Inflammatory pain is characterized by increased perceptual sensitivity and emotional reaction triggered by an inflammatory process associated with tissue injury. The sensation of pain involves a multifaceted interaction between several biological responses of the central and peripheral nervous systems, vascular regulation, and the immune system in reaction to the harms of tissue damage, pathogens, and irritants. Pain provides a crucial protective function for an organism, preventing detrimental stimuli and encouraging the healing of damaged tissue.

Inflammatory mediators, produced during inflammation, induce pain via direct activation and sensitization of neurons. Nociceptors, a specialized subset of sensory neurons, play a key role in mediating noxious mechanical, thermal, and chemical stimuli. They are densely distributed in peripheral tissues like skin, joints, muscles, respiratory and gastrointestinal tracts¹.

Acute tissue damage signals the activation of various receptors, including G-protein coupled receptors (GPCRs), ionotropic receptors, and tyrosine kinase receptors on nerve terminals and cell bodies. This process initiates the local release of inflammatory mediators, which include bradykinin, serotonin, adenosine triphosphate (ATP), histamine, prostaglandins, and cytokines. These substances stimulate nociceptors to produce action potential impulses to transmit sensed intakes to central neurons. Notably, small and unmyelinated nerve fibers called C-fibers induce neurogenic inflammation. This phenomenon is distinguished by an increase in the production and subsequent release of neuropeptides such as neurokinin A, substance P, and calcitonin gene-related peptide (CGRP) in a retrograde way. These events are followed by vasodilatation (redness) and rapid plasma extravasation (swelling) that arise quicker than the immune cell infiltration. Consequently, the local inflammatory response releases free arachidonic acid (AA) from the phospholipids, which are converted into prostaglandins via the cyclooxygenase (COX) pathways².

Pain from inflammation can be categorized into two types: chronic and acute pain. Acute inflammatory pain is typically intense and happens for a short period. It starts as a response to harmful stimuli usually mediated by the Aδ-fibers, a fine and thinly myelinated group of nociceptors. Leukocytes and blood plasma are accumulated at the injury site to aid in the inflammatory process. Nonetheless, chronic inflammation lasts beyond the expected healing period, and C-fibers usually mediate it.

Other secreted molecules act directly or indirectly on nociceptor ion channels and receptors, resulting in hypersensitization. For example, the stimulation of protein kinase A (PKA) activates several sensitization cascades by direct phosphorylation of TRPV1 and Nav1.8 channels, which lowers channel activation thresholds³. Furthermore, a special type of cytokine proteins named interleukins (IL) have essential roles in pro-inflammatory and anti-inflammatory processes and the activation and differentiation of immune cells. Interleukin-1β (IL-1β), for instance, is a critical regulator of the inflammatory pathway that is central for host responses to infection, particularly.

This inflammatory pain pathway depicts a general view of the inflammation process, which involves complex and comprehensive exchange and cooperation at the molecular level.

References

1. Pinho-Ribeiro, F. A., Verri Jr, W. A. & Chiu, I. M. Nociceptor Sensory Neuron-Immune Interactions in Pain and Inflammation.  Trends Immunol.   38, 5–19 (2016).

2. Yam, M. F. et al. General Pathways of Pain Sensation and the Major Neurotransmitters Involved in Pain Regulation.  Int. J. Mol. Sci.   19, 2164 (2018).

3. Matsuda, M., Huh, Y. & Ji, R. R. Roles of inflammation, neurogenic inflammation, and neuroinflammation in pain.  J. Anesth.   33, 131–139 (2019).