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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

Effect of different doses of IPLT BiTox (2, 50, 100, 200 ng) on capsaicin-induced secondary hyperalgesia. Mechanical withdrawal thresholds measured with von Frey filaments (A) and withdrawal response duration (s) after pinprick stimulation (B). The measurements were assessed before injection and then 30 minutes, 1, and 2 hours after capsaicin injection. Data are expressed as means ± SEM, *P < 0.05, **P < 0.01. n = 4 to 6 animals per group.
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Related In: Results  -  Collection


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Figure 10: Effect of different doses of IPLT BiTox (2, 50, 100, 200 ng) on capsaicin-induced secondary hyperalgesia. Mechanical withdrawal thresholds measured with von Frey filaments (A) and withdrawal response duration (s) after pinprick stimulation (B). The measurements were assessed before injection and then 30 minutes, 1, and 2 hours after capsaicin injection. Data are expressed as means ± SEM, *P < 0.05, **P < 0.01. n = 4 to 6 animals per group.

Mentions: We also used capsaicin-induced secondary hyperalgesia to examine the dose–response of BiTox, using 4 different doses (2, 50, 100, and 200 ng). BiTox was injected in the lateral plantar surface 3 days before capsaicin injection in the central plantar area. Mechanical stimuli were applied to the area of secondary hyperalgesia on the lateral plantar surface. BiTox reduced the hypersensitivity maximally at doses of 100 and 200 ng as measured with Von Frey hairs (F(1,6) = 119.503, P = 0.001, Fig. 10A) or pinprick test (F(1,6) = 51.0, P = 0.001, Fig. 10B).


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)

Effect of different doses of IPLT BiTox (2, 50, 100, 200 ng) on capsaicin-induced secondary hyperalgesia. Mechanical withdrawal thresholds measured with von Frey filaments (A) and withdrawal response duration (s) after pinprick stimulation (B). The measurements were assessed before injection and then 30 minutes, 1, and 2 hours after capsaicin injection. Data are expressed as means ± SEM, *P < 0.05, **P < 0.01. n = 4 to 6 animals per group.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 10: Effect of different doses of IPLT BiTox (2, 50, 100, 200 ng) on capsaicin-induced secondary hyperalgesia. Mechanical withdrawal thresholds measured with von Frey filaments (A) and withdrawal response duration (s) after pinprick stimulation (B). The measurements were assessed before injection and then 30 minutes, 1, and 2 hours after capsaicin injection. Data are expressed as means ± SEM, *P < 0.05, **P < 0.01. n = 4 to 6 animals per group.
Mentions: We also used capsaicin-induced secondary hyperalgesia to examine the dose–response of BiTox, using 4 different doses (2, 50, 100, and 200 ng). BiTox was injected in the lateral plantar surface 3 days before capsaicin injection in the central plantar area. Mechanical stimuli were applied to the area of secondary hyperalgesia on the lateral plantar surface. BiTox reduced the hypersensitivity maximally at doses of 100 and 200 ng as measured with Von Frey hairs (F(1,6) = 119.503, P = 0.001, Fig. 10A) or pinprick test (F(1,6) = 51.0, P = 0.001, Fig. 10B).

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