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