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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

Formalin and capsaicin responses were not reduced by IPLT BiTox injection. (A) First and second phases of flinches measured after 2% formalin injection were unimpaired by IPLT BiTox injection into the ipsilateral hindpaw 3 days previously. (B) Thermal hyperalgesia that develops after 0.3% capsaicin injection is unaffected by BiTox treatment 3 days previously. Total c-Fos counts in dorsal horn laminae I to V after 2% formalin (C) or 0.3% capsaicin injection (D) given 3 days after BiTox injection into the ipsilateral hindpaw. No differences were seen between the number of c-Fos positive cells in the BiTox pretreated group and the vehicle group (A). Data are presented as means ± SEM, P > 0.05. n = 6 animals per group.
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Figure 2: Formalin and capsaicin responses were not reduced by IPLT BiTox injection. (A) First and second phases of flinches measured after 2% formalin injection were unimpaired by IPLT BiTox injection into the ipsilateral hindpaw 3 days previously. (B) Thermal hyperalgesia that develops after 0.3% capsaicin injection is unaffected by BiTox treatment 3 days previously. Total c-Fos counts in dorsal horn laminae I to V after 2% formalin (C) or 0.3% capsaicin injection (D) given 3 days after BiTox injection into the ipsilateral hindpaw. No differences were seen between the number of c-Fos positive cells in the BiTox pretreated group and the vehicle group (A). Data are presented as means ± SEM, P > 0.05. n = 6 animals per group.

Mentions: The response to acute injection with capsaicin or formalin was not affected by BiTox pretreatment. Intraplantar injection with BiTox 3 days before 2% formalin injection did not reduce the number of characteristic flinches in the early and late phases (Fig. 2A). The increased thermal sensitivity seen after capsaicin injections (Fig. 2B) was also unchanged by IPLT BiTox injection given 3 days before 0.3% capsaicin injection. C-Fos expression measured 2 hours after IPLT 0.3% capsaicin or 2% formalin injections was also unchanged by IPLT BiTox injections in all laminae analyzed (Fig. 2C and D).


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)

Formalin and capsaicin responses were not reduced by IPLT BiTox injection. (A) First and second phases of flinches measured after 2% formalin injection were unimpaired by IPLT BiTox injection into the ipsilateral hindpaw 3 days previously. (B) Thermal hyperalgesia that develops after 0.3% capsaicin injection is unaffected by BiTox treatment 3 days previously. Total c-Fos counts in dorsal horn laminae I to V after 2% formalin (C) or 0.3% capsaicin injection (D) given 3 days after BiTox injection into the ipsilateral hindpaw. No differences were seen between the number of c-Fos positive cells in the BiTox pretreated group and the vehicle group (A). Data are presented as means ± SEM, P > 0.05. n = 6 animals per group.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Figure 2: Formalin and capsaicin responses were not reduced by IPLT BiTox injection. (A) First and second phases of flinches measured after 2% formalin injection were unimpaired by IPLT BiTox injection into the ipsilateral hindpaw 3 days previously. (B) Thermal hyperalgesia that develops after 0.3% capsaicin injection is unaffected by BiTox treatment 3 days previously. Total c-Fos counts in dorsal horn laminae I to V after 2% formalin (C) or 0.3% capsaicin injection (D) given 3 days after BiTox injection into the ipsilateral hindpaw. No differences were seen between the number of c-Fos positive cells in the BiTox pretreated group and the vehicle group (A). Data are presented as means ± SEM, P > 0.05. n = 6 animals per group.
Mentions: The response to acute injection with capsaicin or formalin was not affected by BiTox pretreatment. Intraplantar injection with BiTox 3 days before 2% formalin injection did not reduce the number of characteristic flinches in the early and late phases (Fig. 2A). The increased thermal sensitivity seen after capsaicin injections (Fig. 2B) was also unchanged by IPLT BiTox injection given 3 days before 0.3% capsaicin injection. C-Fos expression measured 2 hours after IPLT 0.3% capsaicin or 2% formalin injections was also unchanged by IPLT BiTox injections in all laminae analyzed (Fig. 2C and D).

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