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Nonparalytic botulinum molecules for the control of pain.

Mangione AS, Obara I, Maiarú M, Geranton SM, Tassorelli C, Ferrari E, Leese C, Davletov B, Hunt SP - Pain (2016)

Bottom Line: 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.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.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.

View Article: PubMed Central - PubMed

Affiliation: aCell and Developmental Biology, University College London, London, United KingdombLaboratory of Neurophysiology of Integrative Autonomic System, Headache Sci. Ctr., "C. Mondino" Natl. Neurological Inst, Pavia, ItalycSchool of Medicine, Pharmacy and Health., Durham Univ., Stockton-on-Tees, United KingdomdDepartment of Brain and Behavior, University of Pavia, Pavia, ItalyeSchool of Life Science, University of Lincoln, Lincoln, United KingdomfDepartment of Biomedical Science, University of Sheffield, Sheffield, United Kingdom.

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.

No MeSH data available.


Related in: MedlinePlus

Reduced incorporation of BrdU into keratinocytes after IPLT BiTox treatment. Photomicrographs from sections of cutaneous tissue (A) 14 days after vehicle or (B) BiTox IPLT pretreatment. There was a significant reduction of BrdU positive keratinocytes 14 days or 32 days but not 3 days after BiTox pretreatment (C). Scale bar = 60 μm. Arrows point to BrdU labeled cells in the basal epidermis. Data are presented as means ± SEM, *P < 0.05. n = 3 to 4 animals per group.
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Figure 6: Reduced incorporation of BrdU into keratinocytes after IPLT BiTox treatment. Photomicrographs from sections of cutaneous tissue (A) 14 days after vehicle or (B) BiTox IPLT pretreatment. There was a significant reduction of BrdU positive keratinocytes 14 days or 32 days but not 3 days after BiTox pretreatment (C). Scale bar = 60 μm. Arrows point to BrdU labeled cells in the basal epidermis. Data are presented as means ± SEM, *P < 0.05. n = 3 to 4 animals per group.

Mentions: Incorporation of BrdU into proliferating keratinocytes was measured at 4, 15, and 33 days (A, B, and C) after IPLT BiTox injection. In the epidermis of rats pretreated with BiTox 14 and 32 days before systemic BrdU injection, the number of BrdU-labeled cells was reduced compared with the contralateral paw (t(6) = 2.472, P = 0.048 15 days; t(4) = 3.011, P = 0.040 33 days, Fig. 6C). In contrast, there was no significant difference between the paw pretreated (3 days) with IPLT BiTox compared with the contralateral paw (Fig. 6).


Nonparalytic botulinum molecules for the control of pain.

Mangione AS, Obara I, Maiarú M, Geranton SM, Tassorelli C, Ferrari E, Leese C, Davletov B, Hunt SP - Pain (2016)

Reduced incorporation of BrdU into keratinocytes after IPLT BiTox treatment. Photomicrographs from sections of cutaneous tissue (A) 14 days after vehicle or (B) BiTox IPLT pretreatment. There was a significant reduction of BrdU positive keratinocytes 14 days or 32 days but not 3 days after BiTox pretreatment (C). Scale bar = 60 μm. Arrows point to BrdU labeled cells in the basal epidermis. Data are presented as means ± SEM, *P < 0.05. n = 3 to 4 animals per group.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4834813&req=5

Figure 6: Reduced incorporation of BrdU into keratinocytes after IPLT BiTox treatment. Photomicrographs from sections of cutaneous tissue (A) 14 days after vehicle or (B) BiTox IPLT pretreatment. There was a significant reduction of BrdU positive keratinocytes 14 days or 32 days but not 3 days after BiTox pretreatment (C). Scale bar = 60 μm. Arrows point to BrdU labeled cells in the basal epidermis. Data are presented as means ± SEM, *P < 0.05. n = 3 to 4 animals per group.
Mentions: Incorporation of BrdU into proliferating keratinocytes was measured at 4, 15, and 33 days (A, B, and C) after IPLT BiTox injection. In the epidermis of rats pretreated with BiTox 14 and 32 days before systemic BrdU injection, the number of BrdU-labeled cells was reduced compared with the contralateral paw (t(6) = 2.472, P = 0.048 15 days; t(4) = 3.011, P = 0.040 33 days, Fig. 6C). In contrast, there was no significant difference between the paw pretreated (3 days) with IPLT BiTox compared with the contralateral paw (Fig. 6).

Bottom Line: 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.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.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.

View Article: PubMed Central - PubMed

Affiliation: aCell and Developmental Biology, University College London, London, United KingdombLaboratory of Neurophysiology of Integrative Autonomic System, Headache Sci. Ctr., "C. Mondino" Natl. Neurological Inst, Pavia, ItalycSchool of Medicine, Pharmacy and Health., Durham Univ., Stockton-on-Tees, United KingdomdDepartment of Brain and Behavior, University of Pavia, Pavia, ItalyeSchool of Life Science, University of Lincoln, Lincoln, United KingdomfDepartment of Biomedical Science, University of Sheffield, Sheffield, United Kingdom.

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.

No MeSH data available.


Related in: MedlinePlus