Ectopic endometrium-derived leptin produces estrogen-dependent chronic pain in a rat model of endometriosis.
Endometriosis pain is a very common and extremely disabling condition whose mechanism is still poorly understood. While increased levels of leptin have been reported in patients with endometriosis, their contribution to endometriosis pain has not been explored. Using a rodent model of endometriosis we provide evidence for an estrogen-dependent contribution of leptin in endometriosis-induced pain. Rats implanted with autologous uterine tissue onto the gastrocnemius muscle developed endometriosis-like lesions and local chronic pain. Compared to eutopic uterine tissue, leptin mRNA and protein were up-regulated in the endometriosis-like lesions. Intramuscular injection of recombinant leptin in naive rats produced dose-dependent local mechanical hyperalgesia and nociceptor sensitization to mechanical stimulation. Ovariectomy attenuated the mechanical hyperalgesia induced by recombinant leptin, in rats treated with vehicle compared to those treated with 17β-estradiol replacement, at 1 and 24 h after leptin injection. Finally, intralesional injections of a pegylated leptin receptor (Ob-R) antagonist or of an inhibitor of Janus kinase2, which transduces the Ob-R signal, markedly attenuated pain in the endometriosis model. Taken together these data support the hypothesis that leptin, generated in ectopic endometrial lesions produces mechanical hyperalgesia by acting on nociceptors innervating the lesion. This sensitivity to leptin is dependent on estrogen levels. Thus, interventions targeting leptin signaling, especially in combination with interventions that lower estrogen levels, might be useful for the treatment of endometriosis pain.
Department of Oral and Maxillofacial Surgery, University of California San Francisco, San Francisco, CA 94143, USA; Division of Neuroscience, University of California San Francisco, San Francisco, CA 94143, USA.
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Alvarez
Department of Oral and Maxillofacial Surgery, University of California San Francisco, San Francisco, CA 94143, USA; Division of Neuroscience, University of California San Francisco, San Francisco, CA 94143, USA.
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Bogen
Department of Oral and Maxillofacial Surgery, University of California San Francisco, San Francisco, CA 94143, USA; Division of Neuroscience, University of California San Francisco, San Francisco, CA 94143, USA.
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Chen
Department of Obstetrics, Gynecology and Reproductive Sciences, University of California San Francisco, San Francisco, CA 94143, USA; Center for Reproductive Sciences, University of California San Francisco, San Francisco, CA 94143, USA.
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Giudice
Department of Oral and Maxillofacial Surgery, University of California San Francisco, San Francisco, CA 94143, USA; Division of Neuroscience, University of California San Francisco, San Francisco, CA 94143, USA; Department of Medicine, University of California San Francisco, San Francisco, CA 94143, USA. Electronic address: jon.levine@ucsf.edu.
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Levine
D000818:Animals; D059350:Chronic Pain / Q000188:drug therapy / Q000378:metabolism; D004195:Disease Models, Animal; D004715:Endometriosis / Q000188:drug therapy / Q000378:metabolism*; D004717:Endometrium / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004958:Estradiol / Q000494:pharmacology; D004967:Estrogens / Q000378:metabolism* / Q000494:pharmacology; D005260:Female; D006930:Hyperalgesia / Q000188:drug therapy / Q000378:metabolism; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D020738:Leptin / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism / Q000601:surgery; D009619:Nociceptors / Q000378:metabolism; D010052:Ovariectomy; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D054411:Receptors, Leptin / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014110:Touch; D014599:Uterus / Q000187:drug effects / Q000378:metabolism* / Q000637:transplantation
D004791:Enzyme Inhibitors; D004967:Estrogens; D020738:Leptin; D012333:RNA, Messenger; D054411:Receptors, Leptin; D004958:Estradiol; C507927:Jak2 protein, rat; D053614:Janus Kinase 2
BSA; D-PBS; DRG; Dulbecco’s phosphate-buffered saline; JAK2; Janus kinase2; Ob-R; RT-PCR; STAT3; bovine serum albumin; chronic pelvic pain; dorsal root ganglion; endometriosis; leptin; leptin receptor; mechanical hyperalgesia; nociceptor; ob gene; recombinant rat leptin; reverse transcriptase polymerase chain reaction; rrleptin; signal transducer and activator of transcription 3