Immune conditions associated with CD4+ T effector-induced opioid release and analgesia

Pain. 2012 Feb;153(2):485-93. doi: 10.1016/j.pain.2011.11.013. Epub 2011 Dec 19.


Effector CD4(+) T lymphocytes generated in response to antigens produce endogenous opioids. Thus, in addition to their critical role in host defenses against pathogens, effector CD4(+) T lymphocytes contribute to relieving inflammatory pain. In this study, we investigated mechanisms of opioid release by antigen-experienced effector CD4(+) T cells that leave draining lymph nodes and come back into the inflammatory site. Effector antigen-primed CD4(+) T lymphocytes generated in vitro were intravenously injected into nude mice previously immunized with either cognate or irrelevant antigens in complete Freund adjuvant (CFA). CFA-induced mechanical hyperalgesia was only reduced in mice immunized with cognate antigen. Thus, antinociceptive activity of effector CD4(+) T cells requires the presence of the antigen for which they are specific within the inflammatory site. Accordingly, analgesia was inhibited by neutralizing cognate T cell receptor-mediated interaction between effector CD4(+) T lymphocytes and antigen-presenting cells at the site of inflammation. Analgesia was observed by transferring effector CD4(+) T lymphocytes with Th1 or Th2 phenotype, suggesting that antinociceptive activity is a fundamental property of effector CD4(+) T lymphocytes irrespective of their effector functions. Based on the use of agonists and antagonists selective for each of the opioid receptor subclasses, we showed that analgesia induced by T cell-derived opioids is elicited via activation of δ-type opioid receptors in the periphery. Thus, the antinociceptive activity is a fundamental property associated with the effector phase of adaptive immunity, which is driven by recognition of the cognate antigen by effector CD4(+) T lymphocytes at the inflammatory site.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptive Immunity
  • Analgesia / methods*
  • Animals
  • CD4-Positive T-Lymphocytes / immunology
  • CD4-Positive T-Lymphocytes / metabolism*
  • CD4-Positive T-Lymphocytes / pathology
  • Cells, Cultured
  • Enkephalins / blood
  • Enkephalins / genetics
  • Enkephalins / metabolism
  • Inflammation / immunology
  • Inflammation / metabolism
  • Inflammation / pathology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Opioid Peptides / blood
  • Opioid Peptides / genetics
  • Opioid Peptides / metabolism*
  • Pain / immunology*
  • Pain / metabolism
  • Pain / pathology
  • Protein Precursors / blood
  • Protein Precursors / genetics
  • Protein Precursors / metabolism


  • Enkephalins
  • Opioid Peptides
  • Protein Precursors
  • proenkephalin