title: Intradermal injection of Botulinum toxin type A alleviates infraorbital nerve constriction-induced thermal hyperalgesia in an operant assay.
abstract: Recent studies have shown that infraorbital nerve constriction (IoNC)-induced mechanical allodynia has been attenuated by administration of highly purified 150-kDa Botulinum neurotoxin type A (BoNT/A). Here, we extend these studies to determine whether BoNT/A could attenuate IoNC-induced symptoms of thermal hyperalgesia. Instead of testing head withdrawal thresholds, a thermal operant assay was used to evaluate cortical processing of sensory input following IoNC. In this assay, a fasted rat's desire to obtain a food reward (sweetened condensed milk) is coupled to its ability to tolerate facial contact with a warm (45 °C) thermode. Bilateral IoNC decreased the ratio of thermode contact duration/event, which is an indicative of thermal hyperalgesia. BoNT/A injection intradermally in the area of infraorbital nerve (IoN) innervation 7 days after IoNC resulted in decreased number of facial contacts and increased the ratio of contact duration/event (measured at 14 days after IoNC). The BoNT/A (2-200 pg) effects were dose dependent and statistically significant at 100 and 200 pg (P < 0·05). Complete reversal of thermal hyperalgesia symptoms was obtained with a 200-pg dose, without affecting sham rat behaviour. Off-site (neck) injection of BoNT/A did not relieve thermal hyperalgesia, while co-injection of BoNT/A with a neutralising antibody in the area of IoN innervation prevented relief of thermal hyperalgesia. Neither IoNC nor BoNT/A injection affected operant assay parameters with a 24 °C thermode, indicating selectivity of thermal hyperalgesia measurements. These results strongly suggest that intradermal injection of BoNT/A in the area of IoN innervation alleviates IoNC-induced thermal hyperalgesia in an operant assay.
authors.affiliation: Department of Oral Rehabilitation and Regenerative Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Kita-ku, Okayama, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Kumada
authors.forename: Y
authors.initials: Y
authors.lastname: Matsuka
authors.forename: I
authors.initials: I
authors.lastname: Spigelman
authors.forename: K
authors.initials: K
authors.lastname: Maruhama
authors.forename: Y
authors.initials: Y
authors.lastname: Yamamoto
authors.forename: J K
authors.initials: JK
authors.lastname: Neubert
authors.forename: T A
authors.initials: TA
authors.lastname: Nolan
authors.forename: K
authors.initials: K
authors.lastname: Watanabe
authors.forename: K
authors.initials: K
authors.lastname: Maekawa
authors.forename: H
authors.initials: H
authors.lastname: Kamioka
authors.forename: T
authors.initials: T
authors.lastname: Yamashiro
authors.forename: T
authors.initials: T
authors.lastname: Kuboki
authors.forename: K
authors.initials: K
authors.lastname: Oguma
mesh_terms: D000818:Animals; D001904:Botulinum Antitoxin / Q000008:administration & dosage; D019274:Botulinum Toxins, Type A / Q000008:administration & dosage*; D016022:Case-Control Studies; D003251:Constriction, Pathologic / Q000150:complications; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005145:Face; D006358:Hot Temperature / Q000009:adverse effects; D006930:Hyperalgesia / Q000188:drug therapy* / Q000209:etiology; D007271:Injections, Intradermal; D008297:Male; D009498:Neurotoxins / Q000008:administration & dosage*; D009915:Orbit / Q000294:innervation*; D017288:Pain Threshold / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016896:Treatment Outcome
chemical_list: D001904:Botulinum Antitoxin; D009498:Neurotoxins; D019274:Botulinum Toxins, Type A