Neuroendocrine mechanisms of female chronic overlapping pain conditions (COPC)

Project Summary Women have a higher prevalence of chronic pain than men and often suffer from multiple chronic overlapping pain conditions (COPC). Mechanisms promoting COPCs in women are not well understood. COPCs typically peak during reproductive age, are exacerbated by stress or during the menstrual cycle, suggesting that stress- related female hormones may promote female pain and increase the co-occurrence of two or more chronic pain diseases. Endometriosis is a gynecological condition characterized by the growth of endometrial tissue outside the uterus. Women with endometriosis experience pelvic pain and are twice as likely to have comorbid migraine. Endometriosis and migraine patients have high levels of circulating prolactin (PRL), a female predominant neurohormone. PRL is under dual control by stress and estrogen and is released primarily from the anterior pituitary and from other tissues including endometrium. PRL selectively sensitizes nociceptors from female rodents, non-human primates and human organ donors suggesting that this evolutionarily conserved neuroendocrine mechanism is relevant to multiple female pain conditions. We propose to investigate the role of PRL and its receptor (PRLR) in endometriosis-associated pelvic pain and endometriosis-induced comorbid migraine pain. Pelvic and migraine-like pain behaviors will be assessed in a syngeneic mouse model of endometriosis to determine the contributions of pituitary PRL as well as locally secreted PRL from endometriotic lesions. We hypothesize that dorsal root ganglion (DRG) neurons that innervate pelvic structures and trigeminal ganglion (TG) neurons will be sensitized in endometriosis mice, promoting, respectively, endometriosis-associated pelvic pain and increased vulnerability to migraine-like pain. Possible PRL/PRLR-induced neural adaptations in DRG and TG neurons that may underlie the comorbidity of endometriosis and migraine pain will be explored using genetic, transcriptomic (spatial transcriptomics), electrophysiolgical and microscopic techniques. We will also evaluate whether neutralization of PRL with a novel, first-in-class human PRL monoclonal antibody (hPRL-mAb) can block both DRG and TG sensitization and relieve endometriosis-induced pelvic pain and comorbid migraine pain. These studies aim to unravel a neuroendocrine mechanism that may promote widespread sensitivity to pain in women as a basis for development of chronic overlapping pain conditions. Identification of high PRL levels as a contributing factor to COPCs could improve personalized medicine by facilitating early detection, diagnosis and treatment of diseases that primarily affect women or are female specific. Evaluation of the efficacy of hPRL-mAb for the treatment of endometriosis-associated abdominal pain and comorbid migraine will stimulate the advancement of new therapeutic approaches such as hPRL-mAbs specifically tailored for treatment of pain in women. Better treatment options targeting female prevalent COPCs will address the health disparities in women.