Mechanistic analysis for suppression of neuropathic pain in circadian clock gene deficient mice

Because the expression of up to 10% of genes is under the control of the circadian machinery consisting of clock genes, it should not come as a surprise that the disfunction of clock gene affects the onset and/or state of various disease. Diurnal variations in pain hypersensitivity are common in chronic pain disorders, but pathological relevance of clock genes in neuropathic pain hypersensitivity remains unknown. In this study, we investigated the threshold of mechanical pain hypersensitivity in peripheral sciatic nerve-ligated (PSL) animals and found that clock gene deficient mice (Per2m/m mice) failed to develop the neuropathic pain hypersensitivity. As observed in wild-type mice, PSL- Per2m/m mice also activation of glial cells in the dorsal horn of the spinal cord, as well as increased expression of pain-related molecules. On the other hand, the descending pain suppressor system and endocannabinoid system were upregulated in Per2m/m mice, suggesting that the suppression mechanism against neuropathic pain is enhanced by dysfunction of clock gene. Therefore, Per2m/m mice are less likely to develop pain hypersensitivity even when peripheral nerves are injured. These findings indicate that endogenous pain suppression system are under the control of circadian clock. Identification of circadian clock controlled pain suppressor molecule would be a therapeutic target for treatment of neuropathic pain.