Chronic intrathecal infusion of mibefradil, ethosuximide and nickel attenuates nerve ligation-induced pain in rats

Abstract

Background T-type Ca2+ channels (TCC) are important for pain transmission, especially the CaV3.2 subtype. In this study, we examined the effects of intrathecal TCC blockers in the L5/6 spinal nerve ligation pain rat model. Methods Under isoflurane anaesthesia, rats received right L5/6 spinal nerve ligation and intrathecal catheters (attached to an infusion pump) were sited. After surgery, saline, mibefradil, ethosuximide or NiCl2 were given intrathecally for seven days. The right hindpaw withdrawal thresholds to von Frey hair stimuli and withdrawal latencies to radiant heat were measured before and once daily for seven days after surgery. Double immunofluorescence and western blotting were used to examine the expression of CaV3.2 in dorsal root ganglion (DRG) and spinal cord. Results On post-ligation day seven, rats receiving mibefradil, ethosuximide or NiCl2 had significant higher median withdrawal thresholds (15.0, 10.2, and 10.9 g) and latencies (8.0, 7.6 and 7.6 s) than saline-treated rats (1.6 g and 4.3 s, respectively). CaV3.2 was expressed in parvalbumin+, IB4+, CGRP+ and VR1+ neurones in DRG and most neurones in spinal dorsal horn. CaV3.2 was up-regulated in the right L5/6 DRG and spinal cord seven days after nerve ligation. Conclusions In this study, we demonstrated that intrathecal TCC blockers attenuate the development of nerve injury-induced mechanical allodynia and thermal hyperalgesia. Our data suggest that continuous intrathecal infusion of TCC or CaV3.2 blockers may be a promising alternative for the management of nerve injury-induced pain.