Anti-nociceptive effect of a conjugate of substance P and light chain of botulinum neurotoxin type A.
Neuropathic pain is a debilitating condition resulting from damage to sensory transmission pathways in the peripheral and central nervous system. A potential new way of treating chronic neuropathic pain is to target specific pain-processing neurons based on their expression of particular receptor molecules. We hypothesized that a toxin-neuropeptide conjugate would alter pain by first being taken up by specific receptors for the neuropeptide expressed on the neuronal cells. Then, once inside the cell the toxin would inhibit the neurons' activity without killing the neurons, thereby providing pain relief without lesioning the nervous system. In an effort to inactivate the nociceptive neurons in the trigeminal nucleus caudalis in mice, we targeted the NK1 receptor (NK1R) using substance P (SP). The catalytically active light chain of botulinum neurotoxin type A (LC/A) was conjugated with SP. Our results indicate that the conjugate BoNT/A-LC:SP is internalized in cultured NK1R-expressing neurons and also cleaves the target of botulinum toxin, a component-docking motif necessary for release of neurotransmitters called SNAP-25. The conjugate was next tested in a murine model of Taxol-induced neuropathic pain. An intracisternal injection of BoNT/A-LC:SP decreased thermal hyperalgesia as measured by the operant orofacial nociception assay. These findings indicate that conjugates of the light chain of botulinum toxin are extremely promising agents for use in suppressing neuronal activity for extended time periods, and that BoNT/A-LC:SP may be a useful agent for treating chronic pain.
Department of Oral and Maxillofacial Surgery, University of Florida College of Dentistry, Gainesville, FL, USA Department of Neuroscience, University of Florida College of Medicine, McKnight Brain Institute, Gainesville, FL, USA Department of Orthodontics, University of Florida, Gainesville, FL, USA.
Golam
G
Mustafa
Ethan M
EM
Anderson
Yvonne
Y
Bokrand-Donatelli
John K
JK
Neubert
Robert M
RM
Caudle
D000700:Analgesics; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic; D019274:Botulinum Toxins, Type A / Q000494:pharmacology*; D002478:Cells, Cultured; D003216:Conditioning, Operant / Q000187:drug effects; D005157:Facial Pain / Q000188:drug therapy / Q000503:physiopathology / Q000523:psychology; D005260:Female; D006358:Hot Temperature; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008812:Mice, Hairless; D009437:Neuralgia / Q000139:chemically induced / Q000188:drug therapy; D009474:Neurons / Q000378:metabolism; D017239:Paclitaxel; D051381:Rats; D017207:Rats, Sprague-Dawley; D018040:Receptors, Neurokinin-1 / Q000187:drug effects; D012201:Reward; D013373:Substance P / Q000031:analogs & derivatives* / Q000494:pharmacology*; D050825:Synaptosomal-Associated Protein 25 / Q000378:metabolism
D000700:Analgesics; D000972:Antineoplastic Agents, Phytogenic; D018040:Receptors, Neurokinin-1; D050825:Synaptosomal-Associated Protein 25; D013373:Substance P; D019274:Botulinum Toxins, Type A; D017239:Paclitaxel
Botulinum neurotoxin; Neurokinin receptor; Neuropathic pain