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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

Intraplantar BiTox inhibited capsaicin-induced extravasation. Rats were pretreated with IPLT BiTox (200 ng) or vehicle (contralateral paw) 3 days before plasma extravasation was studied. Tail vein injection of Evans blue (50 mg·kg−1) was given 15 minutes before bilateral IPLT injection of capsaicin. Tissue was collected 15 minutes later. (A) The blue color of hindpaw skin was darker and more extensive in the contralateral vehicle paw compared with BiTox injected paw. Histograms show dye concentration in formamide extract of ipsi- and contralateral paw tissue (B) and the area of Evans Blue extravasation generated from the photographic record (C). Data are expressed as means ± SEM, *P < 0.05. n = 6 animals per group.
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Figure 5: Intraplantar BiTox inhibited capsaicin-induced extravasation. Rats were pretreated with IPLT BiTox (200 ng) or vehicle (contralateral paw) 3 days before plasma extravasation was studied. Tail vein injection of Evans blue (50 mg·kg−1) was given 15 minutes before bilateral IPLT injection of capsaicin. Tissue was collected 15 minutes later. (A) The blue color of hindpaw skin was darker and more extensive in the contralateral vehicle paw compared with BiTox injected paw. Histograms show dye concentration in formamide extract of ipsi- and contralateral paw tissue (B) and the area of Evans Blue extravasation generated from the photographic record (C). Data are expressed as means ± SEM, *P < 0.05. n = 6 animals per group.

Mentions: Rats received a single IPLT injection of BiTox into the ipsilateral paw and a single injection of vehicle into the plantar surface of the contralateral paw. After 3 days the animals received a tail vein injection of Evans blue (50 mg·kg−1). Fifteen minutes later 0.3% capsaicin was injected into the ipsilateral (BiTox-treated) and contralateral (vehicle-treated) paws to evoke plasma extravasation. After a further 15-minute period the amount of dye extravasated or the extent of extravasation was measured in paw skin tissue. In the vehicle-injected paw, capsaicin injection induced a massive local extravasation of blue dye. In contrast, intraplantar injection of BiTox induced a reduction in dye extravasation compared with the vehicle-treated paw (t(8) = 3.066, P = 0.015, Fig. 5B; t(10) = 3.011, P = 0.013, Fig. 5C).


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)

Intraplantar BiTox inhibited capsaicin-induced extravasation. Rats were pretreated with IPLT BiTox (200 ng) or vehicle (contralateral paw) 3 days before plasma extravasation was studied. Tail vein injection of Evans blue (50 mg·kg−1) was given 15 minutes before bilateral IPLT injection of capsaicin. Tissue was collected 15 minutes later. (A) The blue color of hindpaw skin was darker and more extensive in the contralateral vehicle paw compared with BiTox injected paw. Histograms show dye concentration in formamide extract of ipsi- and contralateral paw tissue (B) and the area of Evans Blue extravasation generated from the photographic record (C). Data are expressed as means ± SEM, *P < 0.05. n = 6 animals per group.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Figure 5: Intraplantar BiTox inhibited capsaicin-induced extravasation. Rats were pretreated with IPLT BiTox (200 ng) or vehicle (contralateral paw) 3 days before plasma extravasation was studied. Tail vein injection of Evans blue (50 mg·kg−1) was given 15 minutes before bilateral IPLT injection of capsaicin. Tissue was collected 15 minutes later. (A) The blue color of hindpaw skin was darker and more extensive in the contralateral vehicle paw compared with BiTox injected paw. Histograms show dye concentration in formamide extract of ipsi- and contralateral paw tissue (B) and the area of Evans Blue extravasation generated from the photographic record (C). Data are expressed as means ± SEM, *P < 0.05. n = 6 animals per group.
Mentions: Rats received a single IPLT injection of BiTox into the ipsilateral paw and a single injection of vehicle into the plantar surface of the contralateral paw. After 3 days the animals received a tail vein injection of Evans blue (50 mg·kg−1). Fifteen minutes later 0.3% capsaicin was injected into the ipsilateral (BiTox-treated) and contralateral (vehicle-treated) paws to evoke plasma extravasation. After a further 15-minute period the amount of dye extravasated or the extent of extravasation was measured in paw skin tissue. In the vehicle-injected paw, capsaicin injection induced a massive local extravasation of blue dye. In contrast, intraplantar injection of BiTox induced a reduction in dye extravasation compared with the vehicle-treated paw (t(8) = 3.066, P = 0.015, Fig. 5B; t(10) = 3.011, P = 0.013, Fig. 5C).

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