Antinociceptive effects of lacosamide on spinal neuronal and behavioural measures of pain in a rat model of osteoarthritis

Wahida Rahman, Anthony H Dickenson

IntroductionAlterations in voltage gated sodium channel (VGSC) function have been linked to chronic pain and are good targets for analgesics. Lacosamide (LCM) is a novel anticonvulsant that enhances the slow inactivation state of VGSCs. This conformational state can be induced by repeated neuronal firing and/or under conditions of sustained membrane depolarisation; as is expected for hyperexcitable neurones in pathological conditions such as epilepsy and neuropathy, and probably osteoarthritis (OA). This study, therefore, examined the antinociceptive effect of LCM on spinal neuronal and behavioural measures of pain, in vivo, in a rat OA model.MethodsOA was induced in Sprague Dawley rats by intra-articular injection of 2mg monosodium iodoacetate (MIA). Shams were injected with saline. Behavioural responses to mechanical and cooling stimulation of the ipsilateral hind paw and hind-limb weight bearing were recorded. In vivo electrophysiology was performed in anaesthetised MIA or sham rats, recording the effects of spinal or systemic administration of LCM on the evoked responses of dorsal horn neurones to electrical, mechanical (brush, von Frey (vF) 2-60g) and heat (40-50°C) stimulation of the peripheral receptive field. The effect of systemic LCM on nociceptive behaviours was assessed.ResultsBehavioural hypersensitivity, ipsilateral to knee injury, was seen as a reduced paw withdrawal threshold to mechanical stimulation, an increase in paw withdrawal frequency to cooling stimulation and hind-limb weight bearing asymmetry in MIA rats only. Spinal and systemic administration of LCM produced significant reductions of the electrical Aß- and C-fiber evoked neuronal responses and the mechanical and thermal evoked neuronal responses in the MIA group only. Systemic administration of LCM significantly reversed the behavioural hypersensitive responses to mechanical and cooling stimulation of the ipsilateral hind paw, but hind limb weight bearing asymmetry was not corrected.ConclusionsOur in vivo electrophysiological results show that the inhibitory effects of LCM were MIA dependent. This suggests that if used in OA patients, LCM may allow physiological transmission yet suppress secondary hyperlagesia and allodynia. The inhibitory effect on spinal neuronal firing aligned with analgesic efficacy on nociceptive behaviours and suggests that LCM may still prove worthwhile for OA pain treatment and merits further clinical investigation.