The Mechanisms of Inflammatory Pain
What is Inflammatory Pain?
There are three general phases associated with the experience of pain: nociception, pain perception, and the consequences of pain, like suffering and behaviors motivated by pain.1 Inflammation is one cause of pain, but a combination of factors likely cause chronic pain, including physical, emotional, psychological, and social inputs.
Beyond sensitivity to pain, several chronic conditions are associated with inflammatory pain, like fatigue and immune suppression. Inflammatory pain can also be associated with conditions more closely associated with inflammation itself, like osteoarthritis and diabetic neuropathy. Understanding the mechanisms of pain, chronic pain, and inflammatory pain can help clinicians and researchers to identify and develop new therapies to manage the underlying cause of pain and help patients to regain normal function.
Types of Inflammatory Pain
Chronic inflammatory pain affects millions of Americans and appears in many forms. Affecting knees, fingers, and wrists, joint pain can be either in the form of osteoarthritis, which affects approximately 30.8 million American adults, or rheumatoid arthritis, which affects approximately 1.5 million American adults, with women more likely to be affected than men. Pain affecting the lower back is the most common cause of job-related disability, affecting 80 percent of adults.2
Nociceptors, Receptors, and Mediators
Nociceptors are the sensory neurons that alert the body to “potentially damaging stimuli” like bacteria, injury-related stimuli, and changes in temperature or pressure.3 Detection of the stimuli is called transduction. These neurons signal to the spinal cord that the body is in danger, a process known as conduction, and then the information is sent to the brain in a process known as transmission.
The experience of feeling pain, or the detection of painful stimuli, is controlled by pain receptors. Different pain receptors detect different stimuli, such as the vanilloid receptors that detect heat or acid-sensing ion channels (ASICs) that detect acidic substances. Conduction and transmission of pain signals through the nervous system are transmitted via a series of ion channels. In states of inflammatory pain, hormone-like substances, such as prostaglandin E2 (PGE2) and serotonin, can enhance the sensitivity of the channels that mediate transmission of pain signals through the body.
Damaged cells release inflammatory mediators because of injury. Inflammatory mediators either can activate nociceptors immediately or act on inflammatory cells to release more chemicals in the body that activate a pain response. Inflammatory cytokines are one type of mediator that can enhance inflammation and pain response. Some common inflammatory cytokines include tumor necrosis factor alpha (TNF-α) and interleukin (IL) cytokines like IL-1 and IL-6. Prostaglandins are also important inflammatory mediators and typically act on nociceptors, making them more sensitive to damaging stimuli. Commonly studied prostaglandins include PGE2 and the enzymes cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2).
Inflammatory Pain Management
Varieties of pain management strategies are available to manage acute pain and to prevent and resolve chronic inflammatory pain. Non-steroidal anti-inflammatory drugs (NSAIDs; medication like aspirin or ibuprofen) commonly address chronic pain. NSAIDs act on enzymes COX-1 and COX-2 and reduce the formation of prostaglandins, preventing pain sensitization.
Use of opioid painkillers is also very common; overprescription and misuse of opioids has led to a public health crisis of dramatic proportion throughout the United States. Immune cells produce opiates, which act on opioid receptors in the body. Opioid painkillers can prevent nociceptor activity, providing pain relief. However, opioid painkillers can also be highly addictive.
A final category of compounds that inhibit nociceptor activity and pain sensitization is that of cannabinoids. There are two types of cannabinoid receptors in the body: CB1 and CB2. CB1 is expressed on neuronal cells while CB2 is expressed on immune cells. Cannabinoid receptor agonists applied either topically or systematically also inhibits nociceptor activity.
Inflammatory pain can occur acutely on peripheral neuronal cells, but chronic pain and inflammation can also activate different mechanisms. This process is known as central sensitization, and it occurs in individuals with chronic inflammatory conditions. The body can release pain signaling substances that communicate between the peripheral nervous system and the spinal cord (common in acute pain and inflammation), as well as other neuropeptides and neurotrophic factors that can cause long-term changes in how the nervous system communicates with the brain about pain and stimuli.
Furthermore, the increase in the release of neuropeptides and neurotrophic factors makes pain receptors in the brain more sensitive to stimuli, which means individuals with chronic inflammation are likely to have an exaggerated pain response to normal pain stimuli.
While some literature reviews call for an anti-inflammatory co-therapy of NSAIDs and morphine based on the finding that chronic inflammation can lead to more intense pain, resolution of inflammation itself is also a compelling proposition. The role of neurotransmitters in the development of chronic inflammation is not well understood, but research suggests that there might be a bidirectional relationship between the neuroendocrine system and inflammation.4
- Kidd, B.L., Urban, L.A. (1 June 2001). Mechanisms of inflammatory pain, BJA: British Journal of Anaesthesia, 87 (1), 3–11. https://doi.org/10.1093/bja/87.1.3
- Low back pain fact sheet. (n.d.). Retrieved from https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Low-Back-Pain-Fact-Sheet
- Dubin, A. E., & Patapoutian, A. (2010). Nociceptors: the sensors of the pain pathway. The Journal of clinical investigation, 120(11), 3760–3772. https://doi.org/10.1172/JCI42843
- Louati, K., Berenbaum, F. (2015). Fatigue in chronic inflammation – a link to pain pathways. Arthritis Res Ther 17, 254. https://doi.org/10.1186/s13075-015-0784-1