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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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Comparison of the effects of spinal administration of lacosamide and monosodium iodoacetate. These graphs show the effects of lacosamide (LCM; 10, 50 and 100 μg) on the evoked neuronal responses to electrical (a, b), dynamic brush (c, d), mechanical punctate (e, f) and thermal stimulation (g, h) of the peripheral receptive field in sham rats (n = 6, left panel) and monosodium iodoacetate (MIA) rats (n = 7, right panel). The neuronal responses evoked by Aβ-, Aδ- and C-fibres and the input measure of neuronal excitability, dynamic brush, von Frey (vF) 8 to 60 g and 45°C to 48°C heat stimulation were significantly reduced by LCM in the MIA group. LCM did not produce any significant effect on any neuronal measure in the sham group. Asterisks and bars denote statistically significant main effects (one-way repeated-measures analysis of variance (RM-ANOVA)). § denotes significance at 10 μg, + denotes significance at 50 μg and * denotes significance at 100 μg compared with baseline control data (P < 0.05 by one-way RM-ANOVA with Bonferroni-corrected paired t-test). Values are mean ± SEM. PD, Postdischarge; Input, Baseline C-fibre-evoked response measure of afferent input and the resultant spinal neuronal response prior to central neuronal hyperexcitability evoked by subsequent stimuli; W, Wind-up, a frequency-dependent incremental increase in neuronal response to repetitive stimulation of C-fibres (that is, a measure of central neuronal hyperexcitability).
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Fig2: Comparison of the effects of spinal administration of lacosamide and monosodium iodoacetate. These graphs show the effects of lacosamide (LCM; 10, 50 and 100 μg) on the evoked neuronal responses to electrical (a, b), dynamic brush (c, d), mechanical punctate (e, f) and thermal stimulation (g, h) of the peripheral receptive field in sham rats (n = 6, left panel) and monosodium iodoacetate (MIA) rats (n = 7, right panel). The neuronal responses evoked by Aβ-, Aδ- and C-fibres and the input measure of neuronal excitability, dynamic brush, von Frey (vF) 8 to 60 g and 45°C to 48°C heat stimulation were significantly reduced by LCM in the MIA group. LCM did not produce any significant effect on any neuronal measure in the sham group. Asterisks and bars denote statistically significant main effects (one-way repeated-measures analysis of variance (RM-ANOVA)). § denotes significance at 10 μg, + denotes significance at 50 μg and * denotes significance at 100 μg compared with baseline control data (P < 0.05 by one-way RM-ANOVA with Bonferroni-corrected paired t-test). Values are mean ± SEM. PD, Postdischarge; Input, Baseline C-fibre-evoked response measure of afferent input and the resultant spinal neuronal response prior to central neuronal hyperexcitability evoked by subsequent stimuli; W, Wind-up, a frequency-dependent incremental increase in neuronal response to repetitive stimulation of C-fibres (that is, a measure of central neuronal hyperexcitability).

Mentions: The effect of LCM delivered via a spinal or systemic route was assessed upon the evoked responses of deep dorsal horn (lamina V-VI) neurones to electrical and natural stimulation of their peripheral receptive fields. Comparison of the average baseline predrug responses for MIA and shams per route of administration (spinal or systemic) revealed a significantly greater Aβ-fibre- and brush-evoked response in the MIA versus sham animals in the ‘spinal’ study (P < 0.05 by Mann-Whitney U test) (Figures 2a to 2d), but a significantly greater postdischarge in the sham group versus the MIA group (P < 0.05 by Mann-Whitney U test) (Figures 2a and 2b). However, no significant difference was seen with any of the electrical or brush-evoked responses in the ‘systemic’ study (P > 0.05 Mann-Whitney U test) (Figures 3a to 3d). No significant difference was seen between the vF- and heat-evoked response in MIA versus sham rats in either study (P > 0.05 by two-way ANOVA with Bonferroni posttest) (Figures 2e though 2h and Figures 3e through 3h). The relatively small sample size of neurones per group and per route of administration means that the mean can on occasion be shifted dramatically. Furthermore, as the present study was not powered to compare baseline neuronal responses between the MIA and sham groups, any differences in the average baseline neuronal responses were not further analysed or emphasized. It should be noted, however, that when we have previously characterized a large number of cells we observed, on average, greater firing of neurones in response to mechanical and thermal stimulation in the MIA group, but not to electrical or brush stimuli [15].Figure 2


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)

Comparison of the effects of spinal administration of lacosamide and monosodium iodoacetate. These graphs show the effects of lacosamide (LCM; 10, 50 and 100 μg) on the evoked neuronal responses to electrical (a, b), dynamic brush (c, d), mechanical punctate (e, f) and thermal stimulation (g, h) of the peripheral receptive field in sham rats (n = 6, left panel) and monosodium iodoacetate (MIA) rats (n = 7, right panel). The neuronal responses evoked by Aβ-, Aδ- and C-fibres and the input measure of neuronal excitability, dynamic brush, von Frey (vF) 8 to 60 g and 45°C to 48°C heat stimulation were significantly reduced by LCM in the MIA group. LCM did not produce any significant effect on any neuronal measure in the sham group. Asterisks and bars denote statistically significant main effects (one-way repeated-measures analysis of variance (RM-ANOVA)). § denotes significance at 10 μg, + denotes significance at 50 μg and * denotes significance at 100 μg compared with baseline control data (P < 0.05 by one-way RM-ANOVA with Bonferroni-corrected paired t-test). Values are mean ± SEM. PD, Postdischarge; Input, Baseline C-fibre-evoked response measure of afferent input and the resultant spinal neuronal response prior to central neuronal hyperexcitability evoked by subsequent stimuli; W, Wind-up, a frequency-dependent incremental increase in neuronal response to repetitive stimulation of C-fibres (that is, a measure of central neuronal hyperexcitability).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Fig2: Comparison of the effects of spinal administration of lacosamide and monosodium iodoacetate. These graphs show the effects of lacosamide (LCM; 10, 50 and 100 μg) on the evoked neuronal responses to electrical (a, b), dynamic brush (c, d), mechanical punctate (e, f) and thermal stimulation (g, h) of the peripheral receptive field in sham rats (n = 6, left panel) and monosodium iodoacetate (MIA) rats (n = 7, right panel). The neuronal responses evoked by Aβ-, Aδ- and C-fibres and the input measure of neuronal excitability, dynamic brush, von Frey (vF) 8 to 60 g and 45°C to 48°C heat stimulation were significantly reduced by LCM in the MIA group. LCM did not produce any significant effect on any neuronal measure in the sham group. Asterisks and bars denote statistically significant main effects (one-way repeated-measures analysis of variance (RM-ANOVA)). § denotes significance at 10 μg, + denotes significance at 50 μg and * denotes significance at 100 μg compared with baseline control data (P < 0.05 by one-way RM-ANOVA with Bonferroni-corrected paired t-test). Values are mean ± SEM. PD, Postdischarge; Input, Baseline C-fibre-evoked response measure of afferent input and the resultant spinal neuronal response prior to central neuronal hyperexcitability evoked by subsequent stimuli; W, Wind-up, a frequency-dependent incremental increase in neuronal response to repetitive stimulation of C-fibres (that is, a measure of central neuronal hyperexcitability).
Mentions: The effect of LCM delivered via a spinal or systemic route was assessed upon the evoked responses of deep dorsal horn (lamina V-VI) neurones to electrical and natural stimulation of their peripheral receptive fields. Comparison of the average baseline predrug responses for MIA and shams per route of administration (spinal or systemic) revealed a significantly greater Aβ-fibre- and brush-evoked response in the MIA versus sham animals in the ‘spinal’ study (P < 0.05 by Mann-Whitney U test) (Figures 2a to 2d), but a significantly greater postdischarge in the sham group versus the MIA group (P < 0.05 by Mann-Whitney U test) (Figures 2a and 2b). However, no significant difference was seen with any of the electrical or brush-evoked responses in the ‘systemic’ study (P > 0.05 Mann-Whitney U test) (Figures 3a to 3d). No significant difference was seen between the vF- and heat-evoked response in MIA versus sham rats in either study (P > 0.05 by two-way ANOVA with Bonferroni posttest) (Figures 2e though 2h and Figures 3e through 3h). The relatively small sample size of neurones per group and per route of administration means that the mean can on occasion be shifted dramatically. Furthermore, as the present study was not powered to compare baseline neuronal responses between the MIA and sham groups, any differences in the average baseline neuronal responses were not further analysed or emphasized. It should be noted, however, that when we have previously characterized a large number of cells we observed, on average, greater firing of neurones in response to mechanical and thermal stimulation in the MIA group, but not to electrical or brush stimuli [15].Figure 2

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