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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

Behavioural assessment at day 14 after monosodium iodoacetate (n = 27) or saline injection (n = 17). Monosodium iodoacetate (MIA injection) into the knee resulted in behavioural hypersensitivity, compared with the sham controls that received saline injections, as evidenced by the significant reduction in the paw withdrawal threshold to mechanical punctate stimulation (a), an increased paw withdrawal frequency to acetone application (b) and a decrease in the amount of weight borne on the hind limb ipsilateral to injection (c). *P < 0.05 compared with shams by Mann-Whitney U test. Values are means ± SEM.
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Fig1: Behavioural assessment at day 14 after monosodium iodoacetate (n = 27) or saline injection (n = 17). Monosodium iodoacetate (MIA injection) into the knee resulted in behavioural hypersensitivity, compared with the sham controls that received saline injections, as evidenced by the significant reduction in the paw withdrawal threshold to mechanical punctate stimulation (a), an increased paw withdrawal frequency to acetone application (b) and a decrease in the amount of weight borne on the hind limb ipsilateral to injection (c). *P < 0.05 compared with shams by Mann-Whitney U test. Values are means ± SEM.

Mentions: Hypersensitivity to mechanical and cooling stimuli (akin to allodynia) was observed in the MIA group. This was seen as a significant decrease in the ipsilateral PWT in the MIA group (Figure 1a). In addition, a significant increase in the frequency of paw withdrawals to cooling stimulation was seen in MIA rats compared with the same stimulation of the ipsilateral hind paw in sham controls, which elicited few, if any, hind limb withdrawals (Figure 1b).Figure 1


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)

Behavioural assessment at day 14 after monosodium iodoacetate (n = 27) or saline injection (n = 17). Monosodium iodoacetate (MIA injection) into the knee resulted in behavioural hypersensitivity, compared with the sham controls that received saline injections, as evidenced by the significant reduction in the paw withdrawal threshold to mechanical punctate stimulation (a), an increased paw withdrawal frequency to acetone application (b) and a decrease in the amount of weight borne on the hind limb ipsilateral to injection (c). *P < 0.05 compared with shams by Mann-Whitney U test. Values are means ± SEM.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Fig1: Behavioural assessment at day 14 after monosodium iodoacetate (n = 27) or saline injection (n = 17). Monosodium iodoacetate (MIA injection) into the knee resulted in behavioural hypersensitivity, compared with the sham controls that received saline injections, as evidenced by the significant reduction in the paw withdrawal threshold to mechanical punctate stimulation (a), an increased paw withdrawal frequency to acetone application (b) and a decrease in the amount of weight borne on the hind limb ipsilateral to injection (c). *P < 0.05 compared with shams by Mann-Whitney U test. Values are means ± SEM.
Mentions: Hypersensitivity to mechanical and cooling stimuli (akin to allodynia) was observed in the MIA group. This was seen as a significant decrease in the ipsilateral PWT in the MIA group (Figure 1a). In addition, a significant increase in the frequency of paw withdrawals to cooling stimulation was seen in MIA rats compared with the same stimulation of the ipsilateral hind paw in sham controls, which elicited few, if any, hind limb withdrawals (Figure 1b).Figure 1

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