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Regulation of calcitonin gene-related peptide secretion from trigeminal nerve cells by botulinum toxin type A: implications for migraine therapy.
Durham PL, Cady R, Cady R.
Source: Department of Biology, Southwest Missouri State University, MO, USA.
To determine the effect of botulinum toxin type A on calcitonin gene-related peptide secretion from cultured trigeminal ganglia neurons.
The ability of botulinum toxins to cause muscle paralysis by blocking acetylcholine release at the neuromuscular junction is well known. Previous studies and clinical observations have failed to demonstrate sensory changes related to botulinum toxins or the disease of botulism. Recent studies, however, have suggested that botulinum toxin type A injected into pericranial muscles may have a prophylactic benefit in migraine. This observation has renewed the debate of a mechanism of sensory inhibition mediated by botulinum toxin type A.
Primary cultures of rat trigeminal ganglia were utilized to determine whether botulinum toxin type A could directly decrease the release of calcitonin gene-related peptide, a neuropeptide involved in the underlying pathophysiology of migraine. Untreated cultures or cultures stimulated with a depolarizing stimulus (potassium chloride) or capsaicin, an agent known to activate sensory C fibers, were treated for 3, 6, or 24 hours with clinically effective doses of botulinum toxin type A or a control vehicle. The amount of calcitonin gene-related peptide secreted into the culture media following the various treatments was determined using a specific radioimmunoassay.
A high percentage (greater than 90%) of the trigeminal ganglia neurons present in 1- to 3-day-old cultures was shown to express calcitonin gene-related peptide. Treatment with depolarizing stimuli (potassium chloride), a mixture of inflammatory agents, or capsaicin caused a marked increase (4- to 5-fold) in calcitonin gene-related peptide released from the trigeminal neurons. Interestingly, overnight treatment of trigeminal ganglia cultures with therapeutic concentrations of botulinum toxin type A (1.6 or 3.1 units) did not affect the amount of calcitonin gene-related peptide released from these neurons. The stimulated release of calcitonin gene-related peptide following chemical depolarization with potassium chloride or activation with capsaicin, however, was greatly repressed by the botulinum toxin, but not by the control vehicle. A similar inhibitory effect of overnight treatment with botulinum toxin type A was observed with 1.6 and 3.1 units. These concentrations of botulinum toxin type A are well within or below the range of tissue concentration easily achieved with a local injection. Incubation of the cultures with toxin for 24, 6, or even 3 hours was very effective at repressing stimulated calcitonin gene-related peptide secretion when compared to control values.
These data provide the first evidence that botulinum toxin type A can directly decrease the amount of calcitonin gene-related peptide released from trigeminal neurons. The results suggest that the effectiveness of botulinum toxin type A in the treatment of migraine may be due, in part, to its ability to repress calcitonin gene-related peptide release from activated sensory neurons.
Durham PL, Cady R, Cady R (2004). Regulation of calcitonin
gene-related peptide secretion from trigeminal nerve
cells by botulinum toxin type A: implications for migraine
therapy. Headache 44: 35–43.
Botulinum toxin type A
Botulinum neurotoxin type A (BoNT) has been increasingly utilized to treat migraine, tension-type headache, and other primary headache disorders. BoNT has been used clinically for the treatment of neuromuscular disorders, including focal dystonias and relief of pain associated with cervical dystonia and oromandibular dystonias. It is well established that BoNT blocks the presynaptic release of the neurotransmitter acetylcholine at neuromuscular junctions by cleaving the vesicle docking protein SNAP-25, a member of the soluble N-ethlymaleimide- sensitive factor attachment receptor (SNARE) proteins.
However, blockage of acetylcholine release is not likely the primary mechanism by which BoNT functions as a prophylactic treatment of migraine and other headaches, since reduction in pain is often noted by patients before muscle changes. Rather, the clinical benefits of BoNT may involve regulation of neuropeptide release from trigeminal ganglia neurons (Durham et al., 2004). Recent animal studies have provided evidence that BoNT can block the stimulated release of CGRP, glutamate, and substance P from trigeminal neurons as well as reduce c-fos gene expression in second-order neurons.
In addition, data from inflammatory pain models have clearly demonstrated an antinociceptive effect of BoNT. Taken together, it is likely that the therapeutic benefit of BoNT involves inhibition of peripheral sensitization, which results in a reduction in central sensitization and blockage of pain transmission.
In a recently completed assessment of botulinum neurotoxin in the treatment of autonomic disorders and pain by the Therapeutics and Technology Subcommittee of the AAN, two class I (Silberstein et al., 2000; Evers et al., 2004) and two class II (Elkind et al., 2006; Relja et al., 2007) studies were reviewed. The committee concluded that there was insufficient evidence to support or refute the benefit of these injections for the prevention of migraine. Consequently, it may be concluded that, based upon the current evidence, it appears that botulinum toxin injections are not effective for the treatment of episodic migraine headache, and clinical studies are assess efficacy in chronic migraine.
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Headache 40: 445–450.This post was edited on 01/06/2012 at 10:06 pm