Opioids in pain control by M2 macrophages and M2 microglia

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Chronic pain such as pain resulting from nerve damage is associated with chronic neuroinflammation, in both peripheral and central nervous system (CNS). Indeed, peripheral immune cells such as macrophages and CNS microglia are involved in pain pathophysiology. Current research predominately focuses on the contribution of these cells to pain pathogenesis. The main objective of this project is to examine pain-inhibiting actions of macrophages and microglia in the peripheral and central nervous system. We propose that not the general inhibition of neuroinflammation, but fostering the beneficial effects of intrinsic anti-inflammatory M2 macrophages and M2 microglia is more promising for the control of chronic pain. We hypothesize that skewing macrophages and microglia toward an anti-inflammatory M2 phenotype in response to anti-inflammatory cytokine interleukin-4 (IL-4) will result in analgesia involving the endogenous opioid system. Specifically, we postulate that IL-4 acting via IL-4 receptors in macrophages and microglia will shift them from M1 to M2 phenotype, and will lead to elevated intracellular levels and enhanced release of opioid peptides from M2 cells at the injured nerves and in the spinal cord, respectively. The secreted opioids will activate peripheral or spinal opioid receptors to ameliorate mechanical and heat hypersensitivity triggered by nerve damage. In a series of in vivo and closely-related ex vivo experiments using acutely isolated purified macrophages and microglia, we will examine the contribution of opioid peptides and receptors to IL-4-induced analgesia, immune cell composition, M1/M2 status of macrophages and microglia, their opioid peptide content and opioid receptor expression, and direct pain-inhibiting actions in a mouse model of neuropathic pain induced by the sciatic nerve injury. In summary, we will explore the idea that cytokines are not the sole mediators, but that the opioid system is relevant to analgesic actions of IL-4 and M2 cells in the peripheral and central nervous system. In addition to pain specialists interested in basic and translational research, these studies may be relevant to immunologists, neurobiologists and clinical scientists studying the role of IL-4 and M2 cells in neurodegenerative diseases, as the opioid system may also be involved in these CNS neuroinflammatory conditions.