Blocking Neuroimmune Communication as a Treatment for Endometriosis-Associated Pain
Abstract
Endometriosis is an inflammatory disease that affects up to 10% of women in reproductive age with annual health care costs approaching $70 billion in the U.S. alone. Debilitating pain causes affected women to lose, on average, 11 hours of work weekly, primarily as a result of reduced effectiveness during working time, while for the U.S. Army, chronic pain leads to roughly 20,000 days of lost duty time per year. This is also extended to U.S. Army dependents, as more than 75% of U.S. Army dependents who had undergone laparoscopy or laparotomy because of pelvic pain were diagnosed with endometriosis. Moreover, this debilitating chronic pelvic pain also contributes to depressive symptoms and anxiety symptoms that, ultimately, might lead to decreased work, social engagement, and relationships with colleagues and family in endometriosis patients. Current treatments for pain in women with endometriosis are limited to the use of non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen, hormonal agents such as birth control pills, and surgical removal of the lesions. However, patients often do not respond or experience limited benefit from hormonal therapies, NSAIDs present several side effects and should be used with cautious by patients with other comorbidities, and even after surgery, disease and pain recurrence are very common. Therefore, new medical therapies and targets that provide long-term benefits, including pain relief, are still urgently needed. The perception of pain is transmitted by specialized nerve cells called nociceptors. Recent studies demonstrate that nociceptors not only can sense pain but also release neuropeptides such as calcitonin gene-related peptide (CGRP) to orchestrate inflammation and the activity of immune cells. This process is called neuroimmune communication. To produce its effect, CGRP acts on the receptor activity modifying protein 1 (RAMP1). Macrophage is a type of immune cell that is responsible for the engulfment and destruction of target cells and microorganisms. They are the main cells in the peritoneal cavity (abdominal space), and during endometriosis, macrophages change their activity to promote the growth and support of endometriosis lesions. We did preliminary experiments and found that mice without a specific type of nociceptor (TRPV1+ nociceptors) show less pain and grow smaller endometriotic lesions. In corroboration, we also did preliminary experiments with a U.S. Food and Drug Administration (FDA)-approved drug that blocks RAMP1 called rimegepant. Rimegepant-treated animals showed less pain, fewer lesions, and the remaining lesions were smaller when compared to the non-treated animals. This indicates that blocking CGRP/RAMP1 signaling might not only relieve pain but also actively eliminate lesions and reduce the growth of remaining endometriotic lesions. Ultimately, this indicates that CGRP or RAMP1 targeting drugs can provide long-term benefit for patients. In this project, to confirm the efficacy of this type of drug, we will test three additional FDA-approved drugs that target either CGRP or RAMP1, namely ubrogepant (small molecule RAMP1 antagonist, but structurally distinct from rimegepant), fremanezumab (monoclonal antibody against CGRP), and erenumab (monoclonal antibody against RAMP1). We hypothesize that neuropeptide CGRP release by nociceptors is the main driver of endometriosis-associated pain and lesion growth/establishment. Therefore, silencing the communication of nociceptors to macrophages by blocking CGRP/RAMP1 signaling can treat endometriosis pain. Most work on endometriosis therapeutics targets either endocrine hormones and/or their receptors. This multidisciplinary project is conceptually innovative because it combines approaches from three disciplines (neuroscience, immunology, and pharmacology) to validate CGRP/RAMP1 as a non-opioid and non-hormonal therapy for endometriosis-associated pain. Combining different techniques (e.g., chemogenetic ac
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310040
Entities
People
- Victor Fattori
Organizations
- United States Army