SAN DIEGO—Recent scientific advances in understanding the complex connections between inflammation and pain were highlighted in a session called No Pain and Much to Gain: Mechanisms and Targets of Pain in Rheumatic Diseases at ACR Convergence, held Nov. 12 in San Diego. Better understanding of these links may help point the way toward future targets for treating pain—one of the most common, distressing and difficult-to-treat symptoms of osteoarthritis (OA), rheumatoid arthritis (RA) and other rheumatic and inflammatory conditions.
Dr. Rachel Miller
Rachel Miller, PhD, BS, associate professor of medicine in the Division of Rheumatology at Rush University, Chicago, said OA risk factors predispose toward pain partly because they cause a change in joint mechanics, with remodeling of synovial joint tissue and activity-related mechanical sensitization responses accompanied by pain from movement. Her group has studied how these kinds of mechanical sensitization events occur in mouse models of OA, which can be measured using behavioral assays. Could understanding of these pathways lead to new treatment targets for persistent OA pain?
For example, Piezo2, a protein molecule and novel class of ion channels expressed by sensory neurons, is implicated in the development of mechanical sensitization in these animals.1 Dr. Miller’s research has shown that knocking out Piezo2 from nociceptors in mice, using mouse genetic techniques, offers protection from mechanical sensitization and weight-bearing pain—even though it does not protect against actual joint damage. This shows that Piezo2 plays a role in the animals’ ability to develop mechanical sensitization of their joints.
The researchers are also asking what other factors or pathways in the OA joint might be linked to Piezo2. Previous studies, for instance, have shown beneficial effects of treating patients with antibodies against nerve growth factor (NGF). Deleting Piezo2 also blocks NGF injection-induced knee swelling and mechanical hypersensitivity in mice. Over time, the researchers have seen macrophages infiltrating the dorsal root ganglia (DRGs), but that again failed to happen in Piezo2 knockout mice, suggesting that targeting Piezo2 may disrupt processes that support the development of persistent pain.
Neuroinflammation, with its infiltration of immune cells & activation of glial cells, causes both neurologic & psychiatric disorders & is a driving force in chronic pain.
The Dorsal Root Ganglion
Dr. Theodore Price
Theodore Price, PhD, a professor in the Department of Neuroscience at the University of Texas in Dallas, and director of its Center for Advanced Pain Studies, described recent work with human samples of the DRG in an effort to better understand pain mechanisms in rheumatic diseases, such as RA, and how immune changes within arthritic joints could be driving pain by intersecting the increase in cytokines and other ligands acting on the nociceptors. What is changing in the DRGs of people who have chronic pain?
Some of this work has involved a collaboration with the Southwest Transplant Alliance, one of the nation’s biggest organ procurement organizations, for the recovery of dorsal root ganglia in good condition for study in the lab following the removal of organs from organ donors. The team also works with neurosurgeons of cancer patients having thoracic vertebrectomies to recover their DRGs.
Researchers are also doing RNA sequencing to better understand what is changing within neuropathic DRGs that might be driving changes in nociceptor physiology, Dr. Price said. The team is trying to delve deeper into the roles of the cytokines Oncostatin M and leukemia inhibitory factor in potentially driving excitability of nociceptors in the DRG and the signaling of MAP (mitogen-activated protein) kinases. They have also turned to CRISPR editing to design naked plasmids that are taken up by human DRG neurons.
“We think this is a good testing paradigm to better understand what these immune-derived factors in arthritic joints are doing to the nociceptors that enervate those joints,” Dr. Price said. The target is a better understanding of the different subsets of human nociceptors in the DRG in the petri dish.
Neuro-Immune Interactions
Dr. Ru-Rong Ji
Ru-Rong Ji, PhD, professor of anesthesiology and director of the Center for Translational Pain Medicine at Duke University School of Medicine, also discussed the connections between neuroinflammation and immune therapy in pain. He emphasized the distinctions between inflammation—injury to peripheral tissue and systemic response; neuroinflammation within the peripheral and central nervous systems; and neurogenic inflammation, caused by activation of nociceptors and release of neuropeptides.
Neuroinflammation, with its infiltration of immune cells and activation of glial cells, causes both neurologic and psychiatric disorders and is a driving force in chronic pain, Dr. Ji said. Inflammatory mediators can be pro-nociceptive (i.e., pro-inflammatory) and anti-nociceptive (anti-inflammatory), with chronic pain defined as a loss of homeostasis and pro-resolution defined as a return to homeostasis. Acute inflammation can also resolve pain in some cases by producing anti-inflammatory and pro-resolving mediators. Typically, analgesics for joint pain are either neuro-modulators or immune modulators.
Dr. Ji’s lab is interested in neuro-immune interactions and has explored applications such as the injection of human serum from Lupus patients intrathecally into mice to induce persistent pain. His lab also showed that conditioned serum from healthy volunteers can resolve chemotherapy-induced neuropathic pain. He highlighted specialized pro-resolution mediators (SPMs) derived from fish oil, an anti-inflammatory dietary supplement, with potentially more potent analgesic effects than morphine and NSAIDs.
Glial cells, including astrocytes and satellite glial cells, which provide physical and chemical support to neurons, also have a role in pain, Dr. Ji said. This has led him to ask if chronic pain might be described as a gliopathy, or a dysfunction of glial cells.2
Larry Beresford is a medical journalist in Oakland, Calif.
References
- Obeidat AM, Wood MJ, Adamczyk NA, et al. Piezo2 expressing nociceptors mediate mechanical sensitization in experimental osteoarthritis. Nat Commun. Apr 29;14(1):2479.
- Ji RR, Tenugin B, Nederyaard M. Glia and pain: Is chronic pain a gliopathy? Pain. 2013 Dec;154 Suppl 1(0 1):S10–S28.
