Ethosuximide reduces allodynia and hyperalgesia and potentiates morphine effects in the chronic constriction injury model of neuropathic pain

Abstract

Neuropathic pain is caused by a lesion or disease of the somatosensory nervous system and treatment of neuropathic pain remains a challenge. The purpose of the present study was to examine the effect of ethosuximide, an anti-epileptic and relatively selective T-type calcium blocker and morphine, a prototypical opioid in the behavioral responses following the chronic constriction injury (CCI) model of neuropathic pain. Experiments were performed on eight groups (n = 8) of male Sprague–Dawley rats (230–280 g). The animals were injected with saline, ethosuximide (100, 200, 300 mg/kg), morphine (4 mg/kg), and a combination of morphine (4 mg/kg) plus ethosuximide (100 mg/kg, i.p.). The cold-and mechano-allodynia and thermal hyperalgesia were measured prior to surgery (the day 0) and 3, 5, 7, 14 and 21 days post surgery. Ethosuximide and morphine significantly decreased cold and mechano allodynia and thermal hyperalgesia. However, the co-administration of both drugs seems to be more effective than the ethosuximide or morphine alone on cold and mechano allodynia and thermal hyperalgesia .Our results suggest that ethosuximide block tactile and thermal hypersensitivity after the CCI model, also, ethosuximide potentiates the analgesic effects of morphine in neuropathic pain conditions and behavioral responses.

Introduction

Peripheral nerve injuries lead to spontaneous pain followed by accompanying allodynia and hyperalgesia (Dworkin et al., 2003, Hama and Borsook, 2005). The etiology and underlying mechanisms of such pains are poorly understood and the existing treatments including anticonvulsalant agents, local anesthetics and opioids are often ineffective (Hansson and Dickenson, 2005, Jensen et al., 2009). Hence, it is important to increase our understanding of the mechanisms that underlie neuropathic pain states in order to identify new strategies for the development of effective therapies. A numbers of animal nerve injury models have been developed to study the mechanisms underlying neuropathic pain (Bennett and Xie, 1988, Decocted and Woolf, 2000, DeLeo et al., 1994, Fox et al., 2003, Kim and Chung, 1992, Seltzer et al., 1990). According to chronic constriction injury (CCI) model developed by Bennett and Xie (1988), the injury involves loose ligation of the common sciatic nerve in rats. The animals show altered spontaneous behavior consistent with the presence of flowered threshold and exaggerated responses to thermal and mechanical stimuli (Arner and Meyerson, 1988, Banafshe et al., 2012, Liu et al., 1999, Seltzer et al., 1990). Indeed, the sensitization of dorsal horn neurons by ectopic discharge inputs is a critical step in the development and maintenance of neuropathic pain (Pogatzki et al., 2002, Youn et al., 2002). Increase in local Ca²⁺ concentration at the site of injury or spinal cord may contribute to the development of neuropathic pain; this Ca²⁺ current appears to play an important physiological role in near-threshold phenomena and regulation of neuronal excitability (Dogrul et al., 2003, Gold et al., 1994).Therefore, attention has focused on the role of voltage sensing calcium channels (VSCCs), such as T-type Ca²⁺ channels or low voltage-activated Ca²⁺ channels that activate at voltages near the resting membrane potential and permit their involvement in low-amplitude oscillations, and neuronal bursting (Matthews and Dickenson, 2001). Ethosuximide is an anticonvulsant drug used to treat petit-mal seizure (Coulter et al., 1990). It blocks T-type Ca²⁺ channels relatively specific in dorsal root ganglion and rats sensory (nociceptive) neurons (Coulter et al., 1990, Kostyuk et al., 1992, Todorovic and Lingle, 1998). Ethosuximide also inhibits NMDA receptors mediated post discharge spike and spinal sensitization and hypersensitivity (Matthews and Dickenson, 2001).

Several lines of studies have shown the limited efficacy of opioids particularly morphine, in the treatment of neuropathic pain (Christoph et al., 2007, Dellemijn and Vanneste, 1997). One of the important analgesic mechanisms of opioid receptor agonists is the inhibition of neurotransmitter release from the central terminals of nociceptive dorsal root ganglion (DRG) neurons by inhibiting high voltage-activated Ca²⁺ channel (Wu et al., 2004).while the μ-opioid agonists do not affect low voltage-activated (T-type) Ca²⁺ channels (Abdulla and Smith, 1997, Wu et al., 2004). The present study was designed to examine that ethosuximide as a T-type Ca²⁺ channel blocker would alleviates the altered pain sensation in the CCI model of neuropathic pain and potentiates the effects of morphine on cold-and mechano-allodynia and heat hyperalgesia.