title: Nonparalytic botulinum molecules for the control of pain.
abstract: Local injections of botulinum toxins have been reported to be useful not only for the treatment of peripheral neuropathic pain and migraine but also to cause long-lasting muscle paralysis, a potentially serious side effect. Recently, a botulinum A-based molecule ("BiTox") has been synthesized that retains neuronal silencing capacity without triggering muscle paralysis. In this study, we examined whether BiTox delivered peripherally was able to reduce or prevent the increased nociceptive sensitivity found in animal models of inflammatory, surgical, and neuropathic pain. Plasma extravasation and edema were also measured as well as keratinocyte proliferation. No motor deficits were seen and acute thermal and mechanical nociceptive thresholds were unimpaired by BiTox injections. We found reduced plasma extravasation and inflammatory edema as well as lower levels of keratinocyte proliferation in cutaneous tissue after local BiTox injection. However, we found no evidence that BiTox was transported to the dorsal root ganglia or dorsal horn and no deficits in formalin-elicited behaviors or capsaicin or formalin-induced c-Fos expression within the dorsal horn. In contrast, Bitox treatment strongly reduced A-nociceptor-mediated secondary mechanical hyperalgesia associated with either complete Freund's adjuvant (CFA)-induced joint inflammation or capsaicin injection and the hypersensitivity associated with spared nerve injury. These results imply that although local release of neuromodulators from C-fibers was inhibited by BiTox injection, C-nociceptive signaling function was not impaired. Taken together with recent clinical data the results suggest that BiTox should be considered for treatment of pain conditions in which A-nociceptors are thought to play a significant role.
authors.affiliation: Cell and Developmental Biology, University College London, London, United Kingdom Laboratory of Neurophysiology of Integrative Autonomic System, Headache Sci. Ctr., "C. Mondino" Natl. Neurological Inst, Pavia, Italy School of Medicine, Pharmacy and Health., Durham Univ., Stockton-on-Tees, United Kingdom Department of Brain and Behavior, University of Pavia, Pavia, Italy School of Life Science, University of Lincoln, Lincoln, United Kingdom Department of Biomedical Science, University of Sheffield, Sheffield, United Kingdom.
authors.forename: Antonina S
authors.initials: AS
authors.lastname: Mangione
authors.forename: Ilona
authors.initials: I
authors.lastname: Obara
authors.forename: Maria
authors.initials: M
authors.lastname: Maiarú
authors.forename: Sandrine M
authors.initials: SM
authors.lastname: Geranton
authors.forename: Cristina
authors.initials: C
authors.lastname: Tassorelli
authors.forename: Enrico
authors.initials: E
authors.lastname: Ferrari
authors.forename: Charlotte
authors.initials: C
authors.lastname: Leese
authors.forename: Bazbek
authors.initials: B
authors.lastname: Davletov
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Hunt
mesh_terms: D000818:Animals; D019274:Botulinum Toxins, Type A / Q000008:administration & dosage* / Q000494:pharmacology; D002211:Capsaicin / Q000009:adverse effects; D002452:Cell Count; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D005620:Freund's Adjuvant / Q000009:adverse effects; D005727:Ganglia, Spinal / Q000187:drug effects / Q000473:pathology; D006930:Hyperalgesia / Q000188:drug therapy / Q000503:physiopathology; D007249:Inflammation / Q000150:complications / Q000188:drug therapy*; D015603:Keratinocytes / Q000187:drug effects; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D036421:Nerve Fibers, Unmyelinated / Q000187:drug effects / Q000378:metabolism; D009437:Neuralgia / Q000188:drug therapy* / Q000503:physiopathology; D009465:Neuromuscular Agents / Q000008:administration & dosage* / Q000494:pharmacology; D010147:Pain Measurement; D017288:Pain Threshold / Q000187:drug effects; D010149:Postoperative Pain / Q000188:drug therapy* / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D066148:Spinal Cord Dorsal Horn / Q000187:drug effects / Q000473:pathology
chemical_list: D009465:Neuromuscular Agents; D005620:Freund's Adjuvant; D019274:Botulinum Toxins, Type A; D002211:Capsaicin