Inflammatory Pain
Inflammatory pain is considered a subtype of nociceptive pain that arises as a direct consequence of the inflammatory process occurring in non-neural tissues. It is initiated by tissue damage or irritation, which triggers a complex series of cellular and biochemical events known as the inflammatory response. This response, while primarily aimed at healing and protection, is itself a potent source of pain.
Pathophysiology
The development of inflammatory pain involves the release of a host of inflammatory mediators at the site of injury or inflammation. These mediators are released from damaged cells, resident immune cells (like mast cells and macrophages), and infiltrating immune cells (like neutrophils), from nerve endings themselves, and even from glial cells.
Key inflammatory mediators include:
- Prostaglandins (PGs)
- Leukotrienes (LTs)
- Bradykinin
- Histamine
- Serotonin
- Cytokines (e.g., TNF-ฮฑ, IL-1 beta, IL-6)
- Nerve Growth Factor (NGF)
- Substance P
- Calcitonin Gene-Related Peptide (CGRP)
- Protons (acidic pH)
These substances act on nociceptors, leading to peripheral sensitization. The biochemical onslaught effectively lowers the threshold for nociceptor activation and amplifies their response to subsequent stimuli.
Many of these mediators directly interact with nociceptors. Some mediators, like bradykinin and ATP, can directly activate nociceptors by binding to their specific receptors (e.g., B2 receptors for bradykinin, P2X3 receptors for ATP), causing depolarization and action potential firing. Others, such as prostaglandins and NGF, primarily sensitize nociceptors. For instance, NGF, by binding to its high-affinity receptor TrkA expressed on nociceptors, initiates intracellular signaling cascades that lead to increased synthesis, trafficking, and phosphorylation of ion channels (e.g., TRPV1, Nav1.8), thereby enhancing their excitability and transduction capabilities, particularly in chronic inflammatory pain states.
This process involves a reduction in the activation threshold of nociceptors and an increase in their responsiveness to stimuli. As a result, nociceptors may fire spontaneously or respond excessively to both noxious and normally innocuous stimuli. Peripheral sensitisation is responsible for primary hyperalgesia (increased pain sensitivity at the site of injury).
Peripheral sensitisation is characterized by a reduction in the activation threshold of nociceptors and an increase in their responsiveness to both noxious and innocuous stimuli. Both the thinly myelinated A$\delta$-fibers, which typically transmit fast, sharp, well-localized pain, and the unmyelinated C-fibers, responsible for slower, dull, aching, or burning pain, undergo sensitization. As a result of peripheral sensitization, stimuli that would normally be subthreshold (i.e., not painful) can now trigger pain (allodynia), and stimuli that would normally be only mildly painful evoke a much more intense and prolonged pain response (hyperalgesia).
Beyond the direct effects on neurons, the inflammatory process also involves the activation of glial cells, such as microglia and astrocytes, both in the peripheral nervous system (e.g., satellite glial cells in dorsal root ganglia) and the central nervous system (spinal cord and brain). Initially, glial cells play a neuroprotective and supportive role. However, in persistent inflammatory states, they can become chronically activated and transition to a pro-inflammatory phenotype. These activated glial cells release their own array of inflammatory mediators, including cytokines (TNF-ฮฑ, IL-1 beta), chemokines, and reactive oxygen species. This glial-mediated neuroinflammation can further amplify nociceptive signaling, contribute to the maintenance of peripheral and central sensitization, and play a role in the transition from acute to chronic pain.
Inflammatory pain can be further characterized based on its temporal pattern and relationship to activity:
- Chemical inflammatory pain: Often described as constant, though its intensity may fluctuate. This is driven by the persistent presence of inflammatory mediators.
- Mechanical inflammatory pain: Typically intermittent and directly related to movement or mechanical stress on the inflamed tissues. (see Impulse Pain)
Characteristics
Clasically, inflammatory pain is often associated with the cardinal signs of inflammation:
- Rubor (redness) due to vasodilation.
- Tumor (swelling) due to increased vascular permeability and fluid exudation.
- Calor (heat) due to increased blood flow.
- Dolor (pain), as described above.
- Functio laesa (loss of function) due to pain and swelling.
The pain is often worse in the morning or after periods of inactivity (e.g., morning stiffness in rheumatoid arthritis), may improve with gentle activity, but can be exacerbated by excessive activity and often worsens at night or during rest.
On examination there may be signs of peripheral sensitisation such as localised allodynia.
Inflammatory pain serves a protective and healing role in the acute phase. By causing pain and tenderness, it encourages guarding of the injured area, preventing further damage and allowing healing processes to occur. However, when inflammation becomes chronic, as seen in conditions like rheumatoid arthritis or persistent post-traumatic inflammation, this normally adaptive mechanism can become maladaptive. The ongoing production of inflammatory mediators and persistent nociceptor sensitisation contribute to chronic pain, hypersensitivity, and significant functional disability.
Treatments for inflammatory pain often target the underlying inflammatory process, for example, with NSAIDs (which inhibit prostaglandin synthesis) or corticosteroids.
