Intradermal injection of Botulinum toxin type A alleviates infraorbital nerve constriction-induced thermal hyperalgesia in an operant assay

A. Kumada, Y. Matsuka, I. Spigelman, Kotaro Maruhama, Y. Yamamoto, J. K. Neubert, T. A. Nolan, K. Watanabe, K. Maekawa, H. Kamioka, T. Yamashiro, T. Kuboki, K. Oguma

Research output: Contribution to journalReview articlepeer-review

21 Citations (Scopus)


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 7days after IoNC resulted in decreased number of facial contacts and increased the ratio of contact duration/event (measured at 14days after IoNC). The BoNT/A (2-200pg) effects were dose dependent and statistically significant at 100 and 200pg (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.

Original languageEnglish
Pages (from-to)63-72
Number of pages10
JournalJournal of oral rehabilitation
Issue number1
Publication statusPublished - Jan 2012


  • Botulinum toxin
  • Thermal hyperalgesia
  • Thermal stimulation
  • Trigeminal ganglion

ASJC Scopus subject areas

  • Dentistry(all)


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