1983; Willis, 1985) or intense stimulation of muscle or visceral tissue. Those peripheral receptors are called nociceptors, and they can be classified according to how they respond to intense mechanical, thermal, or chemical stimuli. With minor exceptions, nociceptive fibers have finely myelinated or unmyelinated axons. Most, if not all, mammalian species have such nociceptors. The most extensively studied nociceptors are the ones that have myelinated axons and respond only to intense mechanical or mechanical and thermal stimuli and the so-called polymodal nociceptors, which have unmyelinated axons and respond to mechanical, thermal, and chemical stimuli. The myelinated nociceptors appear to encode signals related to pricking first-pain sensations produced by noxious mechanical or thermal stimuli. Second-pain sensations, which follow first-pain sensations and have a burning quality, appear to be encoded by signals arising from unmyelinated nociceptors (Price et al., 1977).

Tissue injury produces a state of hyperalgesia (excessive sensitivity to pain) at the site of injury with increased sensitivity to stimuli and sometimes spontaneous pain sensations. Those alterations have distinct parallels to a phenomenon called sensitization observed in nociceptors. After repeated exposure to noxious heat stimuli, nociceptors exhibit lower thresholds, increased sensitivity to stimuli that exceed their thresholds, and spontaneous activity. Both mechanical-thermal nociceptors and polymodal nociceptors mediate, in part, the hyperalgesia produced by mild thermal injury in humans (Meyer et al., 1985).


Sensitization and hyperalgesia involve the release of various chemical mediators (Hargreaves and Dubner, 1991). A simplification of this process is as follows: Cell injury results in the release of prostaglandins, leukotrienes, bradykinin, substance P, and other autacoids. These products, acting in concert with one another, contribute to inflammation and associated sensitivity and pain, as evidenced by increased vascular permeability, increased leukocyte migration, and increased sensitivity of nociceptors.

Products of arachidonic acid metabolism are mediators of inflammation. Arachidonic acid is released after cell injury from phospholipids embedded in cell membranes. Metabolism proceeds in two directions: The enzyme cyclo-oxygenase converts arachidonic acid to prostaglandins, which increase vascular permeability, activate leukocyte migration, and sensitize nociceptors; and the enzyme lipoxygenase results in the formation of leukotrienes, some of which increase vascular permeability and chemotaxis of polymorphonuclear leukocytes. Leukotriene B4 results in the release from leukocytes of chemicals that produce sensitization of nociceptors.

Another important inflammatory mediator is bradykinin. The precursors of bradykinin circulate in the blood and are released into the tissue whenever there is damage. Injury results in an increase in tissue acidity and in the conversion of the enzyme prekallikrein to kallikrein. Kallikrein then acts on the bradykinin precursor

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