ABSTRACT: Women are disproportionally impacted by functional pain syndromes (FPS), a large subgroup of pain conditions defined by the absence of a clear etiology or tissue injury. These syndromes have a high female:male prevalence ratio and include, but are not limited to, temporomandibular joint and muscle disorders (TMJD) (9:1 ratio), fibromyalgia (9:1 ratio), irritable bowel syndrome (IBS) (3:1 ratio), and migraine (3:1 ratio), as well as female exclusive FPS such as dysmenorrhea, endometriosis and vulvodynia. Reasons for the sexually dimorphic prevalence in FPS remain uncertain but emerging evidence suggests that prolactin (PRL) elicits sensitization of female nociceptors. PRL selectively promotes hyperalgesia and pain in female mice with minimal effects in male animals. PRL signals through mutually inhibitory long- and short-form PRL receptor (PRLR) isoforms that are expressed at higher levels in female nociceptors. Female animals and humans have higher circulating PRL than males. A role for circulating PRL was demonstrated by prevention of opioid-induced hyperalgesia (OIH) selectively in female mice by cabergoline, a dopaminergic D2 agonist which inhibits PRL release from the pituitary. Similarly, migraines associated with PRL-secreting tumors are treated with D2 agonists. Collectively, these data support that PRL selectively promotes female hyperalgesia. Our team now wishes to translate these breakthrough findings into novel and transformative therapeutics for female-prevalent pain conditions. We propose to develop PRL monoclonal antibodies (PRL-mAbs) as first-in- class therapeutics for female FPS, targeting migraine as the primary indication. The specific goals of this SBIR Phase I application are to (i) assess the technical feasibility of the program (i.e., identification of neutralizing PRL-mAb leads) and (ii) validate the working hypothesis (i.e., demonstration that systemic administration of a neutralizing PRL-mAb selectively prevents PRL-induced female hyperalgesia in a migraine relevant model). Impact and