Genetic ablation of delta opioid receptors in nociceptive sensory neurons increases chronic pain and abolishes opioid analgesia

Claire Gaveriaux-Ruff, Chihiro Nozaki, Xavier Nadal, Xavier C. Hever, Raphael Weibel, Audrey Matifas, David Reiss, Dominique Filliol, Mohammed A. Nassar, John N. Wood, Rafael Maldonado, Brigitte L. Kieffer

Research output: Contribution to journalArticle

109 Citations (Scopus)

Abstract

Opioid receptors are major actors in pain control and are broadly distributed throughout the nervous system. A major challenge in pain research is the identification of key opioid receptor populations within nociceptive pathways, which control physiological and pathological pain. In particular, the respective contribution of peripheral vs. central receptors remains unclear, and it has not been addressed by genetic approaches. To investigate the contribution of peripheral delta opioid receptors in pain control, we created conditional knockout mice where delta receptors are deleted specifically in peripheral NaV1.8-positive primary nociceptive neurons. Mutant mice showed normal pain responses to acute heat and to mechanical and formalin stimuli. In contrast, mutant animals showed a remarkable increase of mechanical allodynia under both inflammatory pain induced by complete Freund adjuvant and neuropathic pain induced by partial sciatic nerve ligation. In these 2 models, heat hyperalgesia was virtually unchanged. SNC80, a delta agonist administered either systemically (complete Freund adjuvant and sciatic nerve ligation) or into a paw (sciatic nerve ligation), reduced thermal hyperalgesia and mechanical allodynia in control mice. However, these analgesic effects were absent in conditional mutant mice. In conclusion, this study reveals the existence of delta opioid receptor-mediated mechanisms, which operate at the level of Na V1.8-positive nociceptive neurons. Delta receptors in these neurons tonically inhibit mechanical hypersensitivity in both inflammatory and neuropathic pain, and they are essential to mediate delta opioid analgesia under conditions of persistent pain. This delta receptor population represents a feasible therapeutic target to alleviate chronic pain while avoiding adverse central effects. The conditional knockout of delta-opioid receptor in primary afferent NaV1.8 neurons augmented mechanical allodynia in persistent pain models and abolished delta opioid analgesia in these models.

Original languageEnglish
Pages (from-to)1238-1248
Number of pages11
JournalPain
Volume152
Issue number6
DOIs
Publication statusPublished - 2011 Jun
Externally publishedYes

Keywords

  • Conditional gene knockout
  • Delta
  • Inflammation
  • Neuropathy
  • Nociceptive pathway
  • Opioid receptor

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology
  • Anesthesiology and Pain Medicine

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  • Cite this

    Gaveriaux-Ruff, C., Nozaki, C., Nadal, X., Hever, X. C., Weibel, R., Matifas, A., Reiss, D., Filliol, D., Nassar, M. A., Wood, J. N., Maldonado, R., & Kieffer, B. L. (2011). Genetic ablation of delta opioid receptors in nociceptive sensory neurons increases chronic pain and abolishes opioid analgesia. Pain, 152(6), 1238-1248. https://doi.org/10.1016/j.pain.2010.12.031