Inflammation and Peripheral Pain Sensation

Inflammation is a common pathway in soft-tissue injury of musculoskeletal disorders. Inflammatory processes lead to two outcomes: swelling and pain. Inflammatory processes traditionally are considered to be a necessary part of the remodeling process because inflammatory cells remove damaged tissue. 9 0 However, inflammation also contributes to continued pain and swelling that limits range of motion.

The initial injury exposes membrane phospholipids to phospholipase A2, leading to the formation of arachidonic acid (Fig. 60-2).19,20 Next, arachidonic acid is transformed by cyclooxygenase (COX) to thromboxanes and prosta-glandins (PGs), including prostaglandin E2 (PGE2). PGE2 is the most potent inflammatory mediator; it increases vascular permeability, leading to redness, warmth, and swelling of the affected area. The increased permeability also increases pro-teolysis, or the breakdown of proteins in the damaged tissue.

Neutrophils, lymphocytes, and monocytes are attracted to the area, and monocytes are converted to macrophages.19,20 The macrophages then stimulate additional PG production. Phagocytic cells and other players in the immune system release cy-tokines, including interleukins, interferon, and tumor necrosis factor.

In addition to increasing vascular permeability, PGs also induce pain by sensitizing pain receptors to other substances such as bradykinin. Bradykinin, PGs, leukotrienes, and other inflammatory mediators lower the pain threshold through peripheral pain sensitization. These substances make nerve endings more excitable, and the nerve

fibers are more reactive to serotonin, heat, and mechanical stimuli. The increased sensitization in the damaged tissue causes tenderness, soreness, and hyperalgesia or an exaggerated intensity of pain sensation.21 The process also facilitates production of additional PGs. In a cyclic fashion, the PGs then sensitize the nerves to bradykinin action.

Without interruption, the neurochemicals ultimately lead to a firing of the unmy-elinated or thinly myelinated afferent neurons. This sends messages along the pain pathway in the periphery and communicates the pain message to the CNS. Interruption of this cycle occurs via anti-inflammatory agents such as aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs).

FIGURE 60-2. Eicosanoid synthesis pathway. Cyclooxygenase is inhibited by nonsteroidal anti-inflammatory drugs and aspirin. (From Widmaier E P, Raff H, Strang K T, et al., eds. Vander, Sherman, & Luciano's Human Physiology: The Mechanisms of Body Function. 9th ed. New York: McGraw-Hill; 2004: Fig. 5-11.)

Nerve receptors, or nociceptors, release substance P, a peptide that causes vas-20,22

odilation when released. ' This dilation occurs mainly through substance P-me-diated activation of neurokinin receptors. This receptor activation also increases the sensitivity of nociceptors to painful stimuli. Capsaicin relieves pain by stimulating the release of substance P from sensory nerve fibers, which ultimately depletes stores of substance P.

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