Calcitonin Gene-Related Peptide, or CGRP, is a protein produced by nerve cells and found throughout the body. CGRP exists in two primary forms, alpha and beta. It is widely distributed in both the peripheral and central nervous systems and is primarily localized to sensory nerve fibers associated with pain perception.
The Role of CGRP in Pain Transmission
CGRP functions as a messenger molecule within the nervous system. It is concentrated in sensory nerve fibers that are responsible for detecting and relaying pain signals from the body to the brain. When these nerves are activated by a potentially harmful stimulus, they release CGRP, which then acts on nearby cells to amplify the pain message. This process makes the nervous system more sensitive and responsive to pain.
One way CGRP contributes to pain is through vasodilation, the widening of blood vessels. CGRP is a potent vasodilator, and its release around blood vessels, such as the meningeal arteries surrounding the brain, causes them to expand. This expansion can directly trigger pain receptors embedded in the vessel walls. This action is part of how pain signals are generated in certain types of headaches.
CGRP is also a driver of neurogenic inflammation, a type of localized inflammation initiated by the nervous system. When released from nerve endings, CGRP can interact with various cells, prompting them to release inflammatory substances. This chemical cascade increases blood flow and makes blood vessels leaky, which contributes to swelling. This also sensitizes nerve endings, lowering their threshold for firing and thereby increasing pain perception.
This sensitization occurs at both the peripheral and central levels. Peripherally, CGRP makes the initial sensory nerves more excitable. Centrally, its release in the spinal cord and trigeminal system can make the neurons that receive these signals more responsive. This state of heightened excitability, known as central sensitization, is a mechanism through which acute pain can transition into a more persistent, chronic state.
CGRP and Specific Pain Conditions
The most well-documented connection between CGRP and a specific pain condition is in migraine. During a migraine attack, the trigeminal nervous system becomes activated, leading to a significant release of CGRP in the cranial circulation. Studies have consistently measured elevated levels of CGRP in patients during migraine episodes. This surge of CGRP is directly linked to the throbbing pain of the headache through its vasodilatory and inflammatory effects.
Further evidence for CGRP’s role comes from studies where administering CGRP intravenously to individuals with a history of migraine triggered a migraine-like headache. This direct cause-and-effect relationship has established the peptide as a central figure in migraine. The pain-sensitizing effects of CGRP contribute not only to the headache itself but also to other common migraine symptoms like heightened sensitivity to light and sound.
Beyond migraine, researchers are investigating CGRP’s involvement in other chronic pain conditions. Elevated levels of the peptide are often found in inflammatory and neuropathic pain states. For instance, its role in temporomandibular joint (TMJ) disorders is being explored, as the trigeminal nerve, which is heavily involved in migraine, also supplies sensation to the jaw area.
Similarly, there is ongoing research into the connection between CGRP and fibromyalgia, a condition characterized by widespread musculoskeletal pain. The concept of central sensitization is a leading theory for why patients experience amplified pain responses. Given CGRP’s role in central sensitization, it is plausible that it contributes to the chronic pain state associated with this condition.
Targeting CGRP for Pain Relief
The established link between elevated CGRP levels and pain led researchers to a logical therapeutic strategy: blocking its activity should provide relief. This approach focuses on interrupting the CGRP signaling pathway to counteract its effects when it is overproduced during a pain episode. The goal is not to eliminate CGRP entirely, as it serves other functions.
This therapeutic approach centers on the development of molecules that can act as antagonists, obstructing the peptide’s ability to function. There are two primary ways to achieve this blockade. One method involves creating a molecule that directly binds to the CGRP peptide itself, preventing it from reaching and activating its designated receptor on other cells.
An alternative strategy is to target the CGRP receptor instead of the peptide. CGRP mediates its effects by docking with a specific receptor complex on the surface of cells. By designing a molecule that blocks this receptor, the CGRP peptide is left with nowhere to bind, which prevents the downstream signaling that leads to pain.
Types of CGRP Inhibitors
Therapies designed to block the CGRP pathway fall into two main categories: monoclonal antibodies and small molecule antagonists, often called gepants. Monoclonal antibodies are laboratory-produced proteins engineered to bind to a specific target. Some antibodies attach directly to the CGRP peptide, while another type is designed to block the CGRP receptor. These large molecules are administered via injection, from once a month to every few months, and are used for the preventive treatment of migraine.
The second class of CGRP inhibitors is the gepants, which are small molecule antagonists. Unlike the large protein structure of antibodies, gepants are small enough to be formulated into oral pills. These molecules work by blocking the CGRP receptor, preventing the peptide from binding and initiating its pain-causing effects. Because they are fast-acting and have a shorter duration in the body compared to antibodies, gepants offer more versatility. They can be used for the acute treatment of an ongoing migraine attack, and some have also been approved for preventive use when taken daily.