ABSTRACT
High-voltage-activated (HVA) Ca channels are widely expressed in the nervous system. They play an important role in pain conduction by participating in various physiological processes such as synaptic transmission, changes in synaptic plasticity, and neuronal excitability. Available evidence suggests that the HVA channel is an important therapeutic target for pain management. In this review, we summarize the changes in different subtypes of HVA channel during pain and present the currently available evidence from the clinical application of HVA channel blockers. We also review novel drugs in various phases of development. Moreover, we discuss the future prospects of HVA channel blockers in order to promote "bench-to-bedside" translation.
ABSTRACT
BACKGROUND: A correlation between a T-type voltage activated calcium channel (VACC) and pain mechanism has not yet been established. The purpose of this study is to find out the effect of ethosuximide and mibefradil, representative selective T-type VACC blockers on postoperative pain using an incisional pain model of rats. METHODS: After performing a plantar incision, rats were stabilized on plastic mesh for 2 hours. Then, the rats were injected with ethosuximide or mibefradil, intraperitoneally and intrathecally. The level of withdrawal threshold to the von Frey filament near the incision site was determined and the dose response curves were obtained. RESULTS: After an intraperitoneal ethosuximide or mibefradil injection, the dose-response curve showed a dose-dependent increase of the threshold in a withdrawal reaction. After an intrathecal injection of ethosuximide, the threshold of a withdrawal reaction to mechanical stimulation increased and the increase was dose-dependent. After an intrathecal injection of mibefradil, no change occurred in either the threshold of a withdrawal reaction to mechanical stimulation or a dose-response curve. CONCLUSIONS: The T-type VACC blockers in a rat model of postoperative pain showed the antihyperalgesic effect. This effect might be due to blockade of T-type VACC, which was distributed in the peripheral nociceptors or at the supraspinal level. Further studies of the effect of T-type VACC on a pain transmission mechanism at the spinal cord level would be needed.
Subject(s)
Animals , Rats , Calcium Channel Blockers , Calcium Channels , Calcium , Ethosuximide , Injections, Spinal , Mibefradil , Models, Animal , Nociceptors , Pain, Postoperative , Plastics , Spinal CordABSTRACT
A variety of G protein coupled receptors (GPCRs) are expressed in the presynaptic terminals of central and peripheral synapses and play regulatory roles in transmitter release. The patch-clamp whole-cell recording technique, applied to the calyx of Held presynaptic terminal in brainstem slices of rodents, has made it possible to directly examine intracellular mechanisms underlying the GPCR-mediated presynaptic inhibition. At the calyx of Held, bath-application of agonists for GPCRs such as GABAB receptors, group III metabotropic glutamate receptors (mGluRs), adenosine A1 receptors, or adrenaline alpha2 receptors, attenuate evoked transmitter release via inhibiting voltage-activated Ca2+ currents without affecting voltage-activated K+ currents or inwardly rectifying K+ currents. Furthermore, inhibition of voltage-activated Ca2+ currents fully explains the magnitude of GPCR-mediated presynaptic inhibition, indicating no essential involvement of exocytotic mechanisms in the downstream of Ca2+ influx. Direct loadings of G protein beta gamma subunit (G beta gamma) into the calyceal terminal mimic and occlude the inhibitory effect of a GPCR agonist on presynaptic Ca2+ currents (IpCa), suggesting that G beta gammamediates presynaptic inhibition by GPCRs. Among presynaptic GPCRs glutamate and adenosine autoreceptors play regulatory roles in transmitter release during early postnatal period when the release probability (p) is high, but these functions are lost concomitantly with a decrease in p during postnatal development.