Investigation into NOP Receptor Agonists for the Treatment of Chronic Migraine
Abstract
This proposal pertains to the FY20 PRMRP Topic Area of chronic migraine. Migraine is a sometimes debilitating disease that affects one out of every seven adults. It is considerably more common in women, with twice as many women as men suffering from migraine. Moreover, it is much more prevalent again in active and military Veterans. Chronic head pain is almost universal in those with traumatic brain injury (TBI). Migraine is thought to be caused by dilation of blood vessels just under the skull, leading to release of a neuropeptide called CGRP (Calcitonin Gene Related Peptide) as well as other brain factors, which excite neurons in the pain pathway and cause pain. Head pain induced by TBI is less well characterized but probably is due to the release of similar factors in the pain pathways. It is known that head pain is propagated through a cluster of cells called the trigeminal ganglia, which then sends the signal to pain-related brain regions, first in the pathway is a region called the trigeminal nucleus caudalis. By turning these cells off, one might be able to block the pain signals from reaching the pain centers of the brain, and therefore greatly reduce the severe pain induced by various headache disorders. However, the exact cells in the trigeminal ganglia and the pain-related brain regions that are the targets for the trigeminal ganglia neurons activated by migraine or other head pain disorders are not well characterized. Because of this lack of fundamental knowledge, all of the brain components (such as neuropeptides) that are involved head pain are not known. Therefore, a greater understanding of the basic science behind head pain is crucial for the development of new treatments. The primary headache treatment currently used in practice are triptans, such as sumatriptan. This drug induces cranial vasoconstriction, thereby reversing the migraine-induced vasodilation and in many patients stops the migraine. Newly available treatments target the neuropeptide CGRP (discussed above). Both antibodies, which identify and bind to CGRP, thereby inactivating it, and CGRP receptor antagonists, which block the actions of CGRP, have recently become commercially available. These drugs are proving successful in a certain population of migraine patients. However, in many patients, current treatments are insufficient to block the pain. Many of these people end up taking opiates as a last resort. In fact, this is a very bad idea for many reasons. Not only do opiates have severe side effects, including constipation, respiratory depression, and abuse liability, chronic opioid use surprisingly leads to hyperalgesia (an increased pain sensitivity), which ultimately makes the headaches worse. Because so many migraineurs still respond poorly to current treatments, the development or new therapeutics for both the civilian population and the military is crucial. One previously unexplored target for treatment of chronic migraine and other head pain disorders is the neuropeptide nociceptin and the receptor it activates, called NOP. NOP receptors are in the opioid receptor family, but activation of this receptor leads to very different properties that activation of “normal” opioid receptors. There are four receptors in the opioid receptor family. The receptor activated by morphine and other well-known opiates, such as oxycontin, stimulate what is called the mu receptor. Activation of the mu opioid receptor, which leads to reduced firing of neurons in pain pathways, is the most effective method of blocking pain. However, as mentioned above, this also leads to severe side effects including constipation, respiratory depression (which can lead to overdose and death), and reward, leading to drug dependence. Activation of NOP receptors is more complicated. Like the mu receptor, NOP receptor activation leads to reduced firing of neurons, but depending where these NOP receptors are, and where drugs are administered, it can either block a pain resp
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110410
Entities
People
- Lawrence Toll
Organizations
- Florida Atlantic University
- United States Army