The effect of novel anti-epileptic drugs in rat experimental models of acute and chronic pain

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Abstract

The novel anti-epileptic drugs lamotrigine, felbamate and gabapentin were compared in rat experimental models of acute (tail flick) and chronic pain: the chronic constriction injury and spinal nerve ligation models. Lamotrigine (10–100 mg/kg, s.c.), felbamate (150–600 mg/kg, i.p.) and gabapentin (30–300 mg/kg, i.p.) each reversed cold allodynia (chronic constriction injury model) with ED50 values of 28, 241 and 103 mg/kg, respectively, 1 h post-dose. However, only gabapentin reversed tactile allodynia (spinal nerve ligation model) with an ED50 of 34 mg/kg (i.p.). The established anti-epileptic drugs, carbamazepine (1–30 mg/kg, i.p.) and phenytoin (1–100 mg/kg, s.c.), were ineffective in both models. The anti-allodynic effect of the newer anti-epileptic drugs was observed at doses that were either ineffective or produced only a negligible effect on acute nociceptive function and/or locomotor activity. In conclusion, the data suggest that the newer anti-epileptic drugs appear to have the potential to be effective alternatives to either carbamazepine or phenytoin in the treatment of neuropathic pain. However, only gabapentin ameliorated both cold and touch hyperesthesias. © 1997 Elsevier Science B.V. All rights reserved.

Introduction

Chronic abnormal pain syndromes that follow peripheral nerve damage have been found to have a much reduced sensitivity to the two major classes of analgesics, opioids (Arner and Myerson, 1993) and non-steroidal anti-inflammatory drugs (Max et al., 1988). In the search for alternative forms of treatment, anti-convulsants have emerged amongst the more commonly used pharmacological interventions (reviewed by Swerdlow, 1984; McQuay et al., 1995). Carbamazepine and, to a lesser extent phenytoin, have been found to be useful against various types of neuropathic pain conditions (Swerdlow, 1984; McQuay et al., 1995), but appear to have particular utility when there is a paroxysmal, lancinating component, e.g. trigeminal neuralgia (Campbell et al., 1966; Killian and Fromm, 1968). However, pain relief has often been obtained concomitantly with numerous adverse events (Campbell et al., 1966; Killian and Fromm, 1968; Rull et al., 1969) and/or limitations in efficacy (Killian and Fromm, 1968; Saudek et al., 1977; Leijon and Boivie, 1989) which have restricted tolerability of these drugs.

The novel anti-epileptic drugs lamotrigine, felbamate and gabapentin have emerged as agents with the potential for mono-therapy in the treatment of epilepsy, particularly in those types refractory to the established drugs, carbamazepine and phenytoin (for review see Upton, 1994). It has been suggested that this may be due, in part, to the newer anti-epileptic drugs having either alternative or additional mechanisms of action to the frequency-dependent sodium channel blockade attributed to the anti-epileptic action of carbamazepine and phenytoin (Macdonald and Kelly, 1994; Upton, 1994). For example, it has been proposed that lamotrigine, felbamate and/or gabapentin exert either a pre- or post-synaptic modulation of glutaminergic transmission which may contribute to the overall therapeutic profile (Cheung et al., 1992; White et al., 1992; Leach et al., 1986; McCabe et al., 1993; DeSarro et al., 1994; Singh et al., 1996), although only felbamate has been shown to interact directly with any of the glutamate receptor sub-types. Both gabapentin (Kocsis and Honmou, 1994) and felbamate (Rho et al., 1994) have also been suggested to potentiate GABAergic function without having any direct interaction with GABA/benzodiazepine sites (Swinyard et al., 1986; Rock et al., 1993; Suman-Chauhan et al., 1993).

Recent evidence suggests that several key events contribute towards the pathogenesis of abnormal pain states following a peripheral nerve injury. Thus, high frequency spontaneous discharge from ectopic sites in the peripheral nerve (for review see Devor, 1994) following injury causes enhanced spinal glutamate release leading to an increased responsiveness of dorsal horn neurons (Woolf and Wall, 1986) and expansion of the cutaneous receptive field, i.e. central sensitization (Cook et al., 1987). Spinal neuron disinhibition involving a loss of GABAergic function (Sivilotti and Woolf, 1994) contributes to the hyperexcitable state. A prominent manifestation of central sensitization is allodynia, a state in which normally innocuous input is perceived as pain (Campbell et al., 1988; Woolf and Doubell, 1994). Since all of the novel anti-epileptic drugs have been described as having either a direct or indirect influence on glutaminergic or GABAergic transmission, the present study therefore examined the potential anti-allodynic properties of the novel anti-epileptic drugs against tactile and cold allodynia in two rodent models of neuropathic pain. A comparison was made with drug performance in an acute, high threshold test of nociception (tail flick) and on motor coordination.

Section snippets

Materials and methods

The following experimental procedures for the surgical preparation and testing of animals were reviewed and approved by the Institute Animal Care and Use Committee at Roche Bioscience.

Effects of anti-epileptic drugs on neuropathy-induced cold allodynia

Animals with the chronic constriction injury to the sciatic nerve displayed cold allodynia by lifting only the ligated leg out of the pool of ice-cold (0°C) water with a latency (mean±S.E.M.) of 6.8±0.8 s (n=28). The cut-off latency for the test was 20 s.

At 1 h post-dose, lamotrigine (10–100 mg/kg, s.c.), felbamate (150–600 mg/kg, i.p.) and gabapentin (30–300 mg/kg, i.p.) produced a dose-dependent increase in the latency to paw withdrawal from the cold water stimulus with ED50 (mean with 95%

Discussion

The newer anti-epileptic drugs, lamotrigine, felbamate and gabapentin, all produced a pronounced anti-cold allodynic effect in the chronic constriction injury model at doses that did not appear to be compromized by overt behavioral events. This ability to acutely reverse a prominent manifestation of neuronal sensitization demonstrates the potential of these drugs as analgesics for the relief of chronic pain following tissue/nerve injury. Moreover, the negligible effect of these drugs against an

Acknowledgements

We would like to thank Sophie Chiu of the Department of Biomathematics, Roche Bioscience for validation of the cold and tactile allodynia assay protocols and for performing all the statistical analyses of the data.

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