University of Central Florida Undergraduate Research Journal - Analysis of the Pathomechanism and Treatment of Migraines Related to the Role of the Neuropeptide CGRP
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Calcitonin Gene Related Peptide

CGRP is an important 37 amino acid neuropeptide that was discovered using RNA transcripts26. These transcripts are from the calcitonin gene and alternative processing leads to different mRNAs that encode the hormone calcitonin27. CGRP plays an important role in the primary sensory neurons in which it is localized, specifically through the activation of the trigeminal system29. Its associated areas of action have a wide distribution from the peripheral skin, cornea, respiratory, and urogenital systems to the terminals close to smooth muscle. CGRP-containing neurons and fibers are also found in autonomic ganglia and in parts of the central nervous system and in the cerebral dura29.

Activation of the trigeminal system as well as tissue stimulation and/or tissue injury causes the release of CGRP from the brainstem trigeminal nucleus and spinal cord. Cranial vasodilation, coupled with the activation and sensitization of sensory nerves, has been suggested by several studies to lead to the headache phase29. CGRP is a vasodilator of the cranial vessels that causes the nerve endings to be disturbed and the nerves to be pinched. This, in turn, causes more vasoactive material to be released, such as CGRP, producing a vicious cycle and resulting in neurogenic inflammation. The method of action has been found to be related to CGRP blocking the release of aldosterone secretion as well as promoting the release of catecholamine, which is done through CGRP Type 1 receptors. This action leads to the vasodilation effect that is associated with CGRP27.

CGRP has also been found to enhance the activity of another neuropeptide, Substance P (SP), when they are both co–administered in the CNS. This enhanced activity has been suggested due to CGRP's ability to inhibit an enzyme directly involved in SP degredation29. SP has also been linked to excitation of the neuronal network, where CGRP is believed to control SP degradation. Thus, CGRP release has been shown to have correlations with the duration and intensity of painful stimuli.

CGRP receptors have been found to contain proteins (RAMPs, or receptor activity modifying proteins) that must be present to move the receptor to the membrane of the cell. There are various forms of RAMP: RAMP1, the form of RAMP that is specifically involved with CGRP, moves the functional glycoprotein receptor to the membrane surface to act as a receptor for CGRP30. This glycoprotein in humans is the rate-limiting factor for the release of CGRP in neurons31.

Previously, CGRP receptors were separated into two CGRP receptor types, however, as of now, experiments have confirmed that there is only one CGRP receptor, which is the CGRP1 receptor. There are many components of a CGRP receptor, which include a transmembrane domain for a receptor activity modifying protein type 1 (RAMP1), a G protein coupled receptor, and a receptor component protein (RCP)32. All of these components are necessary to form a working CGRP receptor. It has been determined that the first seven amino acids on the N-terminal end of the CGRP receptor are necessary to lead to the activation of the receptor, and as such various CGRP receptor antagonists are involved with this end of the protein32.

CGRP receptors can be found in many different locations in many different types of cells, and are not just limited to the cardiovascular and nervous system. CGRP receptors are on glia and neurons in the central nervous system, as well as on many second order neurons, in addition to mast cells that are present inside the dura mater32. Various antimigraine treatments act on CGRP release through involvement of CGRP receptors. Nonsteroidal Anti–Inflammatory Drugs (NSAIDs), for example, block the release of CGRP that is promoted through the activation of the prostaglandin receptor. By contrast, neuronal 5HT receptors are activated by triptans, which lead to the blockage of CGRP release33.

Dural surface electrical stimulation has led to a release of CGRP from trigeminal afferents. This release leads to vasodilation and an increase of the meningeal blood flow. Nitric oxide (NO) has a synergistic effect along with CGRP on the blood flow, and this theory has been proposed to explain the NO-mediated facilitation of CGRP synthesis and release in the trigeminal ganglia neurons34. CGRP promoter activity has been increased by overexpression of nitric oxide synthase and NO donors.

Nitric oxide is a vasodilator similar to CGRP that affects the arterial diameter and increases it, which leads to an increase in blood flow throughout the brain, causing a similar role to CGRP in the pathomechanism of a migraine35. In addition, NO increases the production and exocytosis of CGRP, even when the stimulation is electrical34. Accordingly, inhibitors of nitric oxide synthesis prevent CGRP release37.

Sex hormones in females are also important in the synthesis and the eventual expression of the receptor for CGRP26. 17B-estradiol leads to increased neurogenic vasodilation, and the mechanism through which this takes place is possibly through an increase of CGRP. This is believed to be a method by which 17B-estradiol exacerbates migraines in females38.

CGRP has also been found with the brain-derived neurotrophic factor (BDNF) in trigeminal neurons, making BDNF a mediator of trigeminal nociceptive plasticity26. BDNF is a neurotrophin that regulates factors such as maintenance, differentiation, and survival of various central and peripheral neurons. When BDNF is in low concentrations, this can lead to excitation of neurons in the hippocampus, cerebellum, and cortex39.

CGRP has also been found to increase plasma protein leakage by various neuropeptides, including SP. The effect of these neuropeptides has been increased by injection of CGRP40. It has accordingly been theorized that the co-release of CGRP with these neuropeptides may have additive effects in pain. In addition, CGRP and SP levels have been found to increase salivary secretions of patients suffering from migraines26. Thus, inhibiting the release of these neuropeptides, specifically CGRP, is an important treatment for migraines.

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