Effects of intraplantar botulinum toxin-B on carrageenan-induced changes in nociception and spinal phosphorylation of GluA1 and Akt.
Increasing evidence suggests that botulinum neurotoxins (BoNTs) delivered into the skin and muscle in certain human and animal pain states may exert antinociceptive efficacy though their uptake and transport to central afferent terminals. Cleavage of soluble N-methylaleimide-sensitive attachment protein receptor by BoNTs can impede vesicular mediated neurotransmitter release as well as transport/insertion of channel/receptor subunits into plasma membranes, an effect that can reduce activity-evoked facilitation. Here, we explored the effects of intraplantar botulinum toxin- B (BoNT-B) on peripheral inflammation and spinal nociceptive processing in an inflammatory model of pain. C57BL/6 mice (male) received unilateral intraplantar BoNT (1 U, 30 μL) or saline prior to intraplantar carrageenan (20 μL, 2%) or intrathecal N-methyl-D-aspartate (NMDA), substance P or saline (5 μL). Intraplantar carrageenan resulted in edema and mechanical allodynia in the injected paw and increased phosphorylation of a glutamate subunit (pGluA1ser845) and a serine/threonine-specific protein kinase (pAktser473) in spinal dorsal horn along with an increased incidence of spinal c-Fos positive cells. Pre-treatment with intraplantar BoNT-B reduced carrageenan evoked: (i) allodynia, but not edema; (ii) pGluA1 and pAkt and (iii) c-Fos expression. Further, intrathecal NMDA and substance P each increased dorsal horn levels of pGluA1 and pAkt. Intraplantar BoNT-B inhibited NMDA, but not substance P evoked phosphorylation of GluA1 and Akt. These results suggest that intraplantar toxin is transported centrally to block spinal activation and prevent phosphorylation of a glutamate receptor subunit and a kinase, which otherwise contribute to facilitated states.
Wolfson Inst for Biomedical Research, University College London, London, UK.
Shafaq
S
Sikandar
Pharmacy Program, University of Gothenburg, Gothenburg, Sweden.
Ynette
Y
Gustavsson
Department of Anesthesiology, University of California, San Diego, La Jolla, CA, 92093, USA.
Marc J
MJ
Marino
Department of Neuroscience, University College London, London, UK.
Anthony H
AH
Dickenson
Department of Anesthesiology, University of California, San Diego, La Jolla, CA, 92093, USA.
Tony L
TL
Yaksh
Department of Anesthesiology, University of California, San Diego, La Jolla, CA, 92093, USA.
Linda S
LS
Sorkin
Department of Anesthesiology, University of California, San Diego, La Jolla, CA, 92093, USA.
Roshni
R
Ramachandran
D000700:Analgesics / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D019274:Botulinum Toxins, Type A / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D002351:Carrageenan / Q000633:toxicity; D006930:Hyperalgesia / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016202:N-Methylaspartate / Q000494:pharmacology; D059225:Nociception; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D018091:Receptors, AMPA / Q000378:metabolism*; D066148:Spinal Cord Dorsal Horn / Q000378:metabolism* / Q000502:physiology; D013373:Substance P / Q000494:pharmacology
D000700:Analgesics; D019274:Botulinum Toxins, Type A; D002351:Carrageenan; D016202:N-Methylaspartate; D051057:Proto-Oncogene Proteins c-akt; D016760:Proto-Oncogene Proteins c-fos; D018091:Receptors, AMPA; D013373:Substance P; C096323:rimabotulinumtoxinB
botulinum toxin; carrageenan; dorsal root ganglion; spinal sensory processing; vesicle-associated membrane protein