title: Behavioral and immunohistochemical evidence for central antinociceptive activity of botulinum toxin A.
abstract: Botulinum toxin A (BTX-A) is approved for treatment of different cholinergic hyperactivity disorders, and, recently, migraine headache. Although suggested to act only locally, novel observations demonstrated bilateral reduction of pain after unilateral toxin injection, and proposed retrograde axonal transport, presumably in sensory neurons. However, up to now, axonal transport of BTX-A from periphery to CNS was identified only in motoneurons, but with unknown significance. We assessed the effects of low doses of BTX-A injected into the rat whisker pad (3.5 U/kg) or into the sensory trigeminal ganglion (1 U/kg) on formalin-induced facial pain. Axonal transport was prevented by colchicine injection into the trigeminal ganglion (5 mM, 2 μl). To find the possible site of action of axonally transported BTX-A, we employed immunohistochemical labeling of BTX-A-truncated synaptosomal-associated protein 25 (SNAP-25) in medullary dorsal horn of trigeminal nucleus caudalis after toxin injection into the whisker pad. Both peripheral and intraganglionic BTX-A reduce phase II of formalin-induced pain. Antinociceptive effect of BTX-A was prevented completely by colchicine. BTX-A-truncated SNAP-25 in medullary dorsal horn (spinal trigeminal nucleus) was evident 3 days following the peripheral treatment, even with low dose applied (3.5 U/kg). Presented data provide the first evidence that axonal transport of BTX-A, obligatory for its antinociceptive effects, occurs via sensory neurons and is directed to sensory nociceptive nuclei in the CNS.
authors.affiliation: Department of Pharmacology and Croatian Brain Research Institute, University of Zagreb School of Medicine, Zagreb, Croatia.
authors.forename: I
authors.initials: I
authors.lastname: Matak
authors.forename: L
authors.initials: L
authors.lastname: Bach-Rojecky
authors.forename: B
authors.initials: B
authors.lastname: Filipović
authors.forename: Z
authors.initials: Z
authors.lastname: Lacković
mesh_terms: D000700:Analgesics / Q000494:pharmacology; D000818:Animals; D001370:Axonal Transport / Q000187:drug effects / Q000502:physiology; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology*; D019274:Botulinum Toxins, Type A / Q000502:physiology*; D002490:Central Nervous System / Q000187:drug effects / Q000502:physiology; D005157:Facial Pain / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D007150:Immunohistochemistry; D008297:Male; D009619:Nociceptors / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D011984:Sensory Receptor Cells / Q000187:drug effects / Q000502:physiology; D014276:Trigeminal Nerve / Q000187:drug effects / Q000502:physiology*
chemical_list: D000700:Analgesics; D019274:Botulinum Toxins, Type A