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Section II: Cardinal Manifestations and Presentation of Diseases

When repeated intense stimuli are applied to damaged or inflamed tissue, which of the following responses occurs?

A. The threshold for activating primary afferent nociceptors is lowered, and the frequency of firing is higher for all stimulus intensities.

B. The threshold for activating primary afferent nociceptors is lowered, and the frequency of firing is lowered for all stimulus intensities.

C. The threshold for activating primary afferent nociceptors is raised and the frequency of firing is higher for all stimulus intensities.

D. The threshold for activating primary afferent nociceptors is raised and the frequency of firing is lower for all stimulus intensities.

The answer is A. (Chap. 18) When intense, repeated, or prolonged stimuli are applied to damaged or inflamed tissues, the threshold for activating primary afferent nociceptors (pain receptors) is lowered, and the frequency of firing is higher for all stimulus intensities. This process is called sensitization. Inflammatory mediators such as bradykinin, nerve-growth factor, some prostaglandins, and leukotrienes contribute to this process. Following injury and resultant sensitization, normally innocuous stimuli can produce pain (termed allodynia). Sensitization is a clinically important process that contributes to tenderness, soreness, and hyperalgesia (increased pain intensity in response to the same noxious stimulus; e.g., moderate pressure causes severe pain). A striking example of sensitization is the significant pain caused by minimal stimulus (light touch or shower) on sunburned skin. Sensitization is of particular importance for pain and tenderness in deep tissues. Viscera are normally relatively insensitive to noxious mechanical and thermal stimuli, although hollow viscera do generate significant discomfort when distended. In contrast, when affected by a disease process with an inflammatory component, deep structures such as joints or hollow viscera characteristically become exquisitely sensitive to mechanical stimulation.

Substance P, which is released from primary afferent nociceptors, has all of the following biologic activities EXCEPT:

A. Chemoattractant for leukocytes

B. Degranulation of mast cells

C. Increase intracellular concentration of cyclic guanosine monophosphate (GMP)

D. Increase the production and release of inflammatory mediators

E. Vasodilation

The answer is C. (Chap. 18) Substance P is released from primary afferent nociceptors and has multiple biologic activities. It is a potent vasodilator, degranulates mast cells, is a chemoattractant for leukocytes, and increases the production and release of inflammatory mediators. Interestingly, depletion of substance P from joints reduces the severity of experimental arthritis. Phosphodiesterase inhibitors increase intracellular concentration of cyclic guanosine monophosphate (cGMP) or cyclic adenosine monophosphate (cAMP).

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