Spinal sirtuin 2 attenuates bone cancer pain by deacetylating FoxO3a.

Bone cancer pain (BCP) is refractory to currently used analgesics. Recently, sirtuin 2 (SIRT2) was reported to play a vital role in neuropathic pain but its role in BCP remains unknown. It was hypothesized that spinal SIRT2 attenuates BCP by deacetylating FoxO3a and suppressing oxidative stress. The mouse model of BCP established by injecting tumor cells into the intramedullary space of the femur demonstrated that spinal SIRT2 and FoxO3a were downregulated in BCP development. Intrathecal administration of LV-SIRT2 reduced pain hypersensitivity (mechanical and thermal nociception) in BCP mice. Spinal SIRT2 overexpression upregulated FoxO3a and antioxidant genes (SOD2 and catalase) and inhibited FoxO3a acetylation, phosphorylation, and ubiquitination. Moreover, intrathecal administration of SIRT2 shRNA induced pain hypersensitivity in normal mice. Spinal SIRT2 knockdown downregulated FoxO3a and antioxidant genes and increased FoxO3a acetylation, phosphorylation, and ubiquitination. In summary, spinal SIRT2 increases FoxO3a expression in BCP mice and inhibits oxidative stress by deacetylating FoxO3a and further reducing FoxO3a phosphorylation, ubiquitination, and degradation, leading to BCP relief.

A comparative study on the effect of dopamine vs phenylephrine in improving the cutaneous analgesic effect of mexiletine in rats.

BACKGROUND: The present study aimed to compare the effects of the combined administration of two adjuvants, dopamine and phenylephrine, on the cutaneous analgesic effect and duration of mexiletine in rats. METHODS: Nociceptive blockage was evaluated by the inhibition of response to skin pinpricks in rats via the cutaneous trunci muscle reflex (CTMR). After subcutaneous injection, the analgesic activities of mexiletine in the absence and presence of either dopamine or phenylephrine were assessed. Each injection was standardized into 0.6 ml with a mixture of drugs and saline. RESULTS: Subcutaneous injections of mexiletine successfully induced dose-dependent cutaneous analgesia in rats. The results revealed that rats injected with 1.8 µmol mexiletine exhibited 43.75% blockage (%MPE), while rats injected with 6.0 µmol mexiletine showed 100% blockage. Co-application of mexiletine (1.8 or 6.0 µmol) with dopamine (0.06, 0.60, or 6.00 µmol) elicited full sensory block (%MPE). Sensory blockage ranged from 81.25% to 95.83% in rats injected with mexiletine (1.8 µmol) and phenylephrine (0.0059 or 0.0295 µmol), and complete subcutaneous analgesia was observed in rats injected with mexiletine (1.8 µmol) and a higher concentration of phenylephrine (0.1473 µmol). Furthermore, mexiletine at 6.0 µmol completely blocked nociception when combined with any concentration of phenylephrine, while 0.1473 µmol phenylephrine alone exhibited 35.417% subcutaneous analgesia. The combined application of dopamine (0.06/0.6/6 µmol) and mexiletine (1.8/6 µmol) resulted in increased %MPE, complete block time, full recovery time, and AUCs compared to the combined application of phenylephrine (0.0059 and 0.1473 µmol) and mexiletine (1.8/6 µmol) (p < 0.001). CONCLUSION: Dopamine is superior to phenylephrine in improving sensory blockage and enhancing the duration of nociceptive blockage by mexiletine.

A comparative study of serotonin and norepinephrine as adjuncts to improve cutaneous antinociception of mexiletine in response to skin pinpricks in rats.

As adrenaline, serotonin and norepinephrine are two other vasoconstrictors and both of which have been proved to increase the quality and duration of local anesthetics when added as adjuvants. However, the difference in the improvement of the nociception of local anesthetics between the two adjuvants remains unclear. The purpose of this study was to assess the cutaneous nociception of mexiletine by coadministration with serotonin and norepinephrine. Subcutaneous injection of drugs or combinations includes mexiletine 0.6, 1.8, 6.0 µmol, serotonin 1.6500 µmol, noradrenaline 0.8895 nmol, saline, mexiletine 1.8 and 6.0 µmol, respectively combined with serotonin 0.4125, 0.8250, 1.6500 µmol and noradrenaline 0.0356, 0.1779, 0.8895 nmol, with each injection dose of 0.6 ml. The nociception of mexiletine alone and mexiletine coadministered with serotonin and norepinephrine was assessed after subcutaneous injection. Subcutaneous injections of mexiletine elicited dose-related cutaneous antinociception (P < 0.05, 0.01, or 0.001). Compared with mexiletine (1.8 µmol), adding norepinephrine (except for lowest dose) and serotonin to mexiletine (1.8 µmol) solutions for skin nociceptive block potentiated and prolonged the action (P < 0.01 or 0.001). Mexiletine (6.0 µmol) combined with norepinephrine and serotonin extended the duration of cutaneous antinociception when compared with mexiletine (6.0 µmol) alone (P < 0.05, 0.01, or 0.001). Both serotonin and norepinephrine improve the sensory block and enhances the nociceptive block duration of mexiletine, and serotonin is superior to that of norepinephrine.