Calcitonin Gene-related Peptide - Clinical Significance

Clinical Significance

Increased levels of CGRP have been reported in migraine and temporomandibular joint disorder patients as well as a variety of other diseases such as cardiac failure, hypertension, and sepsis.

Preclinical evidence suggests that, during a migraine, activated primary sensory neurons (meningeal nociceptors) in the trigeminal ganglion release CGRP from their peripherally projecting nerve endings located within the meninges. This CGRP then binds to and activates CGRP receptors located around meningeal vessels, causing vasodilation, mast cell degranulation, and plasma extravasation. Human observations have further implicated the role of CGRP in the pathophysiology of migraine. Activation of primary sensory neurons in the trigeminal vascular system in humans can cause the release of CGRP. During some migraine attacks, increased concentrations of CGRP can be found in both saliva and plasma drawn from the external jugular vein. Furthermore intravenous administration of alpha-CGRP is able to induce headache in individuals susceptible to migraine.

The source of CGRP in migraine (and other pain conditions) is largely thought to derive from the peptidergic peripheral innervation where alpha-CGRP is the predominant isoform produced by sensory neurons. It is the alpha-CGRP isoform that is presumed to be the primary contributor to pain mechanisms. However, more recent evidence demonstrates that CGRP is expressed among keratinocytes of the epidermis where it is predominantly the beta form. Furthermore, CGRP expression in keratinocytes is substantially increased in certain human chronic pain conditions and animal models of induced chronic pain conditions, whereas the alpha-CGRP containing peptidergic innervation is decreased in painful skin sites. Therefore, keratinocyte-derived beta-CGRP may have an important role in chronic pain mechanisms, as well as other dermatologic disorders known to involve changes in CGRP levels, such as psoriasis. Although very little is known about the functional differences between these two isoforms, research has demonstrated that the beta-CGRP is also expressed among enteric neurons of the gut, and CGRP has been implicated in mechanisms of visceral pain disorders, such as irritable bowel syndrome.