The anticonvulsant retigabine attenuates nociceptive behaviours in rat models of persistent and neuropathic pain

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Abstract

We have tested for anti-nociceptive effects of the anticonvulsant KCNQ channel opener, N-(2-amino-4-(4-fluorobenzylamino)-phenyl)carbamic acid ethyl ester (retigabine), in rat models of experimental pain. In the chronic constriction injury and spared nerve models of neuropathic pain, injection of retigabine (5 and 20 mg/kg, p.o.) significantly attenuated (P<0.05) mechanical hypersensitivity in response to pin prick stimulation of the injured hindpaw. In contrast, retigabine had no effect on mechanical hypersensitivity to von Frey stimulation of the injured hindpaw in either model. Cold sensitivity in response to ethyl chloride was only attenuated (P<0.05) in the chronic constriction injury model. In the formalin test, retigabine (20 mg/kg, p.o.) attenuated flinching behaviour in the second phase compared with vehicle (P<0.05), and this effect was completely reversed by the KCNQ channel blocker 10,10-bis(4-pyridinylmethyl)-9(10H)-anthracenone (XE-991; 3 mg/kg, i.p.). Neither retigabine nor XE-991 administration affected the latency to respond to noxious thermal stimulation of the tail in control animals. These results suggest that retigabine may prove to be effective in the treatment of neuropathic pain.

Introduction

Dynamic changes in the expression and function of ligand and voltage-gated ion channels can occur within dorsal root ganglion neurones in response to tissue injury Eglen et al., 1999, Waxman, 1999. These contribute to the injury-induced activation of primary afferent fibres, which can induce a state of prolonged neuronal hyperexcitability within the dorsal horn of the spinal cord (Woolf and Salter, 2000), a state that is closely correlated with behavioural hypersensitivity to both noxious (hyperalgesia) and non-noxious (allodynia) stimulation.

Multiple voltage-gated K+ channels have been identified within dorsal root ganglion neurones (Gold et al., 1996a). Recent studies have demonstrated dramatic reductions in voltage-gated K+ currents and K+ channel subunit expression within axotomised dorsal root ganglion neurones (Ishikawa et al., 1999) and in animal models of neuropathic pain (Rasband et al., 2001). One of these, the M-current, is a subthreshold voltage-gated K+ current that serves to stabilise the membrane potential and control neuronal excitability (Brown and Yu, 2000). Functional studies associate the M-current to homo- or hetero-multimers of KCNQ (2–5) protein subunits (Jentsch, 2000). These form voltage-gated K+ channels, which are widely distributed throughout the nervous system. The KCNQ2 and KCNQ3 subunits are mutated in a rare form of inherited epilepsy Jentsch, 2000, Rogawski, 2000, suggesting that drugs which can increase M-channel function may prove effective in depressing sustained neuronal firing and in controlling seizure discharge.

Injury-induced pain behaviours in animal models of chronic pain and in humans with various chronic pain conditions can also be attenuated by anticonvulsant drugs Hunter et al., 1997, Backonja, 2001. The anticonvulsant drug N-(2-amino-4-(4-fluorobenzylamino)-phenyl)carbamic acid ethyl ester (retigabine) has been shown to activate KCNQ channels expressed in mammalian cells (Rundfeldt and Netzer, 2000) and native M-currents in rat sympathetic neurones Tatulian et al., 2001, Wickenden et al., 2001. Taken together, this suggests that retigabine may prove to have as yet undescribed therapeutic potential in the treatment of various chronic pain conditions. To address this issue, we have tested for anti-nociceptive effects of retigabine in rat models of nociceptive, persistent and chronic pain.

Section snippets

Materials and methods

Male Sprague–Dawley rats (body weight, 180–450 g; Möllegaard, Denmark) were housed together in groups of three to four animals under standard conditions with unrestricted access to food and water. Rats were housed in the room in which the testing procedure was performed to try and minimise any stress response to novel environmental cues. All experiments were conducted according to the ethical guidelines for investigations of experimental pain in conscious animals (Zimmerman, 1983), and the

Effects of retigabine in nerve injury

In the chronic constriction injury and spared nerve injury models of neuropathic pain, pronounced mechanical allodynia (0.3±0.7 and 0.4±0.1 g, respectively), in response to von Frey hair stimulation of the ipsilateral hindpaw, was observed, compared with pre-surgery levels that typically ranged from 8.4 to 19.4 g. Both chronic constriction injury and spared nerve injury rats also showed marked mechanical hyperalgesia (10.6±2.0 and 10.6±0.8 s, respectively, compared with <0.5 s before surgery)

Discussion

Retigabine is a structural analogue of flupirtine, which is a non-opiate, centrally acting analgesic used for relieving moderate pain of various types (Friedel and Fitton, 1993). The present study has shown for the first time that retigabine also has anti-nociceptive effects in rat models of persistent and chronic pain. Retigabine attenuated pain behaviours in two different models of nerve injury. In the formalin test, anti-nociceptive effects associated with retigabine administration were

Acknowledgements

We thank Dr. W. Dalby Brown, Dr. D. Strøbæk and Dr. J.A. Lopez-Garcia for their helpful comments relating to this work, and also Nete Ibsen for her expert technical assistance.

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