Estrogen Receptor Beta Selective Agonists as Agents to Treat Chemotherapeutic-Induced Neuropathic Pain

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.

Neuropathic pain; chemotherapy; estrogen receptor beta; oxaliplatin; taxol; vincristine.