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Transient Receptor Potential Vanilloid-1 Receptor Blockade as a Possible Mechanism of Botulinum Toxin Type-A in the Treatment of Chronic Pain
Kelli N. Webb, MD, Louis S. Premkumar and Michael W. Neumeister
Division of Plastic and Reconstructive Surgery, Southern Illinois University School of Medicine, Springfield, IL
Background: Recent emergence of use of botulinum toxin type-A (Btx-A) to treat acute and chronic pain is novel as this neurotoxin has been shown to decrease pain by inhibiting pain modulators and neuropeptides, and by its anti-glutamatergic effects. Human clinical trials provide evidence for the analgesic effects of Btx-A and the benefits it provided against a variety of painful conditions. However, current knowledge on the mechanisms by which Btx-A inhibits pain is very limited. Methods: To evaluate the mechanisms involved in the effects of Btx-A on transient receptor potential vanilloid-1 (TRPV1), two forms of Btx-A were used in wild type and TRPV1-/- adult mice (2 to 3 months of age.) Dorsal root ganglions (DRGs)were recovered from cervical, thoracic and lumbar segments. The cultured DRG neurons were mixed with pure Btx-A (1-10 nM) or BOTOX (5-20 units), heavy or light chain (1-10 nM). Toe extensor function was tested in the mice to test effectiveness of the Btx-A variants. Patch clamp and intracellular Ca2+ imaging experiments were used to determine the effects of formalin and capcasin on TRPV1 activity in the presence or absence of Btx-A (1-10 nM) or BOTOX (5-20 units) in cultured DRG neurons. The cells were stimulated with formalin in the presence and absence of PKC inhibitors [(BIM-Bisindolylmaleimide GF 109203X, 1 „zM) or staurosporin 10 nM] to determine the role of PKC signal transduction. Results: Btx-A inhibited capsaicin-stimulated currents as well as Ca2+ influx into HEKTRPV1 cells. Capsaicin induced a robust current in the control while Btx-A pretreatment significantly decreased this current (B). Also, Btx-A pretreatment significantly inhibited capsaicin - stimulated Ca2+ influx into cells. Conclusions: This research investigates the effects of Btx-A on nociceptive targets that mediate and sensitize pain signaling. A better understanding of the mechanisms by which Btx-A alleviates pain will advance the proof of concept for the development of Btx-A as unique analgesic to treat long-term pain without systemic adverse side effects. Our preliminary data support the hypothesis that BTX-A inhibits pain by down-regulating cellular mechanisms that sensitize pain signaling via nociceptive TRP channels or by inhibiting voltage gated Na+ channels (VGSC) at high frequency stimulations. BTX-A treatment down-regulates the expression of PKC-α and TRPV1 in HEKTRPV1 cells.
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