A comparison of the antinociceptive effects of voltage-activated Na+ channel blockers in two rat models of neuropathic pain

https://doi.org/10.1016/S0014-2999(02)02792-9Get rights and content

Abstract

The pain-relieving effects of various voltage-activated Na+ channel blockers have been evaluated in two rat models of neuropathic pain; the photochemically induced nerve injury model (Gazelius) and spared nerve injury model. Lidocaine (up to 40 mg/kg, i.p.) and lamotrigine (up to 60 mg/kg, i.p.) had no effect on mechanical or cold allodynia in either model. However, lamotrigine (10, 30 and 60 mg/kg) significantly attenuated mechanical hyperalgesia in the spared nerve injury model, while mexiletine (25 and 37.5 mg/kg, i.p.) attenuated mechanical allodynia in the Gazelius model. Tocainide (50, 75 and 100 mg/kg, i.p.) significantly reduced all types of pain behaviour measured. The present results show that these voltage-activated Na+ channel blockers have broadly similar antinociceptive effects in these two models of neuropathic pain. They also show that these drugs can have markedly different effects on distinct neuropathic pain-related behaviours within models.

Introduction

Pathophysiological changes occurring within damaged nerves as a result of injury can contribute to their injury-induced activation and induce a state of prolonged neuronal hyperexcitability within the dorsal horn of the spinal cord (Woolf and Salter, 2000). The associated behavioural hypersensitivity to noxious (hyperalgesia) and non-noxious (allodynia) stimuli can be difficult to treat with conventional analgesics (Arner and Meyerson, 1988), pre-empting the need to identify drugs with alternative mechanisms of action, which can provide adequate pain relief.

At least six of nine voltage-activated Na+ channel pore-forming α-subunits (Nav1.1–1.9) and three β-subunits (β1-3) have been detected in dorsal root ganglion neurones (Baker and Wood, 2001). These contribute to the two types of Na+ current which have been identified in accordance with their pharmacological sensitivity to tetrodotoxin; tetrodotoxin-sensitive or tetrodotoxin-resistant Na+ currents Waxman, 1999, Baker and Wood, 2001. Altered Na+ channel activity and gene expression in dorsal root ganglion neurones has been observed following nerve injury, and these changes may contribute to the increased sensitivity of primary afferent fibres associated with neuropathic pain Waxman, 1999, Baker and Wood, 2001.

A number of local anaesthetics and anti-convulsant drugs have in common the ability to bind to voltage-activated Na+ channels to prevent Na+ influx into cells (Clare et al., 2000), and there is a substantial body of clinical evidence to suggest that such drugs can be effective in the treatment of neuropathic pain McQuay et al., 1997, Backonja, 2001. Despite this, not all types of neuropathic pain patients respond to treatment with local anaesthetics (McQuay et al., 1997), and there is some dispute as to the true analgesic effectiveness of the anti-convulsant lamotrigine against neuropathic pain McCleane, 1999, McCleane, 2000. Animal behavioural models reflecting human neuropathic pain syndromes Bennett and Xie, 1988, Kim and Chung, 1992, Gazelius et al., 1996 are used routinely for identifying novel drugs for treating neuropathic pain. The method used to induce the peripheral nerve injury varies, and as a consequence, the sensitivity of these models to drug treatments can differ as well (Zimmerman, 2001). In this study, we have compared the antinociceptive effects of the local anaesthetics lidocaine, mexiletine and tocainide, and lamotrigine, in two relatively new rat models of neuropathic pain; the photochemically induced nerve ischaemia model (Gazelius et al., 1996) and the spared nerve injury model (Decosterd and Woolf, 2000).

Section snippets

Surgery

Adult male Sprague–Dawley rats (Möllegaard, Denmark) weighing 180–220 g on the day of surgery were used in this study. The experiments were performed according to the Ethical Guidelines of the International Association for the Study of Pain (Zimmerman, 1983) and were approved by local research ethic committees.

Ischaemic lesion of the sciatic nerve was produced as described previously (Kupers et al., 1998). Under chloral hydrate anaesthesia (300 mg/kg, i.p.), the right sciatic nerve was exposed

General observations

In both the Gazelius and spared nerve injury models, pronounced mechanical allodynia (2.5±0.5 and 0.3±0.1 g) in response to von Frey hair stimulation of the injured hindpaw was observed, compared with pre-surgery levels which typically ranged from 5.7 to 51.1 g. Gazelius and spared nerve injury rats also showed marked cold allodynia (2.5±0.5 and 3.0±0.0 compared with a score of 0–1 before surgery) in response to ethyl chloride spray stimulation of the injured hindpaw. Only the spared nerve

Discussion

The present study has compared the pain-relieving effects of various voltage-activated Na+ channel blockers in two separate rat models (spared nerve injury and Gazelius) of neuropathic pain. We have previously reported that systemic administration of mexiletine to spared nerve injury rats can markedly attenuate pain behaviours (Erichsen and Blackburn-Munro, 2002), and here we have extended this observation to show that mexiletine can also attenuate pain behaviours in Gazelius animals. In

Acknowledgments

Support was provided by The Royal Danish School of Pharmacy and the Graduate School of Drug Research. We would like to thank Zsuzsanna Wiesenfeld-Hallin for helpful advice in performance of the Gazelius experiments and Nete Ibsen for technical assistance with the spared nerve injury observations.

References (35)

Cited by (61)

  • An automated method by which effects of compounds on locomotor activity and spontaneous neuropathic pain-specific movements can be simultaneously evaluated in rats with chronic-constriction nerve injury

    2017, European Journal of Pharmaceutical Sciences
    Citation Excerpt :

    In studies using several animal models of neuropathic pain, mexiletine significantly attenuated abnormal pain sensations, which include mechanical allodynia, thermal allodynia, and mechanical hyperalgesia. ( Jett et al., 1997; Erichsen et al., 2003; Nakazato-Imasato et al., 2009). Further, mexiletine causes a significant decrease in formalin-induced nociceptive behaviors (Blackburn-Munro et al., 2002).

  • A novel model of combined neuropathic and inflammatory pain displaying long-lasting allodynia and spontaneous pain-like behaviour

    2012, Neuroscience Research
    Citation Excerpt :

    It has been reported that prostaglandin-regulated descending control from the PAG preferentially targets C-nociceptor evoked activity (Leith et al., 2007), raising the possibility that a component of the antinociceptive effect of diclofenac here could be centrally mediated. Pain state-induced hypersensitivity of dorsal horn neurons is reversed by Na+ channel blockers (Blackburn-Munro and Fleetwood-Walker, 1997), so it was unexpected that mexiletine, a sodium channel blocker, efficacious in both neuropathic and inflammatory pain (Akada et al., 2006; Dworkin et al., 2007; Erichsen et al., 2003; Laird et al., 2001; Nakazato-Imasato et al., 2009) did not reduce SFL here, despite a typically effective dose being used. We cannot exclude of course the possibility that different doses and chronic treatment may be effective.

  • Local anesthetics

    2009, Current Therapy in Pain
View all citing articles on Scopus
View full text