title: Estrogen Receptor Beta Selective Agonists as Agents to Treat Chemotherapeutic-Induced Neuropathic Pain.
abstract: Chemotherapy-induced neuropathic pain (CINP) remains a major unmet medical need. Estrogen receptor beta (ERβ)-selective agonists represent a novel strategy for treating CINP because they are neuroprotective and may also have anticancer activity. We confirmed that ERβ-selective agonists have antiallodynic effects in the spinal nerve ligation model of neuropathic pain. We then showed that structurally diverse ERβ-selective agonists also relieved allodynia in CINP caused by taxol, oxaliplatin, and vincristine. These effects were receptor subtype specific and mediated by ERβ receptors as ERα-selective and nonselective estrogen agonists were inactive, a mixture of an ERβ and ERα agonist was inactive, and ERβ-selective antagonists blocked the effects of the ERβ-selective agonists. The efficacy and potency of ERβ-agonists was greater in male rats than females. To address the possibility that AC-186 might stimulate proliferation of cancers, rendering it unsuitable for treating CINP, we evaluated proliferative effects of AC-186 on prostate cancer cells and found it inhibited growth (LNCaP cells) or had no effect (PC3 cells) on these cells. Thus, ERβ-selective agonists exhibit potential for treating CINP.
authors.affiliation: ACADIA Pharmaceuticals Inc. , 3611 Valley Center Drive, Ste. 300, San Diego, California 92130, United States.
authors.forename: Jian-Nong
authors.initials: JN
authors.lastname: Ma
authors.affiliation: ACADIA Pharmaceuticals Inc. , 3611 Valley Center Drive, Ste. 300, San Diego, California 92130, United States.
authors.forename: Krista
authors.initials: K
authors.lastname: McFarland
authors.affiliation: Chemical Biology & Therapeutics, Department of Experimental Medical Science, Lund University , S-221 84 Lund, Sweden.
authors.forename: Roger
authors.initials: R
authors.lastname: Olsson
authors.affiliation: ACADIA Pharmaceuticals Inc. , 3611 Valley Center Drive, Ste. 300, San Diego, California 92130, United States.
authors.forename: Ethan S
authors.initials: ES
authors.lastname: Burstein
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D047629:Estrogen Receptor beta / Q000378:metabolism*; D004967:Estrogens / Q000737:chemistry / Q000627:therapeutic use*; D005260:Female; D006930:Hyperalgesia / Q000188:drug therapy / Q000209:etiology; D008297:Male; D009437:Neuralgia / Q000139:chemically induced* / Q000188:drug therapy* / Q000209:etiology; D010147:Pain Measurement; D017288:Pain Threshold / Q000187:drug effects; D011471:Prostatic Neoplasms / Q000188:drug therapy; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000970:Antineoplastic Agents; D047629:Estrogen Receptor beta; D004967:Estrogens
keywords: Neuropathic pain; chemotherapy; estrogen receptor beta; oxaliplatin; taxol; vincristine