The circadian clock component REV-ERBs is an analgesic target for cancer-induced tactile pain hypersensitivity

Neuropathic pain is one of the most intractable pain conditions associated with tumor growth compressing and damaging nerves. A troublesome hallmark symptom of neuropathic pain is hypersensitivity to innocuous stimuli, known as “tactile allodynia,” which is often refractory to currently available analgesics. Diurnal variations in pain hypersensitivity are common in patients with cancer, but the underlying mechanisms are enigmatic. Herein, we report that spinal expression of lipocalin-2 (LCN2) enhances pain sensitivity of NCTC2472 fibrosarcoma-implanted male mice during specific stages of the diurnal cycle. As the tumor grew, interleukin-6 (IL-6) levels increased in the spinal cord of the mice. Increased IL-6 levels stimulated LCN2 expression in spinal microglia, but this expression was periodically repressed by the circadian clock components REV-ERBα and REV-ERBβ. Notably, intra-spinal dorsal horn injection of lentiviral vectors expressing REV-ERBα or REV-ERBβ in tumor-bearing mice alleviated tactile allodynia. Furthermore, intrathecal injection of SR9009, a synthetic agonist of REV-ERBs, also attenuated cancer-induced pain hypersensitivity, accompanied by suppressing spinal LCN2 expression. These results suggest that temporal elevation of LCN2 expression decreases the threshold of tactile pain hypersensitivity induced by tumor growth. We propose that the circadian clock component of REV-ERBs is an effective target for alleviation of cancer-induced tactile allodynia, identifying a new class of analgesic agents. Significance statement Spinal expression of lipocalin-2 (LCN2) enhances pain sensitivity of NCTC2472 fibrosarcoma-implanted mice during specific stages of the diurnal cycle. Following tumor growth, an increase in interleukin-6 (IL-6) levels within spinal cord induces the microglial expression of LCN2, which is periodically suppressed by the circadian clock components REV-ERBα and REV-ERBβ. The temporal elevation of LCN2 expression decreases the threshold of tactile allodynia induced by tumor growth. Enhanced expression of REV-ERBs in spinal microglial and their pharmacological activation by the synthetic agonist SR9009 alleviate cancer-induced pain hypersensitivity. These findings reveal the circadian machinery affecting cancer-associated intractable pain and propose that REV-ERBs are an effective target for alleviation of cancer-associated neuropathic pain.