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. 2016 Aug;36(9):875-86.
doi: 10.1177/0333102416636843. Epub 2016 Mar 16.

Extracranial injections of botulinum neurotoxin type A inhibit intracranial meningeal nociceptors' responses to stimulation of TRPV1 and TRPA1 channels: Are we getting closer to solving this puzzle?

XiChun Zhang  1 , Andrew M Strassman  1 , Victor Novack  2 , Mitchell F Brin  3 , Rami Burstein  4
Affiliations

Extracranial injections of botulinum neurotoxin type A inhibit intracranial meningeal nociceptors' responses to stimulation of TRPV1 and TRPA1 channels: Are we getting closer to solving this puzzle?

XiChun Zhang et al. Cephalalgia. 2016 Aug.

Abstract

Background: Administration of onabotulinumtoxinA (BoNT-A) to peripheral tissues outside the calvaria reduces the number of days chronic migraine patients experience headache. Because the headache phase of a migraine attack, especially those preceded by aura, is thought to involve activation of meningeal nociceptors by endogenous stimuli such as changes in intracranial pressure (i.e. mechanical) or chemical irritants that appear in the meninges as a result of a yet-to-be-discovered sequence of molecular/cellular events triggered by the aura, we sought to determine whether extracranial injections of BoNT-A alter the chemosensitivity of meningeal nociceptors to stimulation of their intracranial receptive fields.

Material and methods: Using electrophysiological techniques, we identified 161 C- and 135 Aδ-meningeal nociceptors in rats and determined their mechanical response threshold and responsiveness to chemical stimulation of their dural receptive fields with TRPV1 and TRPA1 agonists seven days after BoNT-A administration to different extracranial sites. Two paradigms were compared: distribution of 5 U BoNT-A to the lambdoid and sagittal sutures alone, and 1.25 U to the sutures and 3.75 U to the temporalis and trapezius muscles.

Results: Seven days after it was administered to tissues outside the calvaria, BoNT-A inhibited responses of C-type meningeal nociceptors to stimulation of their intracranial dural receptive fields with the TRPV1 agonist capsaicin and the TRPA1 agonist mustard oil. BoNT-A inhibition of responses to capsaicin was more effective when the entire dose was injected along the suture lines than when it was injected into muscles and sutures. As in our previous study, BoNT-A had no effect on non-noxious mechanosensitivity of C-fibers or on responsiveness of Aδ-fibers to mechanical and chemical stimulation.

Discussion: This study demonstrates that extracranial administration of BoNT-A suppresses meningeal nociceptors' responses to stimulation of their intracranial dural receptive fields with capsaicin and mustard oil. The findings suggest that surface expression of TRPV1 and TRPA1 channels in dural nerve endings of meningeal nociceptors is reduced seven days after extracranial administration of BoNT-A. In the context of chronic migraine, reduced sensitivity to molecules that activate meningeal nociceptors through the TRPV1 and TRPA1 channels can be important for BoNT-A's ability to act as a prophylactic.

Keywords: Headache; chronic migraine; migraine prophylaxis; pain; trigeminovascular.

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Figures

Figure 1.
Figure 1.
Injection paradigm. (a) The suture paradigm consisted of four injections of BoNT-A, each containing 1.25 units, along the superior sagittal and transverse sinuses. (b) The suture-plus-muscle paradigm consisted of eight injections of BoNT-A, each containing 0.625 units. As depicted by the red dots, four injections were made in the clavicotrapezius muscle, two in the temporalis muscle, and two along the superior sagittal suture. BoNT-A: onabotulinumtoxinA.
Figure 2.
Figure 2.
Mechanical threshold for activation of C- and Aδ-meningeal nociceptors from their dural receptive fields are not affected by extracranial BoNT-A injections. (a) Mechanical response threshold of three different C-type meningeal nociceptors recorded in control rat (top), and in rats treated seven days earlier with BoNT-A injections into the sutures (middle) or the suture plus muscles (bottom). Boxed inset in each plot shows the shock artifact, the spike waveform, and the response latency. (b), (c) Mechanical thresholds for all C-units (b) and Aδ-units (c), shown as scattergraphs (top) and boxplots (bottom). Blue, control rats; red, suture-injected rats; green, suture-plus-muscle injected rats. In the scatterplots for the control rats, the filled and open circles represent values recorded in naïve and saline-injected rats, respectively. Boxplots illustrate median (thick horizontal line), interquartile range (25th–75th percentile; lower and upper box boundaries) and observations below and above the 25th and 75th percentile (whiskers) of the mechanical response threshold. Note that mechanical threshold values represent the smallest mechanical force capable of activating the neurons (i.e. innocuous force). BoNT-A: onabotulinumtoxinA.
Figure 3.
Figure 3.
Effects of extracranial injections of BoNT-A on responsiveness of C-type meningeal nociceptors to stimulation of their intracranial dural receptive fields with the TRPV1 agonist capsaicin. (a)–(c) Mean firing rate of three C-type meningeal nociceptors sampled before (baseline/green) and after (red) application of capsaicin to rats that were untreated (a), or treated with BoNT-A injections into suture (b), or suture plus muscle (c). (d) Response probability. Compared to the control group, the percentage of C-unit meningeal nociceptors activated by capsaicin decreased significantly after suture (χ2 = 7.15; p = 0.0075) but not after suture-plus-muscle (χ2 = 1.52; p = 0.2) injections. (e) Cumulative response probability curves showing the cumulative percentage of neurons activated by each successively higher concentration. (f) Response magnitude. Boxplots illustrate median (thick horizontal line), interquartile range (25th–75th percentile; lower and upper box boundaries) and observations below and above the 25th and 75th percentile (whiskers) of neuronal firing rate before (gray boxes) and after (colored boxes) capsaicin administration to the dura in control, suture-injected, and suture-plus-muscle-injected rats. (g) Mean percent change calculated for the capsaicin-responsive units only (e.g. (a), (c)). (h) Response probability of Aδ-units. As indicated, Aδ-units are generally unresponsive to capsaicin. Of interest are the findings that suture injections blocked the capsaicin response more effectively than the suture-plus-muscle injections. BoNT-A: onabotulinumtoxinA.
Figure 4.
Figure 4.
Effects of extracranial injections of BoNT-A on responsiveness of C-type meningeal nociceptors to stimulation of their intracranial dural receptive fields with the TRPA1 agonist mustard oil (MO). (a)–(c) Mean firing rate of three C-type meningeal nociceptors sampled before (baseline/green) and after (red) application of mustard oil to rats that were untreated (a), or treated with BoNT-A injections into suture (b), or suture plus muscle (c). (d) Response probability. Compared to the control group, the percentage of C-unit meningeal nociceptors activated by MO decreased significantly after suture as well as suture plus muscle injections (χ2 = 4.72; p = 0.03). (e) Cumulative response probability curves showing the cumulative percentage of neurons activated by each successively higher concentration. (f) Response magnitude. Boxplots illustrate median (thick horizontal line), interquartile range (25th–75th percentile; lower and upper box boundaries) and observations below and above the 25th and 75th percentile (whiskers) of neuronal firing rate before (gray boxes) and after (colored boxes) MO administration to the dura in control, suture-injected, and suture-plus-muscle-injected rats. (g) Mean percent change calculated for the MO-responsive units only (depicted in (a)). (h) Response probability of Aδ-units. The decrease in the number of units responding to MO (compared to control) was insignificant for both the suture (χ2 = 1.53; p = 0.2) and the suture plus muscle (χ2 = 0.89; p = 0.3) injection groups. BoNT-A: onabotulinumtoxinA.
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References

    1. Aurora SK, Dodick DW, Turkel CC, et al. OnabotulinumtoxinA for treatment of chronic migraine: Results from the double-blind, randomized, placebo-controlled phase of the PREEMPT 1 trial. Cephalalgia 2010; 30: 793–803. - PubMed
    1. Diener HC, Dodick DW, Aurora SK, et al. OnabotulinumtoxinA for treatment of chronic migraine: Results from the double-blind, randomized, placebo-controlled phase of the PREEMPT 2 trial. Cephalalgia 2010; 30: 804–814. - PubMed
    1. Bolay H, Reuter U, Dunn AK, et al. Intrinsic brain activity triggers trigeminal meningeal afferents in a migraine model. Nat Med 2002; 8: 136–142. - PubMed
    1. Noseda R, Burstein R. Migraine pathophysiology: Anatomy of the trigeminovascular pathway and associated neurological symptoms, cortical spreading depression, sensitization, and modulation of pain. Pain 2013; 154(Suppl 1): S44–S53. - PubMed
    1. Kosaras B, Jakubowski M, Kainz V, et al. Sensory innervation of the calvarial bones of the mouse. J Comp Neurol 2009; 515: 331–348. - PMC - PubMed