Disclaimer: This article is intended solely for informational and educational purposes only. It does not constitute medical advice.
Pain is a significant feature of COVID-19, appearing as headaches, muscle aches, joint discomfort, chest pain, or nerve-related symptoms such as burning, tingling, and hypersensitivity. For some people, these symptoms disappear as the infection resolves. For others, pain can persist as part of long COVID. Research suggests that this pain does not arise from a single cause. Instead, COVID-related pain is driven by several molecular systems involved in inflammation, nerve signaling, blood vessels, and the body’s perception of painful stimuli.
The SARS-CoV-2 virus is covered in spike proteins on its surface, which enable the virus to attach to human cells. Its best-known target is the ACE2 receptor, which helps the virus enter susceptible cells. The spike protein can also interact with other cellular molecules, including a receptor called neuropilin-1, or NRP1. NRP1 is particularly interesting to pain researchers because it is found in the nervous system and participates in processes that influence sensory nerve activity.
Pain begins, in part, with specialized sensory nerve cells called nociceptors. These nerves detect potentially damaging mechanical, thermal, and chemical signals and transmit electrical messages toward the spinal cord and brain. Nociceptors also respond to inflammatory chemicals produced during infection, allowing immune activity to change how easily pain signals are generated. Viral infections can therefore make nociceptors more sensitive, meaning that stimuli that were previously harmless or mildly uncomfortable may become painful.
The interaction between the spike protein and NRP1 is an area of interest for researchers studying the molecular mechanism causing pain in patients with COVID-19. Laboratory research has shown that after the spike protein is processed by human enzymes, part of it can bind to NRP1. NRP1 normally interacts with vascular endothelial growth factor A, or VEGF-A, a signaling molecule that has roles in blood-vessel biology and pain signaling. Experimental studies suggest that spike binding can interfere with this VEGF-A/NRP1 pathway and alter nociceptive signaling.
Interestingly, early laboratory experiments found that this interaction could temporarily reduce certain pain responses rather than increase them. This has led researchers to investigate whether SARS-CoV-2 may affect pain perception differently at different stages of infection. However, these findings largely come from preclinical research so far and do not confirm that circulating spike protein directly explains pain in people with COVID-19.
At the same time, COVID-19 can generate strong inflammatory responses. Immune signaling molecules such as interleukins, tumor necrosis factor, and interferons can affect sensory neurons, lowering their activation thresholds and contributing to a process known as peripheral sensitization. Continued signaling may also contribute to central sensitization, in which pain-processing circuits in the spinal cord and brain become unusually responsive. Research has associated persistent inflammatory signaling with post-COVID symptoms, although the biological picture remains complex.
Nerve injury may contribute as well. Studies of people with painful long COVID have identified abnormalities consistent with small-fiber neuropathy in some patients. Small nerve fibers help transmit pain and temperature sensations and regulate automatic functions such as heart rate and sweating. Damage or dysfunction in these fibers can produce burning pain, pins-and-needles sensations, altered temperature sensitivity, or unusual sensitivity to touch.
COVID-related pain is therefore best understood as the possible result of several overlapping molecular processes rather than one simple mechanism. Spike-protein interactions, immune inflammation, changes in nociceptor sensitivity, vascular effects, and peripheral nerve injury may all contribute. Understanding these pathways may eventually help clinicians identify more targeted treatments for patients whose pain continues long after the initial infection has passed.