T-Cell Mediation of Pregnancy Analgesia Affecting Chronic Pain in Mice

J Neurosci. 2017 Oct 11;37(41):9819-9827. doi: 10.1523/JNEUROSCI.2053-17.2017. Epub 2017 Sep 6.


It has been reported consistently that many female chronic pain sufferers have an attenuation of symptoms during pregnancy. Rats display increased pain tolerance during pregnancy due to an increase in opioid receptors in the spinal cord. Past studies did not consider the role of non-neuronal cells, which are now known to play an important role in chronic pain processing. Using an inflammatory (complete Freund's adjuvant) or neuropathic (spared nerve injury) model of persistent pain, we observed that young adult female mice in early pregnancy switch from a microglia-independent to a microglia-dependent pain hypersensitivity mechanism. During late pregnancy, female mice show no evidence of chronic pain whatsoever. This pregnancy-related analgesia is reversible by intrathecal administration of naloxone, suggesting an opioid-mediated mechanism; pharmacological and genetic data suggest the importance of δ-opioid receptors. We also observe that T-cell-deficient (nude and Rag1-null mutant) pregnant mice do not exhibit pregnancy analgesia, which can be rescued with the adoptive transfer of CD4+ or CD8+ T cells from late-pregnant wild-type mice. These results suggest that T cells are a mediator of the opioid analgesia exhibited during pregnancy.SIGNIFICANCE STATEMENT Chronic pain symptoms often subside during pregnancy. This pregnancy-related analgesia has been demonstrated for acute pain in rats. Here, we show that pregnancy analgesia can produce a complete cessation of chronic pain behaviors in mice. We show that the phenomenon is dependent on pregnancy hormones (estrogen and progesterone), δ-opioid receptors, and T cells of the adaptive immune system. These findings add to the recent but growing evidence of sex-specific T-cell involvement in chronic pain processing.

Keywords: T cells; adaptive immunity; delta-opioid; pain; pregnancy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adoptive Transfer
  • Analgesia*
  • Animals
  • Chronic Pain / chemically induced
  • Chronic Pain / physiopathology*
  • Female
  • Hyperalgesia / physiopathology
  • Mice
  • Mice, Inbred ICR
  • Mice, Nude
  • Microglia / immunology
  • Naloxone / pharmacology
  • Narcotic Antagonists / pharmacology
  • Neuralgia / physiopathology
  • Ovariectomy
  • Pregnancy
  • Pregnancy, Animal / physiology*
  • Receptors, Opioid, delta / drug effects
  • T-Lymphocytes* / immunology


  • Narcotic Antagonists
  • Receptors, Opioid, delta
  • Naloxone