Botulinum neurotoxin type A (BoNTA) decreases the mechanical sensitivity of nociceptors and inhibits neurogenic vasodilation in a craniofacial muscle targeted for migraine prophylaxis

Abstract

The mechanism by which intramuscular injection of BoNTA into the craniofacial muscles decreases migraine headaches is not known. In a blinded study, the effect of BoNTA on the mechanical and chemical responsiveness of individual temporalis muscle nociceptors and muscle neurogenic vasodilation was investigated in female rats. Mechanical threshold was measured for 3h following intramuscular injection of BoNTA or vehicle, and for 10 min after a subsequent injection of the algogen glutamate. Injection of BoNTA significantly increased the mechanical threshold of muscle nociceptors without altering the muscle surface temperature and blocked glutamate-induced mechanical sensitization and neurogenic vasodilation. None of these effects were reproduced by pancuronium-induced muscle paralysis. Western blot analysis of temporalis muscles indicated that BoNTA significantly decreased SNAP-25. Measurement of interstitial glutamate concentration with a glutamate biosensor indicated that BoNTA significantly reduced glutamate concentrations. The mechanical sensitivity of muscle nociceptors is modulated by glutamate concentration through activation of peripheral NMDA receptors. Immunohistochemical experiments were conducted and they indicated that half of the NMDA-expressing temporalis nerve fibers co-expressed substance P or CGRP. Additional electrophysiology experiments examined the effect of antagonists for NMDA, CGRP and NK1 receptors on glutamate-induced effects. Glutamate-induced mechanical sensitization was only blocked by the NMDA receptor antagonist, but muscle neurogenic vasodilation was attenuated by NMDA or CGRP receptor antagonists. These data suggest that injection of BoNTA into craniofacial muscles acts to decrease migraine headaches by rapidly decreasing the mechanical sensitivity of temporalis muscle nociceptors through inhibition of glutamate release and by attenuating the provoked release of CGRP from muscle nociceptors.

Botulinum toxin A, brain and pain

“…However, the mechanism of BoNT/A action on migraine is unknown. It was hypothesized that BoNT/A may reduce the tension of pericranial muscles and reduce the mechanical sensitivity of muscular nociceptors (Gazerani et al, 2010). In contrast to the suggested peripheral site of BoNT/A action, it is widely believed that the patophysiologically most important cause of migraine pain is the neurogenic vasodilation of dural blood vessels (Geppetti et al, 2011).…”

Influence of pro-algesic foods on chronic pain conditions

“…Glutamate-induced vasodilation is mediated through activation of NMDA receptors [21,[27][28][29][30]. Glutamate-induced vasodilation appears to occur, in part, as a result of the release of the vasoactive neuropeptides calcitonin gene related peptide (CGRP) and substance P, and the production of nitric oxide [27,29] . Thus, MSGinduced headaches probably occur as a result of the combination of cerebral vasodilation and nociceptor sensitization.…”

Botulinum Neurotoxin a for Chronic Migraine Headaches: Does it Work and How?

“…BoNTA has been found to decrease the mechanical sensitivity of nociceptors that innervate these muscles as well as the underlying periosteum, within 3 h of injection [13,14]. One important determinant of muscle nociceptor mechanical sensitivity is the concentration of the amino acid glutamate in the interstitial space [15].…”

“…One important determinant of muscle nociceptor mechanical sensitivity is the concentration of the amino acid glutamate in the interstitial space [15]. Intramuscularly injected BoNTA has been shown to significantly decrease muscle interstitial glutamate concentration [14,15]. BoNTA may also block the normal cycling of receptors (e.g., glutamate receptors) from inside the axon to the axon membrane surface [11].…”