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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 blocks capsaicin-induced secondary mechanical hyperalgesia. BiTox (200 ng) or vehicle were injected into the lateral plantar surface of the rat hindpaw (A2). Three days later 0.3% capsaicin was injected into the central plantar area (A1) and mechanical secondary hyperalgesia was measured in the lateral zone. Mechanical withdrawal threshold measured with von Frey filaments (B) or withdrawal response duration after pinprick stimulus (C), were attenuated by BiTox pretreatment. The measurements were made before injection (BL) and then 30 minutes, 1 and 2 hours after capsaicin injection. Data are expressed as means ± SEM, *P < 0.05, ***P < 0.001. n = 6 animals per group.
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Figure 9: Intraplantar BiTox blocks capsaicin-induced secondary mechanical hyperalgesia. BiTox (200 ng) or vehicle were injected into the lateral plantar surface of the rat hindpaw (A2). Three days later 0.3% capsaicin was injected into the central plantar area (A1) and mechanical secondary hyperalgesia was measured in the lateral zone. Mechanical withdrawal threshold measured with von Frey filaments (B) or withdrawal response duration after pinprick stimulus (C), were attenuated by BiTox pretreatment. The measurements were made before injection (BL) and then 30 minutes, 1 and 2 hours after capsaicin injection. Data are expressed as means ± SEM, *P < 0.05, ***P < 0.001. n = 6 animals per group.

Mentions: Capsaicin injection into the central plantar area of the hindpaw induced thermal hypersensitivity close to the injection site and secondary mechanical hyperalgesia in the zone that surrounds the injection site (Fig. 9A). Secondary mechanical hyperalgesia is thought to be maintained by A-nociceptor signaling amplified centrally by sensitization of dorsal horn neurons (Treede et al., 2000, Magerl et al., 2001). BiTox was delivered in the lateral plantar surface 3 days before capsaicin injection in the central area of the paw. Mechanical stimuli were applied to the area of secondary hyperalgesia area on the lateral plantar surface. BiTox reduced the hypersensitivity only in the area of secondary mechanical hyperalgesia measured with Von Frey filaments (between 30 min and 1 hour, F(1,10) = 27.2, P = 0.001, Fig. 9B) or pin-prick (between 30 minutes and 2 hours, F(3,24) = 8.643, P = 0.0005, Fig. 9C). Thermal hyperalgesia in the area of capsaicin injection and a marker of C-fiber sensitization was not affected by BiTox treatment.


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 blocks capsaicin-induced secondary mechanical hyperalgesia. BiTox (200 ng) or vehicle were injected into the lateral plantar surface of the rat hindpaw (A2). Three days later 0.3% capsaicin was injected into the central plantar area (A1) and mechanical secondary hyperalgesia was measured in the lateral zone. Mechanical withdrawal threshold measured with von Frey filaments (B) or withdrawal response duration after pinprick stimulus (C), were attenuated by BiTox pretreatment. The measurements were made before injection (BL) and then 30 minutes, 1 and 2 hours after capsaicin injection. Data are expressed as means ± SEM, *P < 0.05, ***P < 0.001. n = 6 animals per group.
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4834813&req=5

Figure 9: Intraplantar BiTox blocks capsaicin-induced secondary mechanical hyperalgesia. BiTox (200 ng) or vehicle were injected into the lateral plantar surface of the rat hindpaw (A2). Three days later 0.3% capsaicin was injected into the central plantar area (A1) and mechanical secondary hyperalgesia was measured in the lateral zone. Mechanical withdrawal threshold measured with von Frey filaments (B) or withdrawal response duration after pinprick stimulus (C), were attenuated by BiTox pretreatment. The measurements were made before injection (BL) and then 30 minutes, 1 and 2 hours after capsaicin injection. Data are expressed as means ± SEM, *P < 0.05, ***P < 0.001. n = 6 animals per group.
Mentions: Capsaicin injection into the central plantar area of the hindpaw induced thermal hypersensitivity close to the injection site and secondary mechanical hyperalgesia in the zone that surrounds the injection site (Fig. 9A). Secondary mechanical hyperalgesia is thought to be maintained by A-nociceptor signaling amplified centrally by sensitization of dorsal horn neurons (Treede et al., 2000, Magerl et al., 2001). BiTox was delivered in the lateral plantar surface 3 days before capsaicin injection in the central area of the paw. Mechanical stimuli were applied to the area of secondary hyperalgesia area on the lateral plantar surface. BiTox reduced the hypersensitivity only in the area of secondary mechanical hyperalgesia measured with Von Frey filaments (between 30 min and 1 hour, F(1,10) = 27.2, P = 0.001, Fig. 9B) or pin-prick (between 30 minutes and 2 hours, F(3,24) = 8.643, P = 0.0005, Fig. 9C). Thermal hyperalgesia in the area of capsaicin injection and a marker of C-fiber sensitization was not affected by BiTox treatment.

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