title: Botulinum toxin B in the sensory afferent: transmitter release, spinal activation, and pain behavior.
abstract: We addressed the hypothesis that intraplantar botulinum toxin B (rimabotulinumtoxin B: BoNT-B) has an early local effect upon peripheral afferent terminal releasing function and, over time, will be transported to the central terminals of the primary afferent. Once in the terminals it will cleave synaptic protein, block spinal afferent transmitter release, and thereby prevent spinal nociceptive excitation and behavior. In mice, C57Bl/6 males, intraplantar BoNT-B (1 U) given unilaterally into the hind paw had no effect upon survival or motor function, but ipsilaterally decreased: (1) intraplantar formalin-evoked flinching; (2) intraplantar capsaicin-evoked plasma extravasation in the hind paw measured by Evans blue in the paw; (3) intraplantar formalin-evoked dorsal horn substance P (SP) release (neurokinin 1 [NK1] receptor internalization); (4) intraplantar formalin-evoked dorsal horn neuronal activation (c-fos); (5) ipsilateral dorsal root ganglion (DRG) vesicle-associated membrane protein (VAMP); (6) ipsilateral SP release otherwise evoked bilaterally by intrathecal capsaicin; (7) ipsilateral activation of c-fos otherwise evoked bilaterally by intrathecal SP. These results indicate that BoNT-B, after unilateral intraplantar delivery, is taken up by the peripheral terminal, is locally active (blocking plasma extravasation), is transported to the ipsilateral DRG to cleave VAMP, and is acting presynaptically to block release from the spinal peptidergic terminal. The observations following intrathecal SP offer evidence for a possible transsynaptic effect of intraplantar BoNT. These results provide robust evidence that peripheral BoNT-B can alter peripheral and central terminal release from a nociceptor and attenuate downstream nociceptive processing via a presynaptic effect, with further evidence suggesting a possible postsynaptic effect.
authors: Anesthesiology Research, Department of Anesthesiology, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA Department of Anesthesiology, Dokkyo Medical University, School of Medicine, Mibu, Tochigi, Japan.
authors: Marc J
authors: MJ
authors: Marino
authors: Tetsuji
authors: T
authors: Terashima
authors: Joanne J
authors: JJ
authors: Steinauer
authors: Kelly A
authors: KA
authors: Eddinger
authors: Tony L
authors: TL
authors: Yaksh
authors: Qinghao
authors: Q
authors: Xu
mesh_terms: D000344:Afferent Pathways / Q000187:drug effects / Q000502:physiology*; D000818:Animals; D018726:Anti-Dyskinesia Agents / Q000494:pharmacology*; D001905:Botulinum Toxins / Q000494:pharmacology*; D019274:Botulinum Toxins, Type A; D002211:Capsaicin / Q000009:adverse effects; D007839:Functional Laterality / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D019417:Hindlimb Suspension; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D053580:Muscle Strength / Q000187:drug effects; D009619:Nociceptors / Q000187:drug effects*; D010146:Pain / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D017288:Pain Threshold / Q000187:drug effects*; D020671:Posterior Horn Cells / Q000187:drug effects; D018040:Receptors, Neurokinin-1 / Q000378:metabolism; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism*; D013373:Substance P / Q000378:metabolism; D013997:Time Factors
chemical_list: D018726:Anti-Dyskinesia Agents; D018040:Receptors, Neurokinin-1; C096323:rimabotulinumtoxinB; D013373:Substance P; D001905:Botulinum Toxins; D019274:Botulinum Toxins, Type A; D002211:Capsaicin
keywords: Botulinum toxin; Dorsal root ganglion; Neurotransmitter release; Sensory afferent; Spinal cord; Substance P; VAMP