AM404, an inhibitor of anandamide uptake, prevents pain behaviour and modulates cytokine and apoptotic pathways in a rat model of neuropathic pain

Barbara Costa, Dario Siniscalco, Anna Elisa Trovato, Francesca Comelli, Maria Luisa Sotgiu, Mariapia Colleoni, Sabatino Maione, Francesco Rossi, Gabriella Giagnoni

Research output: Contribution to journalArticle

Abstract

An attractive alternative to the use of direct agonists at the cannabinoid receptor type 1 (CB1) in the control of neuropathic pain may be to potentiate the actions of endogenous cannabinoids. Thus, the effects of AM404, an inhibitor of anandamide uptake, were assessed in an experimental model of neuropathic pain in rats. Daily treatment with AM404 prevented, time- and dose-dependently, the development of thermal hyperalgesia and mechanical allodynia in neuropathic rats. Antagonists at cannabinoid CB1 or CB2 receptors, or at the transient receptor potential vanilloid type 1 receptor, each partially reversed effects induced by AM404. A complete reversal was obtained when the three antagonists were given together, suggesting that all three receptors are involved. AM404 treatment affected two pathways involved in the generation and maintenance of neuropathic pain, one mediated by nitric oxide (NO) and the other by cytokines. AM404 completely prevented the overproduction of NO and the overexpression of nNOS, inhibited the increase in tumour necrosis factor α (TNFα) and enhanced the production of interleukin-10. Both NO and TNFα are known to contribute to the apoptotic process, which plays an important role in the establishment of chronic pain states. AM404 treatment prevented the increase in the ratio between pro- and anti-apoptotic gene bax/bcl-2 expression observed in the spinal cord of neuropathic rats. Taken together, these findings suggest that inhibition of endocannabinoid uptake, by blocking the putative anandamide carrier, results in the relief of neuropathic pain and may represent a novel strategy for treating chronic pain.

Original languageEnglish
Pages (from-to)1022-1032
Number of pages11
JournalBritish Journal of Pharmacology
Volume148
Issue number7
DOIs
Publication statusPublished - Aug 12 2006

Keywords

  • AM404
  • Apoptosis
  • Cannabinoid
  • Cytokines
  • Endocannabinoid
  • IL-10
  • Neuropathic pain
  • Nitric oxide
  • TNFα
  • VDM11

ASJC Scopus subject areas

  • Pharmacology

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    Costa, B., Siniscalco, D., Trovato, A. E., Comelli, F., Sotgiu, M. L., Colleoni, M., Maione, S., Rossi, F., & Giagnoni, G. (2006). AM404, an inhibitor of anandamide uptake, prevents pain behaviour and modulates cytokine and apoptotic pathways in a rat model of neuropathic pain. British Journal of Pharmacology, 148(7), 1022-1032. https://doi.org/10.1038/sj.bjp.0706798