Role of nociceptor estrogen receptor GPR30 in a rat model of endometriosis pain |
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| Affiliation: | 1. Department of Oral and Maxillofacial Surgery, University of California San Francisco, San Francisco, CA, USA;2. Division of Neuroscience, University of California San Francisco, San Francisco, CA, USA;3. Department of Medicine, University of California San Francisco, San Francisco, CA, USA;1. Pain Research Laboratory, Institute of Nautical Medicine, Jiangsu Key Laboratory of Inflammation and Molecular Drug Target, Nantong University, Nantong, Jiangsu, China;2. Department of Nutrition, School of Public Health, Nantong University, Nantong, Jiangsu, China;3. Departments of Anesthesiology and Neurobiology, Duke University Medical Center, Durham, NC 27710, USA;1. Department of Pharmacological and Physiological Science, Saint Louis University School of Medicine, 1402 South Grand Blvd, St Louis, MO 63104, USA;2. Department of Clinical and Experimental Medicine and Pharmacology, University of Messina, Messina 98122, Italy;3. Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892-0810, USA;1. Department of Neurosciences, School of Medicine and Dentistry, University of the Basque Country, Bilbao, Spain;2. Movement Disorders and Autonomic Unit, Neurology Service, Cruces University Hospital, Basque Health Service (Osakidetza), Spain;1. Danish Pain Research Center, Aarhus University, Aarhus, Denmark;2. Department of Neurology, Aarhus University Hospital, Aarhus, Denmark;1. Palliative Care, Pain Therapy and Rehabilitation Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy;2. European Palliative Care Research Centre (PRC), Department of Cancer Research and Molecular Medicine, Faculty of Medicine, Norwegian University of Science and Technology (NTNU), Trondheim, Norway;3. Academic Unit of Palliative Care, Leeds Institute of Health Sciences, University of Leeds, Leeds, West Yorkshire, UK;4. Cancer Clinic, St. Olavs Hospital, University Hospital of Trondheim, Trondheim, Norway;5. Division of Palliative Care Medicine Department of Oncology, University of Alberta, Edmonton, AB, Canada;6. Section of Palliative Medicine, Department of Oncology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark;7. Anesthesia and Intensive Care & Pain Relief and Palliative Care Unit, la Maddalena Cancer Center, Palermo and University of Palermo, Palermo, Italy;1. Klinik für Neurologie, Universitätsmedizin Mainz, Mainz, Germany;2. Neuroscience, Physiology and Pharmacology, University College London, London, UK;3. Boehringer Ingelheim Pharma GmbH & Co KG, CNS Research, Biberach, Germany |
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| 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. |
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| Keywords: | 17β-Estradiol Ectopic endometrium Mechanical hyperalgesia Raloxifene |
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