When tissues are injured, they release chemicals that cause the small blood vessels in the area to vasodilate, making the area red and warm (known as rubor and calor). Additionally, the lining of the smaller blood vessels (capillaries and venules) contracts and creates openings that allow fluids and cells to leak into the surrounding tissues, leading to swelling (tumor). These chemicals also cause pain and can make nociceptors overly sensitive. This sensitivity can result in allodynia, where non-painful stimuli like a light touch cause pain, and hyperalgesia, where the pain felt is more intense than the actual stimulus.
Arachidonic acid is released from cell membranes when tissues are damaged or threatened. It is then converted into substances called prostaglandins by an enzyme called cyclooxygenase-2 (COX-2), which is abundant during inflammation. These prostaglandins help continue the inflammation and make nociceptors even more sensitive, particularly prostaglandin E2 (PGE2).
PGE2 works by attaching to specific spots on nociceptors on certain nerve fibers, leading to the production of a chemical called cyclic AMP from ATP, and altering sodium channels on the nerves. This reduces the amount of stimulation needed to trigger a pain signal (allodynia) and increases the intensity of pain from a painful stimulus (hyperalgesia). Other receptors, like one sensitive to high temperatures (TRPV1), can also start reacting to lower temperatures, causing pain when they normally wouldn't. The changes can be so extensive that these nerve fibers (C fibers) might continuously transmit pain signals, causing persistent, severe pain during inflammation.
Bradykinin, another inflammatory mediator, is formed through a chain reaction starting in the liver, where substances like Hageman factor (factor XII), high-molecular-weight kininogen, and prekallikrein are made and released into the bloodstream. When these substances enter inflamed areas, factor XII is activated by substances such as collagen, which then turns prekallikrein into kallikrein. Kallikrein then transforms high-molecular-weight kininogen into bradykinin. Like PGE2, bradykinin stimulates and makes nociceptors more sensitive, contributing to thermal allodynia and hyperalgesia, enhancing the pain response during inflammation.
