Sphingosine-1-Phosphate Receptor Subtype 1: A Novel Target in the Treatment of Chronic Migraine
Abstract
This application is for the FY20 PRMRP topic area Chronic Migraine and Post-Traumatic Headache (PTH). These headaches are highly prevalent, particularly in women, and hugely disabling disorders. They are also far more prevalent in military service personnel, as they are a common feature of mild traumatic brain injury (TBI), with up to 20% of returning military service personnel reporting concussion, a form of TBI. Worse symptoms of PTH are also more common in patients that already suffer migraine. Unfortunately, therapeutic approaches are often ineffective, or unsafe, for many patients, such as with opioids, which have a high dependency risk. Thus, there is an urgent need to identify novel, non-opioid targets for therapeutic development for patients with chronic migraine and PTH that have the potential for rapid translation to the clinic. Sphingosine-1-phosphate (S1P), a chemical neurotransmitter in the brain, causes pain-like responses in rodents and is produced in animal models of pain disorders. These pain-like responses are thought to be a consequence of S1P binding and activating the protein, sphingosine-1-phosphate receptor 1 (S1PR1). Drugs that inhibit S1PR1 activation (functional antagonists) are already available and have FDA approval in the treatment of multiple sclerosis. They are therefore considered safe to use in humans. Also, our studies in rodents demonstrate that these drugs provide persistent pain relief in a range of pain states, and they do not cause tolerance (begin to provide less pain relief over time) and are not addictive (like opioids). These drugs are thought to provide pain relief by preventing the production of a pro-nociceptive (pain-causing) chemical, called peroxynitrite (PN), and the effects it has on different signaling mechanisms in the brain and spinal cord that process noxious stimuli. Together, these data suggest that S1PR1 antagonists are well tolerated, considered safe, and may be suitable for chronic pain management. However, little is known about their potential benefits in patients suffering from migraine and related headaches, or rodent models used to screen for potential therapeutic effectiveness. The aim of this study is to screen the effectiveness of already FDA-approved S1PR1 antagonists in acute (short-term) and chronic (long-term) rodent models of migraine-like headache that translate to the human condition, and are known to be accurate at predicting whether a drug will be effective at treating migraine. These models involve activation of the “trigeminovascular system.” This includes a group of nerve fibers in the brain and spinal cord that process noxious information coming from the head, face, and neck that are involved in mediating the head pain symptoms in migraine and PTH. We will model this in two ways: (1) using a drug (nitroglycerin) that triggers a migraine-like attack in patients and (2) using overuse of a common prescription migraine medication (sumatriptan), which causes a chronic headache condition called medication overuse headache, which is a worsening of their existing headache (migraine) condition. Both approaches have been shown to produce facial “cutaneous allodynia” in rodents, where a stimulus that does not normally produce pain is experienced as painful by the patient, such as shaving and brushing one’s hair. This is a very common symptom related to migraine. It is believed that these headaches, and their additional symptoms, are caused, in part, by a brain phenomenon called “neuronal central sensitization,” where areas of the brain active during migraine pain become overactive and over-responsive to stimuli. Using these models, we will therefore also directly measure these neuronal changes. Finally, a brain phenomenon called “cortical spreading depression” is thought to cause aura symptoms in migraine, where patients can experience unusual phenomena that affect their senses, such as lines spreading across their visual field. This phenomenon has also
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110486
Entities
People
- Daniela Salvemini
Organizations
- Saint Louis University
- United States Army