One of the most important advances in our understanding of pain biology in the past few decades is the demonstration that it is not only the neurons that are responsible for pain processing. Cells of the immune system—including microglia, astrocytes, macrophages, and T cells—also play crucial signaling roles. MOGILab was the first to demonstrate that the involvement of neuroimmune mechanisms in pain was sex-specific, and we have continued to try and elucidate the conditions in which “male” and “female” neuroimmune systems are active, and the nature of the elusive “female” system.
Spinal Microglia vs. T Cells
The demonstration by MOGILab in 2011 that toll-like receptor 4 (TLR4) functionality affected chronic pain behaviour in male but not female mice suggested the possibility that only males were using microglia. Our paper in 2015 showed that this was true, for both inflammatory and neuropathic pain. The finding has been replicated and extended by independent laboratories, and shown to be true in rats as well as mice. The story, as often happens, has become more complicated since then, as some demonstrations of microglial involvement in pain processing in female rodents have been published. The proposed role of T cells in female-specific pain processing mechanisms was suggested based on indirect evidence; direct evidence is proving difficult to obtain since the infiltration of the spinal cord by T cells is extremely controversial.
The late Dr. Alan Gintzler and colleagues first showed a decrease in pain sensitivity associated with pregnancy, but this had never been shown in mice for chronic pain. MOGILab demonstrated that early in pregnancy, female mice switch from microglia-independent to microglia-dependent pain processing, and that later in pregnancy all evidence of injury-induced (inflammatory or neuropathic) pain hypersensitivity is abolished. We find that this pregnancy analgesia is dependent on both estrogen and progesterone, is T cell-dependent, and is mediated by δ-opioid receptors.
T Cells and Opioid Analgesia
In the process of investigating T cell involvement in pregnancy analgesia (see above), we noted that baseline pain sensitivity and opioid analgesic magnitudes are dependent on T cell status. Mice with non-functional T cells (nude, Rag1-/-, and Cd4-/- lines) are more sensitive to multiple pain modalities, and less sensitive opioid analgesia and opioid-mediated stress-induced analgesia. Furthermore, we were able to show that the sex difference in morphine analgesia (males>females) observed in CD-1 mice was T cell-dependent, such that adoptive transfer of male-derived CD4+ cells into either male or female recipients produced higher levels of analgesia.
We are working with our collaborator, Dr. Tuan Trang, to further explain the female-specific role of T cells in pain processing. The answer may involve pannexin-1 channels and their sex-dependent expression.