The antihyperalgesic effects of the T-type calcium channel blockers ethosuximide, trimethadione, and mibefradil

Abstract

The purpose of the present study was to explore the analgesic effects of the low voltage-activated T-type Ca²⁺ channel blockers ethosuximide, trimethadione, and mibefradil in persistent and acute nociceptive tests. The anticonvulsant effects of the compounds were also determined in the intravenous pentylenetetrazol seizure model. Following intraperitoneal administration, ethosuximide and trimethadione dose-dependently reversed capsaicin-induced mechanical hyperalgesia. Similarly, the highest dose of mibefradil tested (30 μg, intracisternal) reversed capsaicin-induced mechanical hyperalgesia. Ethosuximide and mibefradil produced statistically significant analgesic effects in both early and late phase formalin-induced behaviors and trimethadione reduced late phase behaviors. Additionally, ethosuximide and trimethadione produced antinociceptive effects in the rat-tail flick reflex test. In contrast, following intracisternal administration, mibefradil had no effect in the tail flick reflex test. In addition, the anticonvulsants ethosuximide and trimethadione increased the doses of pentylenetetrazol required to produce both first twitch and clonic seizures. In contrast however, mibefradil had no anticonvulsant effect. The present results demonstrate that the clinically used anticonvulsants ethosuximide and trimethadione provide analgesic effects at doses, which are anticonvulsant. Furthermore, the data further supports the idea that T-type Ca²⁺ channels may be important targets for treating persistent pain syndromes.

Introduction

A hallmark of epilepsy and neuropathic as well as inflammatory pain is hyperexcitable neurons. From a pharmacological perspective then, treating persistent pain conditions with antiepileptic drugs may not be entirely unexpected as the primary goal of antiepileptic therapy is to decrease or limit neuronal network excitability. A number of antiepileptic drugs are in fact efficacious in treating some pain syndromes. For instance, the sodium channel blocker carbamazepine is useful in treating trigeminal neuralgia (e.g., Campbell et al., 1966) and diabetic neuropathy (e.g., Gomez-Perez et al., 1996). In addition, the anticonvulsant gabapentin has been reported to be effective in treating diabetic neuropathy (Backonja et al., 1998) and post herpetic neuralgia (e.g., Rowbotham et al., 1998).

Evidence has been accumulating that the anticonvulsant ethosuximide, a low voltage-activated T-type Ca²⁺ channel blocker (Coulter et al., 1989a, Coulter et al., 1989b), may also be efficacious in the treatment of persistent pain. For instance, studies have shown that ethosuximide produced dose-dependent inhibition of mechanical and thermal evoked responses (Matthews and Dickenson, 2001, Doğrul et al., 2003) in the spinal nerve ligation model of Kim and Chung (1992). Moreover, Flatters and Bennett (2004) have shown that ethosuximide reversed paclitaxel-induced cold allodynia and vincristine-induced mechanical hyperalgesia. Additionally, Shannon et al. (2005) have recently shown that ethosuximide produced analgesic effects in the formalin-induced model of persistent pain.

T-type channels were originally characterized in sensory neurons and described as small conductance channels that were activated by weak depolarization (Carbone and Lux, 1984, Nowycky et al., 1985). T-type channels have been reported in dorsal root ganglion and dorsal horn neurons (Ryu and Randic, 1990, Talley et al., 1999, Ikeda et al., 2003, Shin et al., 2003) and T-channel mRNA transcripts have been reported in small and medium but not large sized neurons of the dorsal root ganglion (Talley et al., 1999). Correspondingly, large T-type currents have been recorded in medium-sized dorsal root ganglion neurons (Scroggs and Fox, 1992). Collectively, the data suggest that T-type currents are expressed in smaller sensory neurons, which transmit thermal and nociceptive information.

The primary purpose of the present study was to further investigate the analgesic effects of several T-type calcium channel blockers. Dose–response curves were determined for ethosuximide (Coulter et al., 1989a, Coulter et al., 1989b), trimethadione (Coulter et al., 1990, Zhang et al., 1996), and mibefradil (Clozel et al., 1997) using the formalin, capsaicin, and tail flick tests in rats. Ethosuximide, trimethadione, and mibefradil also were tested in the intravenous pentylenetetrazol seizure model to determine whether doses producing antinociception were also anticonvulsant. In addition, dose–response curves were determined for the opioid agonist morphine in each test for purposes of comparison.