Resveratrol attenuates morphine antinociceptive tolerance via SIRT1 regulation in the rat spinal cord

- Chronic morphine tolerance was induced by intrathecal injections of morphine.
- Heat pain threshold, Ac-H3 and SIRT1 expressions were examined in different groups.
- downregulated SIRT1 and upregulated Ac-H3 in spinal cord after morphine tolerance.
- Resveratrol activated SIRT1 and suppressed Ac-H3 expressions in spinal cord.
- Resveratrol intrathecal injections reverse the morphine tolerance.

In recent years, researchers have begun to pay more attention to the role of Sirtuin 1 (SIRT1, a class III histone deacetylase) in pain. However, little research has been conducted examining the involvement of SIRT1 in chronic morphine tolerance. The aim of this study was to investigate the role of spinal SIRT1 and acetyl-histone H3(Ac-H3) in chronic morphine tolerance in rats. Chronic morphine tolerance was induced by twice-daily intrathecal (i.t.) injections of morphine (10 μg) for 6 days. Control rats received normal saline (NS). Resveratrol (Res, a SIRT1 stimulant, 30 μg i.t.) or dimethyl sulfoxide (DMSO, 10 μl i.t.) was then injected on days 7-13. The thermal paw withdrawal threshold was assessed to determine the analgesic effects of morphine (10 μg). qRT-PCR, western blotting and immunohistochemistry were used to detect the expression of SIRT1 and global Ac-H3. Administration of morphine for 6 days induced a stabilized antinociceptive tolerance, down-regulated SIRT1 expression and up-regulated Ac-H3 expression in the spinal dorsal horn. Resveratrol treatment from day 7 to 13 increased SIRT1 expression, suppressed global Ac-H3 expression compared to the morphine tolerance (MT) group, and significantly reversed morphine antinociceptive tolerance. These results suggest that resveratrol reversed morphine tolerance by upregulating the expression of SIRT1 in the spinal dorsal horn. SIRT1 and global Ac-H3 in the spinal cord may play an important role in the mechanisms of chronic morphine tolerance.

82Resveratrol attenuates the development of morphine antinociceptive tolerance. For tolerance induction, morphine (10 μg i.t.) was injected twice daily for 6 days. To evaluate the possible reversibility of developed tolerance by chronic co-administered Res (30 μg i.t.) and morphine, analgesia produced by morphine (10 μg i.t.) was assessed 30 min after morphine injection. # p < 0.05 compared to NS group; * p < 0.05 compared to MT group.