Elsevier

NeuroToxicology

Volume 26, Issue 5, October 2005, Pages 785-793
NeuroToxicology

Review
Review of a Proposed Mechanism for the Antinociceptive Action of Botulinum Toxin Type A

https://doi.org/10.1016/j.neuro.2005.01.017Get rights and content

Abstract

Botulinum toxin type A (BOTOX®) has been used to treat pathological pain conditions although the mechanism is not entirely understood. Subcutaneous (s.c.) BOTOX® also inhibits inflammatory pain in the rat formalin model, and the present study examined whether this could be due to a direct action on sensory neurons. BOTOX® (3.5–30 U/kg) was injected s.c. into the subplantar surface of the rat hind paw followed 1–5 days later by 50 mL of 5% formalin. Using microdialysis, we found that BOTOX® significantly inhibited formalin-induced glutamate release (peak inhibitions: 35%, 41%, and 45% with 3.5, 7, and 15 U/kg, respectively). BOTOX® also dose dependently reduced the number of formalin-induced Fos-like immunoreactive cells in the dorsal horn of the spinal cord and significantly (15 and 30 U/kg) inhibited the excitation of wide dynamic range neurons of the dorsal horn in Phase II but not Phase I of the formalin response. These results indicate that s.c. BOTOX® inhibits neurotransmitter release from primary sensory neurons in the rat formalin model. Through this mechanism, BOTOX® inhibits peripheral sensitization in these models, which leads to an indirect reduction in central sensitization.

Section snippets

INTRODUCTION

Botulinum toxin A (BoNT-A) inhibits the exocytotic release of acetylcholine from motor nerve terminals (Simpson, 1981), a property that has made it useful for the treatment of many pathological conditions involving excessive muscle contractions (Jankovic, 2004). During the early years of BoNT-A treatment for motor conditions such as dystonia, investigators noted a significant benefit of BoNT-A on pain that often exceeded the improvement in muscle contractions and did not strictly correspond to

INHIBITION OF ACETYLCHOLINE RELEASE

The inhibition of neurotransmitter release by BoNT-A occurs in a multi-step process that is initiated when the heavy chain of BoNT-A binds to specific acceptors/receptors on cholinergic neurons (Black and Dolly, 1986a). BoNT-A is then internalized by the cell and the light chain is translocated across the vesicle membrane into the cytosol (Black and Dolly, 1986b, Pellizzari et al., 1999). Here the light chain portion of the BoNT-A molecule acts as an enzyme, cleaving a specific bond on SNAP-25

INHIBITION OF NEUROPEPTIDE RELEASE—POSSIBLE ROLE IN PAIN REDUCTION

The apparent specificity of BoNT-A for cholinergic neurons in vivo is due to the presence of specific membrane acceptors/receptors on the motor nerve (Black and Dolly, 1986a), as BoNT-A readily inhibits exocytotic release of other neurotransmitters such as norepinephrine in model systems in which it can access the intracellular compartment (Bigalke et al., 1981, Knight, 1986, Lawrence et al., 2002). Under in vivo conditions most nerve cells do not possess extracellular BoNT-A

EFFECTS OF BoNT-A IN FORMALIN-PAIN MODELS

In a previous study, we reported that subcutaneous administration of BoNT-A dose-dependently inhibited formalin-induced inflammatory pain in rats (Cui et al., 2004) and that this inhibition was associated with a reduction in neurotransmitter release from the peripheral terminals of nociceptive sensory neurons (Cui et al., 2002). This study provided the first evidence that BoNT-A had a direct action on nociceptive sensory nerves in vivo. Although the possibility of a direct action of BoNT-A on

STUDIES OF BoNT-A ON NOCICEPTION IN HUMAN VOLUNTEERS

Two recent studies have examined the antinociceptive effects of BoNT-A in humans (Blersch et al., 2002, Voller et al., 2003). Both of these studies were double-blind, controlled designs that entailed the injection of BoNT-A into the forearm of healthy volunteers. In the first of these studies, BoNT-A (Dysport®) was injected subcutaneously into one arm and placebo into the other of 50 volunteers (Blersch et al., 2002). Thermal (heat and cold) and electrical pain thresholds were compared in the

SUMMARY AND CONCLUSIONS

The traditional mechanism of action described for BoNT-A is the inhibition of acetylcholine exocytosis through cleavage of SNAP-25, one of the SNARE proteins. A growing amount of evidence suggests that BoNT-A also inhibits the release of selected neuropeptide transmitters from primary sensory neurons. This mechanism has been thought to underlie the frequently reported reduction of pain with BoNT-A in the treatment of migraine and other painful conditions.

In an animal model of formalin-induced

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