Targeting Prolactin for Prevention of Female-Selective Nociceptor Sensitization for Treatment of Female-Predominant Pain Syndromes
Abstract
Background/Rationale: The effects of living with chronic pain on patient wellbeing are severe and can often be debilitating and diminish quality of life. For reasons that are not well understood, the majority of pain patients are women. Women are more likely than men to experience certain forms of pain such as migraine, fibromyalgia, irritable bowel syndrome, painful bladder syndrome, and others. Women also suffer from female-specific pain syndromes such as dysmenorrhea, endometriosis, and pelvic pains. Many of these pain syndromes are exacerbated by stress, and women also show greater stress responses than men. There are currently no available treatments designed specifically for pain and stress-related pain syndromes in women. This proposal seeks to provide the first truly female-selective chronic pain therapy to treat female pain. One explanation for the increased pain in women is the presence of a neurohormone, called prolactin. Prolactin circulates at higher levels in females compared to males. The release of prolactin is normal under certain conditions, such as to stimulate milk production following pregnancy. However, the release of prolactin can also be stimulated by undergoing repetitive, uncontrolled or unpredictable stress such as encountered on the battlefield, in training exercises or following an injury. We have previously demonstrated that stress causes increased release of prolactin which in turn increases the sensitivity of pain sensors in female mice. This increased sensitivity could explain why female patients experience pain episodes more frequently than male patients. Based on these findings, we are developing a therapy that targets prolactin and prevents its enhancement of the activity of the body’s pain sensing systems. The approach of removing prolactin from both the local tissues and from the circulation could provide a means of better treating pain syndromes that commonly occur in female Service Members, Veterans, and civilians. Objectives: This proposal will (1) determine whether human prolactin increases the sensitivity of human pain sensors (i.e., nociceptors) and whether this can be blocked by an antibody that targets prolactin; (2) identify the characteristics of the nociceptors that are activated by stress-related release of prolactin from the pituitary; and (3) demonstrate that therapies that target human prolactin can alleviate migraine-like pain and post-surgical pain in mice genetically modified to express human prolactin. Ultimate Applicability: Our work will ultimately be applicable to understanding and treating pain in female Service Members as well as women in the general population. Specifically, our work will help to advance the development of a therapy that targets prolactin in humans and so would be highly useful for treating chronic pain in individuals that experience high levels of stress, especially Soldiers, which then increases their vulnerability to development of chronic pain. Also, our work will provide a non-opioid therapy that will have improved safety benefits. Who Will This Help? The results of the work conducted from this proposal will directly benefit women experiencing pain, including migraine, dysmenorrhea, endometriosis, temporomandibular joint disorder, irritable bowel syndrome, and fibromyalgia, as well as stress-related pain disorders, including post-operative pain. This research will benefit women because it will advance and support efforts to identify a clinical candidate prolactin monoclonal antibody by validating its efficacy in human tissues. This will dramatically increase the chances of success when entering the clinical trial phase of drug development. Clinical Applications: The mechanism that we are identifying and the efficacy of the antibody that will be validated as a part of this work will have direct impact on understanding female pain syndromes and identifying a non-opioid treatment of female pain. Currently avai
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310853
Entities
People
- Frank Porreca
Organizations
- United States Army
- University of Arizona