Regulation of Calcitonin Gene‐Related Peptide Secretion From Trigeminal Nerve Cells by Botulinum Toxin Type A: Implications for Migraine Therapy

Abstract

Objective.-To determine the effect of botulinum toxin type A on calcitonin gene-related peptide secretion from cultured trigeminal ganglia neurons.Background.-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.Methods.-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.Results. Conclusions.-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.

Long-term benefits of botulinum toxin type A (BOTOX) in chronic daily headache: a five-year long experience

“…BoNT-A inhibits the release of calcitonin gene-related peptide (CGRP), as demonstrated by Durham et al In this study, CGRP was expressed in trigeminal ganglia neurons present in 1-3-day-old cultures, incubated afterwards with toxin. This incubation shows the reduction of the secretory stimulation of CGRP neurotransmitter with respect to control cultures [11]. These data suggest a contribution of CGRP to migraine pathophysiology.…”

Botulinum toxin type-A therapy in cluster headache: an open study

“…Alternatively, it is discussed that BTX-A may reduce or even prevent sensitisation of peripheral trigeminal afferents, which through attenuation of the nociceptive input may also result in inhibition of central sensitisation [24]. In the context of neurogenic inflammation, there is evidence that BTX-A is retrogradely transported into the CNS [25] and modulates the release of neurotransmitters such as substance P [26] or CGRP [27] in the trigeminal terminals.…”

Botulinum toxin A, brain and pain

“…BoNT/A effects were dependent on the presence of extracellular Ca 2+ . BoNT/A was similarly effective in reducing K + or capsaicin-stimulated CGRP release from sensory neurons isolated from trigeminal ganglion, while the basal CGRP release was unaffected (Durham et al, 2004). In another study, BoNT/A inhibited the CGRP release from trigeminal sensory neurons evoked by K + , bradykinin, and to a lesser degree by capsaicin (Meng et al, 2007).…”

“…However, it was subsequently discovered that the toxin enters many different neuronal types and blocks the neurotransmitter release from non-cholinergic synapses, too. Mostly in vitro experiments demonstrated that BoNT/A prevents the release of serotonin, dopamine, noradrenaline, glutamate, gamma-aminobutyric acid (GABA), enkephalin, glycine, Substance P and calcitonin gene-related peptide (CGRP) (Nakov et al, 1989, Mc Mahon et al, 1992Welch et al, 2000;Morris et al, 2002;Durham et al, 2004;Verderio et al, 2007).…”