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

Rahman W, Dickenson AH - Arthritis Res. Ther. (2014)

Bottom Line: Spinal and systemic administration of LCM produced significant reductions of the electrical Aβ- and C-fibre evoked neuronal responses and the mechanical and thermal evoked neuronal responses in the MIA group only.Our in vivo electrophysiological results show that the inhibitory effects of LCM were MIA-dependent.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.

View Article: PubMed Central - PubMed

ABSTRACT

Introduction: Alterations 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). In this study, therefore, we examined the antinociceptive effect of LCM on spinal neuronal and behavioural measures of pain, in vivo, in a rat OA model.

Methods: OA was induced in Sprague Dawley rats by intraarticular injection of 2 mg of monosodium iodoacetate (MIA). Sham rats received saline injections. Behavioural responses to mechanical and cooling stimulation of the ipsilateral hind paw and hindlimb weight-bearing were recorded. In vivo electrophysiology experiments were performed in anaesthetised MIA or sham rats, and we recorded the effects of spinal or systemic administration of LCM on the evoked responses of dorsal horn neurones to electrical, mechanical (brush, von Frey, 2 to 60 g) and heat (40°C to 50°C) stimulation of the peripheral receptive field. The effect of systemic LCM on nociceptive behaviours was assessed.

Results: Behavioural 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-treated rats only. Spinal and systemic administration of LCM produced significant reductions of the electrical Aβ- and C-fibre 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.

Conclusions: Our 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 but suppress secondary hyperalgesia 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.

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Related in: MedlinePlus

Effects of lacosamide after monosodium iodoacetate injection. These graphs depict the effects of lacosamide (LCM) on paw withdrawal threshold after mechanical punctate stimulation (a), paw withdrawal frequency after cooling stimulation (b) and hind limb weight-bearing (c) after monosodium iodoacetate (MIA) injection. LCM at 30 mg/kg reversed the mechanical hypersensitive response. LCM at both doses reversed the hypersensitivity to cooling stimulation but had no effect on hind limb weight-bearing. * denotes significant effect (P < 0.05 by Kruskal-Wallis test with Dunn’s post hoc test) comparing LCM effect with vehicle-treated animals. Data are from five animals per group. Values are mean ± SEM.
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Fig4: Effects of lacosamide after monosodium iodoacetate injection. These graphs depict the effects of lacosamide (LCM) on paw withdrawal threshold after mechanical punctate stimulation (a), paw withdrawal frequency after cooling stimulation (b) and hind limb weight-bearing (c) after monosodium iodoacetate (MIA) injection. LCM at 30 mg/kg reversed the mechanical hypersensitive response. LCM at both doses reversed the hypersensitivity to cooling stimulation but had no effect on hind limb weight-bearing. * denotes significant effect (P < 0.05 by Kruskal-Wallis test with Dunn’s post hoc test) comparing LCM effect with vehicle-treated animals. Data are from five animals per group. Values are mean ± SEM.

Mentions: LCM at 3 and 30 mg/kg reversed some of the behavioural measures of hypersensitivity seen in the MIA group compared with the vehicle-treated group. Treatment with LCM at 30 mg/kg significantly increased the PWT of the arthritic hind paw from 1.4 ± 0.4 g to 7.4 ± 2.3 g (Figure 4a). Treatment with the lower dose of LCM (3 mg/kg) produced some reversal of mechanical allodynia, but this did not reach significance overall (Figure 4a). LCM at both doses significantly reduced the paw withdrawal frequency to cooling stimulation of the hind paw compared with vehicle effect (Figure 4b). In contrast, ongoing joint discomfort and/or pain, as measured by hind limb weight-bearing, was not significantly improved by LCM at these doses (Figure 4c).Figure 4


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

Rahman W, Dickenson AH - Arthritis Res. Ther. (2014)

Effects of lacosamide after monosodium iodoacetate injection. These graphs depict the effects of lacosamide (LCM) on paw withdrawal threshold after mechanical punctate stimulation (a), paw withdrawal frequency after cooling stimulation (b) and hind limb weight-bearing (c) after monosodium iodoacetate (MIA) injection. LCM at 30 mg/kg reversed the mechanical hypersensitive response. LCM at both doses reversed the hypersensitivity to cooling stimulation but had no effect on hind limb weight-bearing. * denotes significant effect (P < 0.05 by Kruskal-Wallis test with Dunn’s post hoc test) comparing LCM effect with vehicle-treated animals. Data are from five animals per group. Values are mean ± SEM.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4308925&req=5

Fig4: Effects of lacosamide after monosodium iodoacetate injection. These graphs depict the effects of lacosamide (LCM) on paw withdrawal threshold after mechanical punctate stimulation (a), paw withdrawal frequency after cooling stimulation (b) and hind limb weight-bearing (c) after monosodium iodoacetate (MIA) injection. LCM at 30 mg/kg reversed the mechanical hypersensitive response. LCM at both doses reversed the hypersensitivity to cooling stimulation but had no effect on hind limb weight-bearing. * denotes significant effect (P < 0.05 by Kruskal-Wallis test with Dunn’s post hoc test) comparing LCM effect with vehicle-treated animals. Data are from five animals per group. Values are mean ± SEM.
Mentions: LCM at 3 and 30 mg/kg reversed some of the behavioural measures of hypersensitivity seen in the MIA group compared with the vehicle-treated group. Treatment with LCM at 30 mg/kg significantly increased the PWT of the arthritic hind paw from 1.4 ± 0.4 g to 7.4 ± 2.3 g (Figure 4a). Treatment with the lower dose of LCM (3 mg/kg) produced some reversal of mechanical allodynia, but this did not reach significance overall (Figure 4a). LCM at both doses significantly reduced the paw withdrawal frequency to cooling stimulation of the hind paw compared with vehicle effect (Figure 4b). In contrast, ongoing joint discomfort and/or pain, as measured by hind limb weight-bearing, was not significantly improved by LCM at these doses (Figure 4c).Figure 4

Bottom Line: Spinal and systemic administration of LCM produced significant reductions of the electrical Aβ- and C-fibre evoked neuronal responses and the mechanical and thermal evoked neuronal responses in the MIA group only.Our in vivo electrophysiological results show that the inhibitory effects of LCM were MIA-dependent.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.

View Article: PubMed Central - PubMed

ABSTRACT

Introduction: Alterations 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). In this study, therefore, we examined the antinociceptive effect of LCM on spinal neuronal and behavioural measures of pain, in vivo, in a rat OA model.

Methods: OA was induced in Sprague Dawley rats by intraarticular injection of 2 mg of monosodium iodoacetate (MIA). Sham rats received saline injections. Behavioural responses to mechanical and cooling stimulation of the ipsilateral hind paw and hindlimb weight-bearing were recorded. In vivo electrophysiology experiments were performed in anaesthetised MIA or sham rats, and we recorded the effects of spinal or systemic administration of LCM on the evoked responses of dorsal horn neurones to electrical, mechanical (brush, von Frey, 2 to 60 g) and heat (40°C to 50°C) stimulation of the peripheral receptive field. The effect of systemic LCM on nociceptive behaviours was assessed.

Results: Behavioural 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-treated rats only. Spinal and systemic administration of LCM produced significant reductions of the electrical Aβ- and C-fibre 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.

Conclusions: Our 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 but suppress secondary hyperalgesia 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.

Show MeSH
Related in: MedlinePlus