title: Role of nociceptor estrogen receptor GPR30 in a rat model of endometriosis pain.
abstract: Endometriosis, the most common cause of chronic pelvic pain, is an estrogen-dependent disease in which classic estrogen receptors (ERα, ERβ) play an important role. Although recent evidence suggests that the novel G protein-coupled estrogen receptor (GPR30) also plays a key role in the progression of endometriosis, whether it is also involved in endometriosis pain is still unknown. Here we tested the hypothesis that GPR30 expressed by nociceptors contributes to endometriosis pain. Intramuscular injection of the GPR30 agonists raloxifene or 17β-estradiol produced a fast-onset, persistent, mechanical hyperalgesia at the site of the injection. Intrathecal antisense (AS) oligodeoxynucleotides (ODN), but not mismatch (MM) ODN, targeting mRNA for GPR30 markedly inhibited its protein expression in nociceptors and attenuated the mechanical hyperalgesia induced by local raloxifene or 17β-estradiol. Pretreatment with the GPR30 antagonist G-36 also inhibited the hyperalgesia induced by raloxifene or 17β-estradiol in naive control rats. Surgical implant of autologous uterine tissue onto the gastrocnemius muscle, which induces endometriosis-like lesions, produced local mechanical hyperalgesia. Intrathecal AS, but not MM, ODN targeting GPR30 mRNA reversibly inhibited the mechanical hyperalgesia at the site of endometriotic lesions. Finally, intralesional injection of the GPR30 antagonist G-36 also inhibited the mechanical hyperalgesia at the site of ectopic uterine tissue. We conclude that local GPR30 agonists produce persistent mechanical hyperalgesia in naive female rats, whereas local GPR30 antagonists inhibit mechanical hyperalgesia in a model of endometriosis pain. Thus, GPR30 expressed by nociceptors innervating ectopic uterine lesions might play a major role in endometriosis pain.
authors.affiliation: Department of Oral and Maxillofacial Surgery, University of California San Francisco, San Francisco, CA, USA Division of Neuroscience, University of California San Francisco, San Francisco, CA, USA Department of Medicine, University of California San Francisco, San Francisco, CA, USA.
authors.forename: Pedro
authors.initials: P
authors.lastname: Alvarez
authors.forename: Oliver
authors.initials: O
authors.lastname: Bogen
authors.forename: Jon D
authors.initials: JD
authors.lastname: Levine
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004715:Endometriosis / Q000139:chemically induced / Q000150:complications*; D004958:Estradiol / Q000009:adverse effects; D004965:Estrogen Antagonists / Q000009:adverse effects; D005260:Female; D005727:Ganglia, Spinal / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D006930:Hyperalgesia / Q000139:chemically induced; D009619:Nociceptors / Q000187:drug effects / Q000378:metabolism*; D016376:Oligonucleotides, Antisense; D017288:Pain Threshold / Q000187:drug effects / Q000502:physiology; D017699:Pelvic Pain / Q000209:etiology*; D051744:Protein Kinase C-epsilon / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D020849:Raloxifene Hydrochloride / Q000009:adverse effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*
chemical_list: D004965:Estrogen Antagonists; C520305:Gper1 protein, rat; D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger; D043562:Receptors, G-Protein-Coupled; D020849:Raloxifene Hydrochloride; D004958:Estradiol; D051744:Protein Kinase C-epsilon
keywords: 17β-Estradiol; Ectopic endometrium; Mechanical hyperalgesia; Raloxifene