Clip 1 - Tissue Injury

• Tissue injury causes the release of various inflammatory and pain mediators resulting in peripheral sensitization_1,2,3

• Pain response mediators: ATP, acetylcholine and serotonin are released from damaged endothelial cells and platelets; prostaglandin E2 is synthesized by Cyclooxygenase I and II enzymes in damaged cells; bradykinin is released from plasma from damaged vessels_1,2

• Bradykinin stimulates further synthesis/release of prostaglandins, and, together with prostaglandins, sensitizes primary afferent sensory fibers in response to stimulation by ATP, acetylcholine, serotonin and mechanical and thermal stimuli_1,2,3

• Primary afferent sensory fibers release Substance P and calcitonin gene-related peptide (CGRP) which contribute to the pain response by triggering the release of histamine from mast cells, which, in turn, excites the peripheral afferent sensory fibers_1,2,3

• Inflammatory response mediators: Histamine is released from mast cells in response to Substance P and CGRP; additional mediators are released from blood cells (cytokines, complement factors C3a and C5a, serotonin, platelet-activating factor, neutrophil chemotactic factor, fibrinopeptides, leukotrienes)_1,2

• Together with bradykinin and prostaglandins, these inflammatory mediators cause peripheral vasodilation, increased vascular permeability, plasma extravasation, migration of leucocytes to the site of injury, and clotting responses₁

• Sensitization of the primary afferent sensory fibers by mediators of the pain response results in greater, more frequent transmission of action potentials to the nociceptive neurons than in ‘normal’ pain responses_1,2,5

• At the synapse level, sensitized primary afferent sensory fibers decrease the threshold for activation of nociceptor neurons, which become hyperexcitable and transmit frequent action potentials_1,2

• Central sensitization results and the individual perceives greater and more prolonged pain_1,2,3.

References

Kandel ER, Schwartz JH, Jessell TM, editors. Principles of Neural Science (Fourth Edition). New York: McGraw Hill (Health Professions Division). 2000;472–491.