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