Botulinum neurotoxin A enhances the analgesic effects on inflammatory pain and antagonizes tolerance induced by morphine in mice

Valentina Vacca, Sara Marinelli, Cecilia Eleuteri, Siro Luvisetto, Flaminia Pavone

Research output: Contribution to journalArticlepeer-review


Over the recent years compelling evidence has accumulated indicating that botulinum neurotoxin serotype A (BoNT/A) results in analgesic effects on neuropathic as well as inflammatory pain, both in humans and in animal models. In the present study, the pharmacological interaction of BoNT/A with morphine in fighting inflammatory pain was investigated in mice using the formalin test. Moreover, the effects of BoNT/A on the tolerance-induced by chronic administration of morphine were tested and the behavioral effects were correlated with immunofluorescence staining of glial fibrillary acidic protein, the specific marker of astrocytes, at the spinal cord level. An ineffective dose of BoNT/A (2. pg/paw) combined with an ineffective dose of morphine (1. mg/kg) exerted a significant analgesic action both during the early and the late phases of formalin test. A single intraplantar injection of BoNT/A (15. pg/paw;, administered the day before the beginning of chronic morphine treatment (7. days of s.c. injections of 20. mg/kg), was able to counteract the occurrence of tolerance to morphine. Moreover, BoNT/A reduces the enhancement of the expression of astrocytes induced by inflammatory formalin pain. Side effects of opiates, including the development of tolerance during repeated use, may limit their therapeutic use, the possibility of using BoNT/A for lowering the effective dose of morphine and preventing the development of opioid tolerance would have relevant implications in terms of potential therapeutic perspectives.

Original languageEnglish
Pages (from-to)489-499
Number of pages11
JournalBrain, Behavior, and Immunity
Issue number3
Publication statusPublished - Mar 2012


  • Behavior
  • Botulinum neurotoxins
  • Formalin pain
  • Glial cells
  • Immunofluorescence
  • Morphine tolerance
  • Opioid
  • Spinal cord

ASJC Scopus subject areas

  • Immunology
  • Behavioral Neuroscience
  • Endocrine and Autonomic Systems


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