Chronic inflammatory pain: new molecules & mechanisms

Abstract

Pain is an important self-protecting signal. The pain system detects and reacts to (withdrawal reflex) the presence of an acute potentially injurious stimulus such as heat, pressure, tissue damage or inflammation to avoid possible (further) tissue damage. However, after inflammation or tissue damage has resolved, persistent pain can develop without further protective or restorative goal. Persistent or chronic pain has become a major health problem in many countries, especially because there is no effective medication available to prevent or combat chronic pain states. Understanding the mechanisms underlying the transition from acute to chronic pain is therefore of great importance. In this thesis I mainly focused on the investigation of neurobiological mechanisms underlying transition from acute to chronic inflammation-induced pain. We described that G protein-coupled receptor kinase 2 (GRK2) plays a key role in regulating the transition from acute to chronic inflammation-induced pain. Furthermore, we found that the GRK2 levels in a specific cell subtype, the peripheral monocytes/macrophages, are crucial to promote resolution of inflammation-induced pain. Mice with a 50% reduction of GRK2 in macrophages (LysM-GRK2+/-) develop persistent pain (> 8 days) after a single intraplantar injection of the pro-inflammatory cytokine IL-1b, while in control WT mice the pain was resolved within one day. Moreover, depletion of peripheral monocytes/macrophages caused transition from acute to persistent IL-1b-induced pain WT mice. This finding indicates that monocytes/macrophages are key to preventing the transition to chronic pain after a transient peripheral inflammatory stimulus. Chronic pain will be maintained by the activation of microglia cells in the spinal cord. The prolonged pain response in LysM-GRK2+/- mice was prevented by an intrathecal injection and reversible by an intraperitoneal injection of the microglia/macrophage inhibitor minocycline, indicating a contribution of spinal cord and/or dorsal root ganglion (DRG) microglia/macrophages in the transition to persistent pain. Furthermore, in this thesis we identified several other compounds that can prevent or treat chronic pain. Finally we performed a genetic research to investigate DNA polymorphism in genes that can be responsible for the development of chronic pain. We identified a single nucleotide polymorphism (SNP) nearby two different genes (FAM173b and CCT5) in patients with “chronic widespread pain (CWP)” compared to healthy controls. Interestingly, we found an upregulation of FAM173b and CCT5 in the spinal cord during inflammatory- induced chronic pain in mice. This could be a clinic relevant finding, since those two genes can be identified as new targets to treat chronic pain.