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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

Plantar incision produced mechanical hypersensitivity that was transiently reduced by IPLT BiTox injection. Effect of IPLT injection of BiTox (200 ng) or vehicle on the mechanical withdrawal threshold measured with von Frey filaments in a postsurgical pain model. Measurements were made before injury to determine baseline pain threshold (BL) and 24 hours after the incision, at which time BiTox was injected and behavior followed for 5 days. Mechanical hypersensitivity was reduced on days 2 and 3 after BiTox injection. Data are presented as means ± SEM, *P < 0.05. n = 8 animals per group.
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Figure 4: Plantar incision produced mechanical hypersensitivity that was transiently reduced by IPLT BiTox injection. Effect of IPLT injection of BiTox (200 ng) or vehicle on the mechanical withdrawal threshold measured with von Frey filaments in a postsurgical pain model. Measurements were made before injury to determine baseline pain threshold (BL) and 24 hours after the incision, at which time BiTox was injected and behavior followed for 5 days. Mechanical hypersensitivity was reduced on days 2 and 3 after BiTox injection. Data are presented as means ± SEM, *P < 0.05. n = 8 animals per group.

Mentions: Plantar incision increased response to mechanical stimulation around the site of incision measured over 5 days. Twenty-four hours after incision, rats received local BiTox injection or vehicle. Intraplantar BiTox transiently reduced mechanical sensitivity from 1 to 2 days after treatment (between day 2 and day 3, F(1,14) = 6.07, P < 0.027, Fig. 4).


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)

Plantar incision produced mechanical hypersensitivity that was transiently reduced by IPLT BiTox injection. Effect of IPLT injection of BiTox (200 ng) or vehicle on the mechanical withdrawal threshold measured with von Frey filaments in a postsurgical pain model. Measurements were made before injury to determine baseline pain threshold (BL) and 24 hours after the incision, at which time BiTox was injected and behavior followed for 5 days. Mechanical hypersensitivity was reduced on days 2 and 3 after BiTox injection. Data are presented as means ± SEM, *P < 0.05. n = 8 animals per group.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 4: Plantar incision produced mechanical hypersensitivity that was transiently reduced by IPLT BiTox injection. Effect of IPLT injection of BiTox (200 ng) or vehicle on the mechanical withdrawal threshold measured with von Frey filaments in a postsurgical pain model. Measurements were made before injury to determine baseline pain threshold (BL) and 24 hours after the incision, at which time BiTox was injected and behavior followed for 5 days. Mechanical hypersensitivity was reduced on days 2 and 3 after BiTox injection. Data are presented as means ± SEM, *P < 0.05. n = 8 animals per group.
Mentions: Plantar incision increased response to mechanical stimulation around the site of incision measured over 5 days. Twenty-four hours after incision, rats received local BiTox injection or vehicle. Intraplantar BiTox transiently reduced mechanical sensitivity from 1 to 2 days after treatment (between day 2 and day 3, F(1,14) = 6.07, P < 0.027, Fig. 4).

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