The Pain Pathway The Initial Insult

After having discussed the subjective qualities and different classification of pain, we will spend the core of this chapter discussing the pain pathway from the periphery to actual perception of pain which takes place at the level of the cerebral cortex.

The pain pathway begins with the activation of peripheral nociceptors. Nociceptors are located anywhere in the body and convey noxious sensation, either externally (i.e., skin, mucosa) or internally (i.e., joints, intestines). Nociceptors can be triggered by any painful stimuli, most of which can be categorized as either mechanical, chemical, or thermal in nature. Nociceptors are classified by the specific stimulus they respond to (i.e., "thermal nociceptor") and have a sensory specificity. Therefore, they will only be activated and an action potential when a certain threshold has been reached.

Transduction refers to the process in which noxious stimuli, chemical, thermal, or mechanical, are translated into electrical activity at the level of the nociceptors. The cell bodies of these nociceptors are found in the dorsal root ganglia (DRG) of the spinal cord. After the sensory threshold has been reached, nociceptor activation initiates a depolarizing Ca2+ current or generator potential, which depolarizes the distal axon and further initiates an inward Na+ current which self-propagates action potential. In addition, following the initial insult, or tissue injury, several cellular mediators activate the terminal endings of the nociceptors such as potassium, hydrogen ions, prostaglandins, and bradykinin. Prostaglandin (PGE), which is synthesized by cyclooxygenase-2 (COX-2), is responsible for nociceptor sensitization and plays an important role in peripheral inflammation. Action potential through sensitized nociceptors also leads to the release of several peptides in and around the site of injury. These include substance P (sP), cholecytokinin (CCK), and calcitonin gene-related peptide (CGRP). Substance P is responsible for the further release of bradykinin and also fuels the release of histamine from mast cells and serotonin (5-HT) from platelets, which further increases vascular permeability and nociceptor irritability (Wang et al. 2005). The interactions of the mediators and peptides that are released during transduction exacerbate the inflammatory response, recruit adjacent nociceptors, and result in peripheral nociceptor sensitization (Treed et al. 1992).

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