40). In the current study pregabalin was effective in increasing the threshold for stimulation to induce SD in WT but not R192Q or S218L mice.…”

“…Although pregabalin's exact mechanism of action has not been deciphered, it has been shown to inhibit calcium currents acutely (24) and to suppress calcium channel trafficking chronically (25). Furthermore, pregabalin displays greater efficacy for P/Q-type (Ca V 2.1) channels than for L-type (Ca V 1.1-Ca V 1.4) and N-type (Ca V 2.2) channels (26).…”

Mechanisms and Mediators That Drive Arthritis Pain

“…Following peripheral nerve injury, there is an increase in CaV α2δ-1 subunit mRNA expression in the ipsilateral DRG [65], as well as increased protein expression in the somas and spinal terminals of these neurones [66]. In animal studies, gabapentin, a CaV α2δ-1 subunit blocker [67], effectively decreased articular afferent firing [68], as well as reduced behavioural pain responses in the MIA OA model [69]. Similarly, voltage-gated sodium channel (NaV) expression and function are also affected by nerve injury.…”

Calcium channel functions in pain processing

“…The direct actions of gabapentinoids on ion channels are reviewed by Dr. Osvaldo Uchitel in this issue. 118 Recently, a panel of experts recommended these gabapentinoid drugs as the first line treatment for neuropathic pain conditions. 119 Even though these drugs were designed to mimic the structure of the inhibitory neurotransmitter γ-aminobutyric acid (GABA), later studies have found that their actions are not mainly mediated through the GABAergic system (reviewed in ref.…”