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Botulinum Toxin Type-A Blocks Sodium Channels: A Possible Mechanism in the Treatment of Chronic Hand Pain
Kelli N. Webb, MD1; Louis S. Premkumar, PhD2; Michael W. Neumeister1
1Division of Plastic and Reconstructive Surgery, Southern Illinois University School of Medicine, Springfield, IL; 2Department of Pharmacology, Southern Illinois University, Springfield, IL

Background: Sensory neuron injury is associated with an increased neuronal excitability and spontaneous firing. This often involves modulations in the expression and activity of voltage-gated Na+ channels (VGSC). Recent studies demonstrating inhibitory actions of botulinum toxin type-A (Btx-A) on VGSC expression and activity are suggestive of direct effect of Btx-A on VGSC and pain sensation. However, the mechanisms by which Btx-A inhibition of pain is coupled to modulations in the expression and activity of VGSC still remain to be determined.

Methods: Modulation of Na+ channels by BTX-A: From wild type mice, dissociated cells with pure Btx-A (1-10 nM), BOTOX (5-20 units), heavy or light chain (1-10 nM) for 5-15 min. Na+ currents were recorded over a period of 30 minutes eliciting currents every 5 minutes (5, 10 and 20 mV steps and using a ramp protocol (-100 to +60 mV) in 50 ms). Modulation of action potential waveform and frequency by BTX-A: Action potentials were recorded in DRG neurons under current-clamp conditions. Neurons with membrane potential more negative than -55 mV were used for generating action potentials. Current pulses were delivered in increments of 0.05 nA until generation of action potentials.

Results: Btx-A blocks Na+ channels in this DRG model. Na+ current recordings in control conditions at 0 and 20 minutes were unchanged whereas Na+ current recordings in the presence of BTX-A showed remarkable attenuation. Analyses of data show that after Btx-A the current amplitudes are significantly reduced , the half-width is significantly increased and the decay time constant is significantly increased. Btx-A also causes action potential prolongation and failure. In the presence of Btx-A, stimulus interval dependent action potential failures occur.

Conclusion: The results from this investigation advance our knowledge on mechanisms by which Btx-A counteracts pain and advances the clinical use of Btx-A in pain management. Selectively targeting sensory components with Btx-A is an effective strategy to counteract chronic pain conditions that have a peripheral counterpart. Our preliminary data support the overarching hypothesis that Btx-A inhibits pain by down-regulating cellular mechanisms that sensitize pain signaling via multiple pathways including inhibiting VGSC at high frequency stimulations. Inhibiting the sensitization and excitation of primary afferent neurons to noxious stimuli is a novel mechanism for the inhibitory actions of Btx-A on pain and provides new therapeutic perspectives for using Btx-A to treat pain pathologies.

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