title: Botulinum toxin in migraine: Role of transport in trigemino-somatic and trigemino-vascular afferents.
abstract: Migraine secondary to meningeal input is referred to extracranial regions innervated by somatic afferents that project to homologous regions in the trigeminal nucleus caudalis (TNC). Reported efficacy of extracranial botulinum toxin (BoNT) in treating migraine is surprising since a local extracranial effect of BoNT cannot account for its effect upon meningeal input. We hypothesize that intradermal BoNT acts through central transport in somatic afferents. Anesthetized C57Bl/6 mice (male) received unilateral supraorbital (SO) injections of BoNT-B (1.5 U/40 μl) or saline. 3 days later, mice received ipsilateral (ipsi)-SO capsaicin (20 μl of 0.5mM solution) or meningeal capsaicin (4 μl of 0.35 μM). Pre-treatment with ipsi-SO BoNT-B i) decreased nocicsponsive ipsilateral wiping behavior following ipsi-SO capsaicin; ii) produced cleavage of VAMP in the V1 region of ipsi-TG and in TG neurons showing WGA after SO injection; iii) reduced expression of c-fos in ipsi-TNC following ipsi-SO capsaicin; iv) reduced c-fos activation and NK-1 internalization in ipsi-TNC secondary to ipsi-meningeal capsaicin; and vi) SO WGA did not label dural afferents. We conclude that BoNT-B is taken up by peripheral afferents and transported to central terminals where it inhibits transmitter release resulting in decreased activation of second order neurons. Further, this study supports the hypothesis that SO BoNT exerts a trans-synaptic action on either the second order neuron (which receives convergent input from the meningeal afferent) or the terminal/TG of the converging meningeal afferent.
authors.affiliation: Anesthesiology Research, Department of Anesthesiology, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
authors.forename: Roshni
authors.initials: R
authors.lastname: Ramachandran
authors.affiliation: Anesthesiology Research, Department of Anesthesiology, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
authors.forename: Carmen
authors.initials: C
authors.lastname: Lam
authors.affiliation: Anesthesiology Research, Department of Anesthesiology, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA. Electronic address: tyaksh@ucsd.edu.
authors.forename: Tony L
authors.initials: TL
authors.lastname: Yaksh
mesh_terms: D000344:Afferent Pathways / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D000818:Animals; D019274:Botulinum Toxins, Type A / Q000494:pharmacology*; D002211:Capsaicin; D004268:DNA-Binding Proteins; D004195:Disease Models, Animal; D005145:Face; D008297:Male; D049990:Membrane Transport Modulators / Q000494:pharmacology*; D008578:Meninges / Q000098:blood supply / Q000187:drug effects / Q000473:pathology; D008810:Mice, Inbred C57BL; D008881:Migraine Disorders / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009475:Neurons, Afferent / Q000187:drug effects* / Q000473:pathology / Q000502:physiology; D059226:Nociceptive Pain / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D009687:Nuclear Proteins / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D018040:Receptors, Neurokinin-1 / Q000378:metabolism; D050600:SNARE Proteins / Q000378:metabolism; D012867:Skin / Q000187:drug effects / Q000294:innervation; D014275:Trigeminal Caudal Nucleus / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology
chemical_list: D004268:DNA-Binding Proteins; D049990:Membrane Transport Modulators; D009419:Nerve Tissue Proteins; C492380:NeuN protein, mouse; D009687:Nuclear Proteins; D016760:Proto-Oncogene Proteins c-fos; D018040:Receptors, Neurokinin-1; D050600:SNARE Proteins; C096323:rimabotulinumtoxinB; D019274:Botulinum Toxins, Type A; D002211:Capsaicin
keywords: Botulinum toxin; Migraine; Referred pain; Trans-synaptic; Transcytosis