... messengers of threats to tissue injury but also play an active role in Chapter 012. Pain: Pathophysiology and Management (Part 2) Sensitization When intense, repeated, or prolonged stimuli ... nociceptors is lowered and the frequency of firing is higher for all stimulus intensities. Inflammatory mediators such as bradykinin, nerve growth factor, some prostaglandins, and leukotrienes contribute ... nociceptors, and their characteristic properties may explain how under pathologic conditions the relatively insensitive deep structures can become the source of severe and debilitating pain and tenderness....