The good and the bad side of pain

Acute pain is an essential warning mechanism that keeps us safe from tissue damage caused by the environment and informs us about potential pathological mechanisms ongoing in the body. Have you ever put your hand on a hot stove? Ouch! You have barely touched the plate before you start feeling the pain and remove your hand. The pain limited the tissue damage caused.

What happens if you cannot feel pain? A large family in Northern Sweden carries a mutation that prevents them from experiencing deep body pain; this means they can destroy their joints without ever feeling any warning signs.¹

Unlike acute pain, chronic pain is a pathological state that affects more than 30% of the population worldwide.² Rheumatoid arthritis (RA) is an autoimmune disease where chronic joint pain is one of the most prominent symptoms. While the last few decades have led to the development of revolutionary drugs that target the immune system and prevent tissue destruction, many patients continue to experience pain despite disease remission.³ Our group is interested in the molecular mechanisms that underlie this problem.

In addition to the joint itself and the central nervous system (CNS), components of the peripheral nervous system (PNS) called dorsal root ganglia (DRG) are very important for pain signaling. This is where the cell bodies of pain-sensing sensory neurons are located. From the DRG, these neurons innervate the joint and connect to other neurons in the spinal cord that then connect to neurons in the brain. Our group has shown that these neurons have receptors for antibodies in immune complexes, which is a prominent feature of RA.⁴ The group has also shown that these neurons can communicate with the surrounding glial cells through lysophosphatidic acid signaling and cause pain-like behavior in a rodent model of pain after the resolution of inflammation.⁵

Most recently, we have focused on characterizing the DRG in terms of vascular permeability and the immune landscape.⁶ We show that this part of the PNS is much more permeable than the adjecent nerve and the CNS. We also show that there are different kinds of immune cells in the DRG and that a subgroup of them is taking up biomolecules from the blood. Future studies will focus on investigating these properties in different pathological states.

Reference:

1. Einarsdottir, E. et al. A mutation in the nerve growth factor beta gene (NGFB) causes loss of pain perception. Hum. Mol. Genet. 13, 799–805 (2004).
2. Cohen, S. P., Vase, L. & Hooten, W. M. Chronic pain: an update on burden, best practices, and new advances. Lancet 397, 2082–2097 (2021).
3. Kim, H.-A., Park, S. Y. & Shin, K. Implications of Persistent Pain in Patients With Rheumatoid Arthritis Despite Remission Status: Data From the KOBIO Registry. J. Rheum. Dis. 29, 215–222 (2022).
4. Farinotti, A. B. et al. Cartilage-binding antibodies induce pain through immune complex–mediated activation of neurons. J. Exp. Med. 216, 1904–1924 (2019).
5. Su, J. et al. Pain-like behavior in the collagen antibody-induced arthritis model is regulated by lysophosphatidic acid and activation of satellite glia cells. Brain. Behav. Immun. 101, 214–230 (2022).
6. Lund, H. et al. CD163+ macrophages monitor enhanced permeability at the blood–dorsal root ganglion barrier. J. Exp. Med. 221, e20230675 (2023).