{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T20:03:49Z","timestamp":1791489829718,"version":"4.3.4"},"reference-count":49,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2021,12,29]],"date-time":"2021-12-29T00:00:00Z","timestamp":1640736000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["NS072204"],"award-info":[{"award-number":["NS072204"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["NS104200"],"award-info":[{"award-number":["NS104200"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["headachejournal.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Headache"],"published-print":{"date-parts":[[2022,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>The aim of this study was to determine if prolactin signaling modulates stress\u2010induced behavioral responses in a preclinical migraine model.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Migraine is one of the most complex and prevalent disorders. The involvement of sex\u2010selective hormones in migraine pathology is highly likely as migraine is more common in women and its frequency correlates with reproductive stages. Prolactin has been shown to be a worsening factor for migraine. Normally prolactin levels are low; however levels can surge during stress. Dopamine receptor agonists, which suppress pituitary prolactin release, are an effective migraine treatment in a subset of patients. Previously, we showed that administration of prolactin onto the dura mater induces female\u2010specific behavioral responses, suggesting that prolactin may play a sex\u2010specific role in migraine.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      The effects of prolactin signaling were assessed using a preclinical migraine model we published recently in which behavioral sensitization is induced by repeated stress. Plasma prolactin levels were assessed in na\u00efve and stressed CD\u20101 mice (\n                      <jats:italic>n<\/jats:italic>\n                      \u00a0=\u00a03\u20135\/group) and transgenic mice with conditional deletion of the Prlr in Nav1.8\u2010positive sensory neurons (Prlr conditional knock\u2010out [CKO];\n                      <jats:italic>n<\/jats:italic>\n                      \u00a0=\u00a03\/group). To assess the contribution of prolactin release during stress, na\u00efve or stressed male and female CD\u20101 mice were treated with the prolactin release inhibitor bromocriptine (2\u00a0mg\/kg;\n                      <jats:italic>n<\/jats:italic>\n                      \u00a0=\u00a07\u201312\/group) or vehicle for 5\u00a0days (8\u201312\/group) and tested for facial hypersensitivity following stress. Additionally, the contribution of ovarian hormones in regulating the prolactin\u2010induced responses was assessed in ovariectomized female CD\u20101 mice (\n                      <jats:italic>n<\/jats:italic>\n                      \u00a0=\u00a06\u201310\/group). Furthermore, the contribution of Prlr activation on Nav1.8\u2010positive sensory neurons was assessed. Na\u00efve or stressed male and female Prlr CKO mice and their control littermates were tested for facial hypersensitivity (\n                      <jats:italic>n<\/jats:italic>\n                      \u00a0=\u00a08\u20139\/group). Immunohistochemistry was used to confirm loss of Prlr in Nav1.8\u2010positive neurons in Prlr CKO mice. The total sample size is\n                      <jats:italic>n<\/jats:italic>\n                      \u00a0=\u00a0245; the full analysis sample size is\n                      <jats:italic>n<\/jats:italic>\n                      \u00a0=\u00a0221.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Stress significantly increased prolactin levels in vehicle\u2010treated female mice (39.70\u00a0\u00b1\u00a02.77;\n                      <jats:italic>p<\/jats:italic>\n                      \u00a0&lt;\u00a00.0001). Bromocriptine significantly reduced serum prolactin levels in stressed female mice compared to vehicle\u2010treated mice (\u221244.85\u00a0\u00b1\u00a03.1;\n                      <jats:italic>p<\/jats:italic>\n                      \u00a0&lt;\u00a00.0001). Additionally, no difference was detected between female stressed mice that received bromocriptine compared to na\u00efve mice treated with bromocriptine (\u22120.70\u00a0\u00b1\u00a02.9;\n                      <jats:italic>p<\/jats:italic>\n                      \u00a0=\u00a00.995). Stress also significantly increased serum prolactin levels in male mice, although to a much smaller extent than in females (0.61\u00a0\u00b1\u00a00.08;\n                      <jats:italic>p<\/jats:italic>\n                      \u00a0&lt;\u00a00.001). Bromocriptine significantly reduced serum prolactin levels in stressed males compared to those treated with vehicle (\u22120.49\u00a0\u00b1\u00a00.08;\n                      <jats:italic>p<\/jats:italic>\n                      \u00a0=\u00a00.002). Furthermore, bromocriptine attenuated stress\u2010induced behavioral responses in female mice compared to those treated with vehicle (maximum effect observed on day 4 post stress [0.21\u00a0\u00b1\u00a00.08;\n                      <jats:italic>p<\/jats:italic>\n                      \u00a0=\u00a00.03]). Bromocriptine did not attenuate stress\u2010induced behavior in males at any timepoint compared to those treated with vehicle. Moreover, loss of ovarian hormones did not affect the ability of bromocriptine to attenuate stress responses compared to vehicle\u2010treated ovariectomy mice that were stressed (maximum effect observed on day 4 post stress [0.29\u00a0\u00b1\u00a00.078;\n                      <jats:italic>p<\/jats:italic>\n                      \u00a0=\u00a00.013]). Similar to CD\u20101 mice, stress increased serum prolactin levels in both Prlr CKO female mice (27.74\u00a0\u00b1\u00a09.96;\n                      <jats:italic>p<\/jats:italic>\n                      \u00a0=\u00a00.047) and control littermates (28.68\u00a0\u00b1\u00a09.9;\n                      <jats:italic>p<\/jats:italic>\n                      \u00a0=\u00a00.041) compared to their na\u00efve counterparts. There was no significant increase in serum prolactin levels detected in male Prlr CKO mice or control littermates. Finally, conditional deletion of Prlr from Nav1.8\u2010positive sensory neurons led to a female\u2010specific attenuation of stress\u2010induced behavioral responses (maximum effect observed on day 7 post stress [0.32\u00a0\u00b1\u00a00.08;\n                      <jats:italic>p<\/jats:italic>\n                      \u00a0=\u00a00.007]) compared to control littermates.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>These data demonstrate that prolactin plays a female\u2010specific role in stress\u2010induced behavioral responses in this preclinical migraine model through activation of Prlr on sensory neurons. They also support a role for prolactin in migraine mechanisms in females and suggest that modulation of prolactin signaling may be an effective therapeutic strategy in some cases.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/head.14248","type":"journal-article","created":{"date-parts":[[2021,12,30]],"date-time":"2021-12-30T02:06:52Z","timestamp":1640830012000},"page":"11-25","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":37,"title":["Prolactin signaling modulates stress\u2010induced behavioral responses in a preclinical mouse model of migraine"],"prefix":"10.1111","volume":"62","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7674-1313","authenticated-orcid":false,"given":"Bianca N.","family":"Mason","sequence":"first","affiliation":[{"name":"Department of Neuroscience Center for Advanced Pain Studies University of Texas at Dallas  Richardson Texas 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