CGRP: The Pivotal Neuropeptide Revolutionizing Migraine Treatment and Pain Research
Structure and Biological Synthesis
Calcitonin Gene-Related Peptide also known as CGRP is a 37 amino acid neuropeptide which exists in two forms namely the α-CGRP and the β-CGRP. The α-CGRP is mainly localized in the central and enteric peripheral nervous system. This while neuropeptide the is β-CGRP expressed is through mainly the alternative splicing of the calcitonin gene therefore having a molecular structure that allows it to bind to receptors located in various body parts. The CGRP receptors are macromolecular structures which involve several proteins such as calcitonin receptor-like receptor (CLR) and receptor activity modifying protein 1 (RAMP1) that are necessary for the functional CGRP receptor.
Physiological Functions and Distribution
CGRP is involved in many different physiological processes which occur all over the body. Due to its ability to dilate blood vessels, it maintains blood flow and the tone of the vascular smooth muscle. In the nervous system, CGRP acts as a neuropeptide that has a role in modulation of pain and sensory signalling. The peptide is present in large numbers in the central and peripheral nervous system with a very dense innervation of the sensory neurons, trigeminal ganglia and dorsal root ganglia. CGRP containing neurons project to many other organs and structures in the body including the cardiovascular system, the gastrointestinal tract and the skin, whereby they are involved in the regulation of inflammation, the immune response and tissue repair.
Role in Migraine Pathophysiology
The connection between CGRP and migraine has revolutionized our understanding of this debilitating condition. During migraine attacks, CGRP levels become elevated in both the peripheral and central nervous systems, leading to neurogenic inflammation, vasodilation, and enhanced pain transmission. The release of CGRP from trigeminal nerve endings triggers a cascade of events that result in the characteristic symptoms of migraine, including severe headache, sensitivity to light and sound, and nausea. This understanding has led to the development of targeted therapies, including CGRP receptor antagonists (gepants) and monoclonal antibodies against CGRP or its receptor, which have shown remarkable effectiveness in migraine prevention and treatment.
Therapeutic Applications and Drug Development
The role of CGRP in migraine has been identified and this has led to the creation of new therapeutic strategies. There are several classes of CGRP targeted medications that have been created and used for clinical practice. Some of the monoclonal antibodies including erenumab, fremanezumab, and galcanezumab have been found to be effective in preventing migraine attacks while small molecule CGRP receptor antagonists such as ubrogepant and rimegepant are used in the acute treatment. Apart from migraine, there is an investigation on the effectiveness of CGRP-targeted therapies for other diseases such as cluster headaches, osteoarthritis, and inflammatory diseases. These medications are the latest advancement in neurological specific therapies which is a great advancement for patients with hitherto intractable conditions.
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