Peptide-mediated transdermal delivery of botulinum neurotoxin type A reduces neurogenic inflammation in the skin.
Release of inflammatory pain mediators from peripheral sensory afferent endings contributes to the development of a positive feedback cycle resulting in chronic inflammation and pain. Botulinum neurotoxin type A (BoNT-A) blocks exocytosis of neurotransmitters and may therefore block the release of pain modulators in the periphery. Subcutaneous administration of BoNT-A (2.5, 5 and 10U) reduced plasma extravasation (PE) caused by electrical stimulation of the saphenous nerve or capsaicin in the rat hindpaw skin (ANOVA, Post hoc Tukey, p<0.05, n=6). Subcutaneous BoNT-A also reduced blood flow changes evoked by saphenous nerve stimulation (ANOVA, Post hoc Tukey, p<0.05, n=6). Subcutaneous BoNT-A had no effect on PE induced by local injection of substance P (SP) or vasodilation induced by local CGRP injection. Although BoNT-A is an effective treatment for a wide range of painful conditions, the toxin's large size necessitates that it be injected at numerous sites. We found that a short synthetic peptide (TD-1) can facilitate effective transdermal delivery of BoNT-A through intact skin. Coadministration of TD-1 and BoNT-A to the hindpaw skin resulted in a significant reduction in PE evoked by electrical stimulation. The findings show that BoNT-A can be administered subcutaneously or topically with a novel transdermal delivery peptide to reduce inflammation produced by activating nociceptors in the skin. Peptide-mediated delivery of BoNT-A is an easy and non-invasive way of administering the toxin that may prove to be useful in clinical practice.
Carmichael
Nicole M E
NME
University of Toronto, Department of Physiology, Toronto, Ontario, Canada M5S1A8.
Dostrovsky
Jonathan O
JO
Charlton
Milton P
MP
D000279:Administration, Cutaneous; D000818:Animals; D019274:Botulinum Toxins, Type A / Q000008:administration & dosage*; D002211:Capsaicin / Q000494:pharmacology; D003872:Dermatitis / Q000188:drug therapy* / Q000503:physiopathology; D004195:Disease Models, Animal; D016503:Drug Delivery Systems; D004558:Electric Stimulation / Q000009:adverse effects; D005089:Exocytosis / Q000187:drug effects / Q000502:physiology; D006614:Hindlimb / Q000294:innervation / Q000503:physiopathology; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors / Q000378:metabolism; D008297:Male; D020078:Neurogenic Inflammation / Q000188:drug therapy* / Q000503:physiopathology; D009619:Nociceptors / Q000187:drug effects / Q000502:physiology; D010146:Pain / Q000188:drug therapy* / Q000503:physiopathology; D010455:Peptides / Q000008:administration & dosage* / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D011984:Sensory Receptor Cells / Q000187:drug effects / Q000502:physiology; D018689:Sensory System Agents / Q000494:pharmacology; D016896:Treatment Outcome
D018836:Inflammation Mediators; D010455:Peptides; D018689:Sensory System Agents; D019274:Botulinum Toxins, Type A; D002211:Capsaicin