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• W2977306621 abstract "•Local or spinal PRL injection induces hyperalgesia in a female-selective manner•Sensory neuron Prlr regulates tissue injury-induced pain only in females•PRL regulates excitability in Prlr+ neurons depending on sex and estrogen•Regulation of Prlr translation defines female-selective neuronal excitability Many clinical and preclinical studies report an increased prevalence and severity of chronic pain among females. Here, we identify a sex-hormone-controlled target and mechanism that regulates dimorphic pain responses. Prolactin (PRL), which is involved in many physiologic functions, induces female-specific hyperalgesia. A PRL receptor (Prlr) antagonist in the hind paw or spinal cord substantially reduced hyperalgesia in inflammatory models. This effect was mimicked by sensory neuronal ablation of Prlr. Although Prlr mRNA is expressed equally in female and male peptidergic nociceptors and central terminals, Prlr protein was found only in females and PRL-induced excitability was detected only in female DRG neurons. PRL-induced excitability was reproduced in male Prlr+ neurons after prolonged treatment with estradiol but was prevented with addition of a translation inhibitor. We propose a novel mechanism for female-selective regulation of pain responses, which is mediated by Prlr signaling in sensory neurons via sex-dependent control of Prlr mRNA translation. Many clinical and preclinical studies report an increased prevalence and severity of chronic pain among females. Here, we identify a sex-hormone-controlled target and mechanism that regulates dimorphic pain responses. Prolactin (PRL), which is involved in many physiologic functions, induces female-specific hyperalgesia. A PRL receptor (Prlr) antagonist in the hind paw or spinal cord substantially reduced hyperalgesia in inflammatory models. This effect was mimicked by sensory neuronal ablation of Prlr. Although Prlr mRNA is expressed equally in female and male peptidergic nociceptors and central terminals, Prlr protein was found only in females and PRL-induced excitability was detected only in female DRG neurons. PRL-induced excitability was reproduced in male Prlr+ neurons after prolonged treatment with estradiol but was prevented with addition of a translation inhibitor. We propose a novel mechanism for female-selective regulation of pain responses, which is mediated by Prlr signaling in sensory neurons via sex-dependent control of Prlr mRNA translation. In recent years a renewed focus on sexual dimorphic mechanisms of pain has emerged. It is now widely recognized that many key mechanisms driving persistent pain differ between males and females in both animals and humans (Martin et al., 2019Martin L.J. Acland E.L. Cho C. Gandhi W. Chen D. Corley E. Kadoura B. Levy T. Mirali S. Tohyama S. et al.Male-specific conditioned pain hypersensitivity in mice and humans.Curr. Biol. 2019; 29: 192-201.e4Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar, Mogil et al., 2011Mogil J.S. Sorge R.E. LaCroix-Fralish M.L. Smith S.B. Fortin A. Sotocinal S.G. Ritchie J. Austin J.S. Schorscher-Petcu A. Melmed K. et al.Pain sensitivity and vasopressin analgesia are mediated by a gene-sex-environment interaction.Nat. Neurosci. 2011; 14: 1569-1573Crossref PubMed Scopus (84) Google Scholar, North et al., 2019North R. Yan L. Ray P. Rhines L. Tatsui C. Rao G. Johansson C. Kim Y.H. Zhang B. Dussor G. et al.Electrophysiologic and transcriptomic correlates of neuropathic pain in human dorsal root ganglion neurons.Brain. 2019; 142: 1215-1226Crossref PubMed Scopus (75) Google Scholar, Sorge et al., 2011Sorge R.E. LaCroix-Fralish M.L. Tuttle A.H. Sotocinal S.G. Austin J.S. Ritchie J. Chanda M.L. Graham A.C. Topham L. Beggs S. et al.Spinal cord Toll-like receptor 4 mediates inflammatory and neuropathic hypersensitivity in male but not female mice.J. Neurosci. 2011; 31: 15450-15454Crossref PubMed Scopus (271) Google Scholar). Although time course and magnitudes of nociceptive hypersensitivity for a variety of pain conditions are often similar in females and males, the mechanisms responsible for this hypersensitivity and degree of chronicity are sex dependent (Martin et al., 2019Martin L.J. Acland E.L. Cho C. Gandhi W. Chen D. Corley E. Kadoura B. Levy T. Mirali S. Tohyama S. et al.Male-specific conditioned pain hypersensitivity in mice and humans.Curr. Biol. 2019; 29: 192-201.e4Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar, Mogil et al., 2011Mogil J.S. Sorge R.E. LaCroix-Fralish M.L. Smith S.B. Fortin A. Sotocinal S.G. Ritchie J. Austin J.S. Schorscher-Petcu A. Melmed K. et al.Pain sensitivity and vasopressin analgesia are mediated by a gene-sex-environment interaction.Nat. Neurosci. 2011; 14: 1569-1573Crossref PubMed Scopus (84) Google Scholar, Rosen et al., 2017Rosen S. Ham B. Mogil J.S. Sex differences in neuroimmunity and pain.J. Neurosci. Res. 2017; 95: 500-508Crossref PubMed Scopus (136) Google Scholar, Sorge et al., 2011Sorge R.E. LaCroix-Fralish M.L. Tuttle A.H. Sotocinal S.G. Austin J.S. Ritchie J. Chanda M.L. Graham A.C. Topham L. Beggs S. et al.Spinal cord Toll-like receptor 4 mediates inflammatory and neuropathic hypersensitivity in male but not female mice.J. Neurosci. 2011; 31: 15450-15454Crossref PubMed Scopus (271) Google Scholar, Sorge et al., 2015Sorge R.E. Mapplebeck J.C. Rosen S. Beggs S. Taves S. Alexander J.K. Martin L.J. Austin J.S. Sotocinal S.G. Chen D. et al.Different immune cells mediate mechanical pain hypersensitivity in male and female mice.Nat. Neurosci. 2015; 18: 1081-1083Crossref PubMed Scopus (621) Google Scholar). Gonadal hormones, for instance, are known to be key contributors to sex differences in a variety of physiological and pathophysiological processes (Karp et al., 2017Karp N.A. Mason J. Beaudet A.L. Benjamini Y. Bower L. Braun R.E. Brown S.D.M. Chesler E.J. Dickinson M.E. Flenniken A.M. et al.Prevalence of sexual dimorphism in mammalian phenotypic traits.Nat. Commun. 2017; 8: 15475Crossref PubMed Scopus (112) Google Scholar, Morselli et al., 2017Morselli E. Santos R.S. Criollo A. Nelson M.D. Palmer B.F. Clegg D.J. The effects of oestrogens and their receptors on cardiometabolic health.Nat. Rev. Endocrinol. 2017; 13: 352-364Crossref PubMed Scopus (72) Google Scholar). Human and animal studies of pain symptoms and severity have established correlations with the menstrual cycle, menopause, and alterations in gonadal hormone concentrations (Aloisi and Sorda, 2011Aloisi A.M. Sorda G. Relationship of female sex hormones with pain perception: focus on estrogens.Pain Manag. 2011; 1: 229-238Crossref PubMed Google Scholar, Houghton et al., 2002Houghton L.A. Lea R. Jackson N. Whorwell P.J. The menstrual cycle affects rectal sensitivity in patients with irritable bowel syndrome but not healthy volunteers.Gut. 2002; 50: 471-474Crossref PubMed Scopus (178) Google Scholar, LeResche et al., 2003LeResche L. Mancl L. Sherman J.J. Gandara B. Dworkin S.F. Changes in temporomandibular pain and other symptoms across the menstrual cycle.Pain. 2003; 106: 253-261Abstract Full Text Full Text PDF PubMed Scopus (285) Google Scholar, Slade et al., 2011Slade G.D. Bair E. By K. Mulkey F. Baraian C. Rothwell R. Reynolds M. Miller V. Gonzalez Y. Gordon S. et al.Study methods, recruitment, sociodemographic findings, and demographic representativeness in the OPPERA study.J. Pain. 2011; 12: T12-T26Abstract Full Text Full Text PDF PubMed Scopus (101) Google Scholar, Traub and Ji, 2013Traub R.J. Ji Y. Sex differences and hormonal modulation of deep tissue pain.Front. Neuroendocrinol. 2013; 34: 350-366Crossref PubMed Scopus (48) Google Scholar). Recent findings on sexual dimorphisms have demonstrated a role for spinal microglia in male-specific pain mechanisms (Sorge et al., 2011Sorge R.E. LaCroix-Fralish M.L. Tuttle A.H. Sotocinal S.G. Austin J.S. Ritchie J. Chanda M.L. Graham A.C. Topham L. Beggs S. et al.Spinal cord Toll-like receptor 4 mediates inflammatory and neuropathic hypersensitivity in male but not female mice.J. Neurosci. 2011; 31: 15450-15454Crossref PubMed Scopus (271) Google Scholar) and a T cell selective contribution to nociceptive transmission in females (Rosen et al., 2019Rosen S.F. Ham B. Haichin M. Walters I.C. Tohyama S. Sotocinal S.G. Mogil J.S. Increased pain sensitivity and decreased opioid analgesia in T-cell-deficient mice and implications for sex differences.Pain. 2019; 160: 358-366Crossref PubMed Scopus (30) Google Scholar, Sorge et al., 2015Sorge R.E. Mapplebeck J.C. Rosen S. Beggs S. Taves S. Alexander J.K. Martin L.J. Austin J.S. Sotocinal S.G. Chen D. et al.Different immune cells mediate mechanical pain hypersensitivity in male and female mice.Nat. Neurosci. 2015; 18: 1081-1083Crossref PubMed Scopus (621) Google Scholar), although other investigators have described T cells to be involved in protection and resolution of pain (Krukowski et al., 2016Krukowski K. Eijkelkamp N. Laumet G. Hack C.E. Li Y. Dougherty P.M. Heijnen C.J. Kavelaars A. CD8+ T cells and endogenous IL-10 are required for resolution of chemotherapy-induced neuropathic pain.J. Neurosci. 2016; 36: 11074-11083Crossref PubMed Scopus (96) Google Scholar, Laumet et al., 2019Laumet G. Edralin J.D. Dantzer R. Heijnen C.J. Kavelaars A. Cisplatin educates CD8+ T cells to prevent and resolve chemotherapy-induced peripheral neuropathy in mice.Pain. 2019; 160: 1459-1468Crossref PubMed Scopus (26) Google Scholar). It is possible that a neuron-specific, sexually dimorphic pain mechanism also could be involved and mediated by gonadal hormone controlled signaling. A prime candidate for this potential mechanism is prolactin (PRL) and its receptor (Prlr), since responsiveness to PRL in a variety of cell types depends on sex, menstrual cycle phase, pregnancy status, and lactation (Belugin et al., 2013Belugin S. Diogenes A.R. Patil M.J. Ginsburg E. Henry M.A. Akopian A.N. Mechanisms of transient signaling via short and long prolactin receptor isoforms in female and male sensory neurons.J. Biol. Chem. 2013; 288: 34943-34955Crossref PubMed Scopus (31) Google Scholar, Childs et al., 1999Childs G.V. Unabia G. Miller B.T. Collins T.J. Differential expression of gonadotropin and prolactin antigens by GHRH target cells from male and female rats.J. Endocrinol. 1999; 162: 177-187Crossref PubMed Scopus (34) Google Scholar, Diogenes et al., 2006Diogenes A. Patwardhan A.M. Jeske N.A. Ruparel N.B. Goffin V. Akopian A.N. Hargreaves K.M. Prolactin modulates TRPV1 in female rat trigeminal sensory neurons.J. Neurosci. 2006; 26: 8126-8136Crossref PubMed Scopus (100) Google Scholar, Pi and Voogt, 2002Pi X. Voogt J.L. Sex difference and estrous cycle: expression of prolactin receptor mRNA in rat brain.Brain Res. Mol. Brain Res. 2002; 103: 130-139Crossref PubMed Scopus (19) Google Scholar). PRL is involved in female-specific regulation of transient receptor potential (TRP) and other ligand-gated channels in sensory neurons (Diogenes et al., 2006Diogenes A. Patwardhan A.M. Jeske N.A. Ruparel N.B. Goffin V. Akopian A.N. Hargreaves K.M. Prolactin modulates TRPV1 in female rat trigeminal sensory neurons.J. Neurosci. 2006; 26: 8126-8136Crossref PubMed Scopus (100) Google Scholar, Liu et al., 2016Liu T.T. Qu Z.W. Ren C. Gan X. Qiu C.Y. Hu W.P. Prolactin potentiates the activity of acid-sensing ion channels in female rat primary sensory neurons.Neuropharmacology. 2016; 103: 174-182Crossref PubMed Scopus (10) Google Scholar, Patil et al., 2013bPatil M.J. Ruparel S.B. Henry M.A. Akopian A.N. Prolactin regulates TRPV1, TRPA1, and TRPM8 in sensory neurons in a sex-dependent manner: contribution of prolactin receptor to inflammatory pain.Am. J. Physiol. Endocrinol. Metab. 2013; 305: E1154-E1164Crossref PubMed Scopus (44) Google Scholar). Global ablation of PRL and Prlr leads to a substantial and female-selective reduction in postoperative and inflammatory heat hypersensitivity (Patil et al., 2013aPatil M.J. Green D.P. Henry M.A. Akopian A.N. Sex-dependent roles of prolactin and prolactin receptor in postoperative pain and hyperalgesia in mice.Neuroscience. 2013; 253: 132-141Crossref PubMed Scopus (34) Google Scholar, Patil et al., 2013bPatil M.J. Ruparel S.B. Henry M.A. Akopian A.N. Prolactin regulates TRPV1, TRPA1, and TRPM8 in sensory neurons in a sex-dependent manner: contribution of prolactin receptor to inflammatory pain.Am. J. Physiol. Endocrinol. Metab. 2013; 305: E1154-E1164Crossref PubMed Scopus (44) Google Scholar) and mechanical hypersensitivity, but the latter effect is observed in male and female mice (Patil et al., 2013aPatil M.J. Green D.P. Henry M.A. Akopian A.N. Sex-dependent roles of prolactin and prolactin receptor in postoperative pain and hyperalgesia in mice.Neuroscience. 2013; 253: 132-141Crossref PubMed Scopus (34) Google Scholar, Patil et al., 2013bPatil M.J. Ruparel S.B. Henry M.A. Akopian A.N. Prolactin regulates TRPV1, TRPA1, and TRPM8 in sensory neurons in a sex-dependent manner: contribution of prolactin receptor to inflammatory pain.Am. J. Physiol. Endocrinol. Metab. 2013; 305: E1154-E1164Crossref PubMed Scopus (44) Google Scholar). These studies demonstrate a clear role for PRL-Prlr signaling in pain hypersensitivity after injury, but the cells mediating these effects and the mechanisms generating female-specific nociceptive responses remain unknown. The central goals of the work described here were to gain insight into whether Prlr expression in sensory neurons drives female-specific nociceptive responses to PRL and to understand how these female-specific effects emerge. We show that PRL signaling to Prlr expressed in sensory neurons at the level of peripheral and central terminals regulates female-specific hyperalgesia in several pain models. We also elucidate mechanisms responsible for PRL's female-selective actions in the regulation of pain. Gonadal hormones regulate cellular phenotypes via classic genomic and transient non-genomic signaling pathways (Amandusson and Blomqvist, 2013Amandusson A. Blomqvist A. Estrogenic influences in pain processing.Front. Neuroendocrinol. 2013; 34: 329-349Crossref PubMed Scopus (70) Google Scholar, Kelly et al., 1976Kelly M.J. Moss R.L. Dudley C.A. Differential sensitivity of preoptic-septal neurons to microelectrophoresed estrogen during the estrous cycle.Brain Res. 1976; 114: 152-157Crossref PubMed Scopus (148) Google Scholar, Revankar et al., 2005Revankar C.M. Cimino D.F. Sklar L.A. Arterburn J.B. Prossnitz E.R. A transmembrane intracellular estrogen receptor mediates rapid cell signaling.Science. 2005; 307: 1625-1630Crossref PubMed Scopus (1773) Google Scholar). However, surprisingly, our work points to a novel mechanism for sex-specific regulation of nociceptor plasticity that is dependent on selective and estrogen-dependent translation of Prlr mRNA in female DRG neurons. Overall, our work establishes sensory neuron participation of a major neuroendocrine hormone PRL in female-selective regulation of pain as well as a novel paradigm connecting sex- and gonadal hormone-dependent translational control that could be critical to understanding sexual dimorphism in many biological processes. Exogenous fully processed and non-modified human PRL (PRL) generated in an expression system sensitizes a subset of mouse female sensory neurons (Belugin et al., 2013Belugin S. Diogenes A.R. Patil M.J. Ginsburg E. Henry M.A. Akopian A.N. Mechanisms of transient signaling via short and long prolactin receptor isoforms in female and male sensory neurons.J. Biol. Chem. 2013; 288: 34943-34955Crossref PubMed Scopus (31) Google Scholar, Patil et al., 2013bPatil M.J. Ruparel S.B. Henry M.A. Akopian A.N. Prolactin regulates TRPV1, TRPA1, and TRPM8 in sensory neurons in a sex-dependent manner: contribution of prolactin receptor to inflammatory pain.Am. J. Physiol. Endocrinol. Metab. 2013; 305: E1154-E1164Crossref PubMed Scopus (44) Google Scholar). Statistically significant sensitization in male sensory neurons is achieved with approximately a 40-fold higher concentration of PRL (Patil et al., 2013bPatil M.J. Ruparel S.B. Henry M.A. Akopian A.N. Prolactin regulates TRPV1, TRPA1, and TRPM8 in sensory neurons in a sex-dependent manner: contribution of prolactin receptor to inflammatory pain.Am. J. Physiol. Endocrinol. Metab. 2013; 305: E1154-E1164Crossref PubMed Scopus (44) Google Scholar). To establish if this major difference is also found in vivo, we evaluated whether PRL produces hyperalgesia in female and/or male mice. PRL injected into the hind paw (ipl) generated profound heat (Figure 1A) and mechanical hyperalgesia (Figure 1B) in a dose-dependent manner in estrus female mice (two-way ANOVA; heat - F (3, 40) = 13.4; P < 0.0001; mechanical - F (3, 37) = 10.9; P < 0.0001). As low as 0.1 μg PRL generated thermal and mechanical hyperalgesia in females, whereas 1 μg PRL injected in the contralateral paw did not produce an effect ipsilaterally (bars “Cont” on Figures 1A and 1B). This indicates that PRL-induced hyperalgesia involves peripheral (i.e., local) mechanisms. In contrast, for male mice, higher amounts of PRL (10 μg) produced heat (two-way ANOVA; P < 0.0001; Figure 1A) but not mechanical hypersensitivity P = 0.1; Figure 1B). Administration of PRL into the spinal cord via intrathecal injection (it) also produced substantial heat (Figure 1C) and mechanical hypersensitivity (Figure 1D) predominantly in females (two-way ANOVA; heat - F (3, 51) = 14; P < 0.0001; mechanical - F (3, 45) = 20.6; P < 0.0001). Spinal PRL-induced hypersensitivity was not significant in male mice (two-way ANOVA; heat P = 0.1; mechanical P = 0.2; Figures 1C and 1D). Unbound PRL protein undergoes relatively fast degradation (Freeman et al., 2000Freeman M.E. Kanyicska B. Lerant A. Nagy G. Prolactin: structure, function, and regulation of secretion.Physiol. Rev. 2000; 80: 1523-1631Crossref PubMed Scopus (1705) Google Scholar). Consistent with this pharmacokinetic property, PRL (1 and 10 μg) injected in the hind paw (Figures S1A and S1B) or spinal cord (Figures S1C and S1D) of female mice produced significant heat and mechanical hypersensitivity for up to ~4 h (especially for high doses) and peaked at 1–2 h post administration. Prolonged withdrawal of estrogen and progesterone in ovariectomized (OVX) females totally ablates PRL responsiveness in rats (Diogenes et al., 2006Diogenes A. Patwardhan A.M. Jeske N.A. Ruparel N.B. Goffin V. Akopian A.N. Hargreaves K.M. Prolactin modulates TRPV1 in female rat trigeminal sensory neurons.J. Neurosci. 2006; 26: 8126-8136Crossref PubMed Scopus (100) Google Scholar). We evaluated whether PRL responsiveness depends on the estrous phase of mice. Intraplantar (ipl) or spinal cord (it) injection of PRL (1 μg) induced mechanical hypersensitivity in females but not in males (Figures 1E and 1F two-way ANOVA; peripheral - F (6, 48) = 9.7; P < 0.0001; n = 5; Figure 1E; and spinal - F (6, 48) = 4.5; P = 0.0011; n = 5). PRL sensitivity was not affected by female estrous phases (Figure 1F). These results show that exogenous PRL delivered locally into the hind paw or spinal cord triggers 4-h-long-lasting pain hypersensitivity in a female-selective manner, but independent of female estrous phases. Incision surgery and inflammation up-regulates PRL in a sex-dependent fashion in the hind paw and especially spinal cord, where the larger magnitude of upregulation is found (Patil et al., 2013aPatil M.J. Green D.P. Henry M.A. Akopian A.N. Sex-dependent roles of prolactin and prolactin receptor in postoperative pain and hyperalgesia in mice.Neuroscience. 2013; 253: 132-141Crossref PubMed Scopus (34) Google Scholar, Scotland et al., 2011Scotland P.E. Patil M. Belugin S. Henry M.A. Goffin V. Hargreaves K.M. Akopian A.N. Endogenous prolactin generated during peripheral inflammation contributes to thermal hyperalgesia.Eur. J. Neurosci. 2011; 34: 745-754Crossref PubMed Scopus (25) Google Scholar). We used the specific Prlr antagonist, Δ1-9-G129R-hPRL (ΔPRL) (Rouet et al., 2010Rouet V. Bogorad R.L. Kayser C. Kessal K. Genestie C. Bardier A. Grattan D.R. Kelder B. Kopchick J.J. Kelly P.A. et al.Local prolactin is a target to prevent expansion of basal/stem cells in prostate tumors.Proc. Natl. Acad. Sci. U S A. 2010; 107: 15199-15204Crossref PubMed Scopus (67) Google Scholar), which is a modified PRL that binds to and blocks the function of Prlr in rat, mouse, and human (Bernichtein et al., 2003Bernichtein S. Kayser C. Dillner K. Moulin S. Kopchick J.J. Martial J.A. Norstedt G. Isaksson O. Kelly P.A. Goffin V. Development of pure prolactin receptor antagonists.J. Biol. Chem. 2003; 278: 35988-35999Crossref PubMed Scopus (98) Google Scholar), to evaluate the role of Prlr in the regulation of postoperative pain in female and male mice and rats. In estrus female mice at 1 day post incision, ΔPRL (5 μg) applied into the spinal cord by intrathecal injection (it) significantly reversed heat (two-way ANOVA; F (6, 44) = 8.2; P < 0.0001; n = 4–5; Figure S2A) and mechanical hypersensitivity (P = 0.014 at 60 min; P = 0.03 at 120 min; n = 5–6; Figure S2B). In contrast, ΔPRL (5 μg) did not show antagonism of incision-induced heat and mechanical hypersensitivity in male mice (Figures S2C and S2D). We did not escalate the dosage of ΔPRL, since at dosages >25 μg, it could show agonistic properties (Scotland et al., 2011Scotland P.E. Patil M. Belugin S. Henry M.A. Goffin V. Hargreaves K.M. Akopian A.N. Endogenous prolactin generated during peripheral inflammation contributes to thermal hyperalgesia.Eur. J. Neurosci. 2011; 34: 745-754Crossref PubMed Scopus (25) Google Scholar). However, 5 μg of ΔPRL did not exhibit agonistic or antagonistic properties on mice that underwent sham procedures (Figures S2A–S2D). Since peak effects were observed at 60 min post ΔPRL, we recorded vehicle and ΔPRL actions at 60 min post injection. Male and estrous females were injected with vehicle or ΔPRL into hind paws (ipl) at 1 day post incision. Heat hypersensitivity in females, but not in males, was significantly reversed with ΔPRL (two-way ANOVA; F (4, 31) = 9.4; P < 0.0001; n = 4–5; Figure 2A). Mechanical hyperalgesia in males as well as females was not significantly affected by hind paw administration of ΔPRL (two-way ANOVA; F (4, 50) = 0.2; P = 0.9; Figure 2B). Spinal injection of ΔPRL substantially reversed both heat (two-way ANOVA; F (4, 41) = 12.6; P < 0.0001; n = 4–6; Figure 2C) and mechanical hypersensitivity (F (4, 40) = 18.2; P < 0.0001; n = 5–6; Figure 2D) in a female-selective fashion. PRL actions could vary between species and PRL release from the pituitary depends on the estrous phase (Freeman et al., 2000Freeman M.E. Kanyicska B. Lerant A. Nagy G. Prolactin: structure, function, and regulation of secretion.Physiol. Rev. 2000; 80: 1523-1631Crossref PubMed Scopus (1705) Google Scholar), but exogenous PRL responsiveness at periphery and spinal cord of naive female mice is not dependent on the estrous phase (Figures 1E and 1F). Accordingly, we evaluated whether ΔPRL effects differ in diestrus (diestrus 1 and 2 combined) versus estrus female rats. Spinal (it) injection of ΔPRL (5 μg) at 1 day post incision significantly reversed postoperative mechanical hypersensitivity in diestrus and estrus female (two-way ANOVA; F (8, 60) = 6.5; P < 0.0001; n = 5) but not in male rats (Figure 3A). The inhibition of mechanical hypersensitivity was more pronounced in estrus compared with diestrus female rats (two-way ANOVA; P = 0.011; Figure 3A). Our findings indicate that blockage of Prlr leads to female-selective inhibition of postoperative hypersensitivity, which depends on the site of Prlr antagonist action (Figures 1B versus 1D) and partially on the estrous phase (Figure 3A) but not the rodent species (Figures 2 and 3A). Inflammatory hypersensitivity was induced by hind paw injection of interleukin (IL)-6 (Melemedjian et al., 2010Melemedjian O.K. Asiedu M.N. Tillu D.V. Peebles K.A. Yan J. Ertz N. Dussor G.O. Price T.J. IL-6- and NGF-induced rapid control of protein synthesis and nociceptive plasticity via convergent signaling to the eIF4F complex.J. Neurosci. 2010; 30: 15113-15123Crossref PubMed Scopus (147) Google Scholar). Co-injection of IL-6 (1 ng; into the hind paw, ipl) and ΔPRL (5 μg; into the spinal cord, it) effectively inhibited mechanical hypersensitivity in female mice, whereas IL-6 and vehicle or ΔPRL co-administration into the hind paw did not produce anti-mechanical hypersensitivity effects (two-way ANOVA; F (2, 28) = 13.3; P < 0.0001; n = 5–6; Figure 3B). The concentration of endogenous PRL in serum of rodents could be increased up to 100 ng/mL during inflammatory conditions (Patil et al., 2013aPatil M.J. Green D.P. Henry M.A. Akopian A.N. Sex-dependent roles of prolactin and prolactin receptor in postoperative pain and hyperalgesia in mice.Neuroscience. 2013; 253: 132-141Crossref PubMed Scopus (34) Google Scholar, Scotland et al., 2011Scotland P.E. Patil M. Belugin S. Henry M.A. Goffin V. Hargreaves K.M. Akopian A.N. Endogenous prolactin generated during peripheral inflammation contributes to thermal hyperalgesia.Eur. J. Neurosci. 2011; 34: 745-754Crossref PubMed Scopus (25) Google Scholar). It could be presumed that inflammation will sensitize Prlr signaling. To evaluate this possibility, we used the hyperalgesic priming model (Melemedjian et al., 2010Melemedjian O.K. Asiedu M.N. Tillu D.V. Peebles K.A. Yan J. Ertz N. Dussor G.O. Price T.J. IL-6- and NGF-induced rapid control of protein synthesis and nociceptive plasticity via convergent signaling to the eIF4F complex.J. Neurosci. 2010; 30: 15113-15123Crossref PubMed Scopus (147) Google Scholar) and examined whether hind paw injection of PRL could precipitate hyperalgesic priming in mice primed with IL-6. IL-6 (0.1 ng) was injected into the hind paw and following hypersensitivity resolution (5 days post IL-6), PRL was injected into the same hind paw. Priming with IL-6 dramatically (>100-fold) sensitized Prlr signaling wherein estrus female, but not male mice, showed hypersensitivity to as low as 0.5 ng PRL (two-way ANOVA; for females; F (3, 24) = 7; P = 0.0015; n = 5; Figure 3C and for males; F (3, 20) = 2.5; P = 0.085; n = 5; Figure 3D). It is well documented that many inflammatory and idiopathic chronic pain conditions have 2- to 6-fold greater prevalence, chronicity, and symptom severity in women as compared with men (Berkley, 1997Berkley K.J. Sex differences in pain.Behav. Brain Sci. 1997; 20 (discussion 435–513): 371-380Crossref PubMed Scopus (851) Google Scholar, Fillingim et al., 2009Fillingim R.B. King C.D. Ribeiro-Dasilva M.C. Rahim-Williams B. Riley J.L. Sex, gender, and pain: a review of recent clinical and experimental findings.J. Pain. 2009; 10: 447-485Abstract Full Text Full Text PDF PubMed Scopus (1547) Google Scholar, Traub and Ji, 2013Traub R.J. Ji Y. Sex differences and hormonal modulation of deep tissue pain.Front. Neuroendocrinol. 2013; 34: 350-366Crossref PubMed Scopus (48) Google Scholar, Unruh, 1996Unruh A.M. Gender variations in clinical pain experience.Pain. 1996; 65: 123-167Abstract Full Text PDF PubMed Scopus (1121) Google Scholar). Hence, we examined whether addition of exogenous PRL to IL-6 could alter chronicity and/or severity of mechanical hypersensitivity. Single co-administration of PRL (1 μg) and IL-6 (1 ng) into the hind paw resulted in a substantial increase in the duration of mechanical hypersensitivity compared with co-injection of vehicle and IL-6 into females (two-way ANOVA; F (14, 136) = 4.6; P < 0.0001; n = 5–6; Figure 3E). However, PRL did not increase the severity (i.e., magnitude) of inflammatory hypersensitivity (Figure 3E). In summary, these results indicate that peripheral and spinal Prlr signaling is involved in modulation of inflammatory pain in females. Prlr is expressed not only in sensory neurons but also in DRG fibroblasts and satellite glial cells, some immune cells, and possibly by intrinsic spinal cord neurons (Ben-Jonathan et al., 2008Ben-Jonathan N. LaPensee C.R. LaPensee E.W. What can we learn from rodents about prolactin in humans?.Endocr. Rev. 2008; 29: 1-41Crossref PubMed Scopus (377) Google Scholar, Haring et al., 2018Haring M. Zeisel A. Hochgerner H. Rinwa P. Jakobsson J.E.T. Lonnerberg P. La Manno G. Sharma N. Borgius L. Kiehn O. et al.Neuronal atlas of the dorsal horn defines its architecture and links sensory input to transcriptional cell types.Nat. Neurosci. 2018; 21: 869-880Crossref PubMed Scopus (156) Google Scholar, Patil et al., 2014Patil M.J. Henry M.A. Akopian A.N. Prolactin receptor in regulation of neuronal excitability and channels.Channels (Austin). 2014; 8: 193-202Crossref PubMed Scopus (49) Google Scholar, Patil et al., 2019Patil M. Hovhannisyan A.H. Wangzhou A. Mecklenburg J. Koek W. Goffin V. Grattan D. Boehm U. Dussor G. Price T.J. et al.Prolactin receptor expression in mouse dorsal root ganglia neuronal subtypes is sex-dependent.J. Neuroendocrinol. 2019; 31: e12759Crossref PubMed Scopus (13) Google Scholar). Here, we evaluated whether sensory neuronal Prlr is essential in female-selective regulation of chemical-induced, inflammatory, and neuropathic pain. To do so, we ablated the Prlr gene in the Nav1.8+ subset of sensory neurons (Prlr CKO). The Prlrfl/fl line was generated by insertion of inverse lox sites around exon 5 (Brown et al., 2016Brown R.S.E. Kokay I.C. Phillipps H.R. Yip S.H. Gustafson P. Wyatt A. Larsen C.M. Knowles P. Ladyman S.R. LeTissier P. et al.Conditional deletion of the prolactin receptor reveals functional subpopulations of dopamine neurons in the arcuate nucleus of the hypothalamus.J. Neurosci. 2016; 36: 9173-9185Crossref PubMed Scopus (50) Google Scholar). Hence, cre-recombination ablates the gene and activates GFP in Nav1.8+ neurons (Figures S3A and S3B). Cre-recombination was verified by GFP mRNA expression that can be amplified from DRG RNA of Prlr CKO but not Prlrfl/fl female mice (Figure S3C). To show conditional ablation of Prlr prote" @default.
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• W2977306621 date "2019-10-01" @default.
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• W2977306621 title "Prolactin Regulates Pain Responses via a Female-Selective Nociceptor-Specific Mechanism" @default.
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• W2977306621 doi "https://doi.org/10.1016/j.isci.2019.09.039" @default.
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