Rosuvastatin Synergistically Enhances the Antinociceptive Efficacy of Duloxetine in Paclitaxel-Induced Neuropathic Pain in Mice.

Paclitaxel, a widely used cancer chemotherapeutic agent, has high incidence of neurotoxicity associated with the production of neuropathic pain, for which only duloxetine has shown significant but moderate analgesic effect. Since statins, classically used to reduce hypercholesterolemia, have shown antinociceptive effect in preclinical studies on neuropathic pain, we studied whether the antinociceptive efficacy of duloxetine could be synergistically potentiated by rosuvastatin in a model of paclitaxel-induced neuropathy in mice. The astrocytic and microglial responses in the spinal cord of paclitaxel-treated mice were also assessed by measuring GFAP and CD11b proteins, respectively. Paclitaxel treatment did not impair motor coordination and balance in rotarod testing. Rosuvastatin, duloxetine, and the rosuvastatin/duloxetine combination (combined at equieffective doses) dose-dependently decreased mechanical allodynia (ED30, von Frey testing) and thermal hyperalgesia (ED50, hot plate testing) in paclitaxel-treated mice. Isobolographic analysis showed a superadditive interaction for rosuvastatin and duloxetine, as both the ED30 and ED50 for the rosuvastatin/duloxetine combination contained only a quarter of each drug compared to the individual drugs. The rosuvastatin/duloxetine combination reversed paclitaxel-induced GFAP overexpression, indicating that such effects might depend in part on astrocyte inactivation. Results suggest that statins could be useful in synergistically enhancing the efficacy of duloxetine in some chemotherapy-induced neuropathic conditions.

The antinociceptive effect of resveratrol in bone cancer pain is inhibited by the Silent Information Regulator 1 inhibitor selisistat.

OBJECTIVES: To study the antinociceptive effect of single and repeated doses of resveratrol in a bone cancer pain model, and whether this effect is prevented by the Silent Information Regulator 1 (SIRT1) inhibitor selisistat. METHODS: The femoral intercondylar bone of BALB/c mice was injected with 1 000 000 BJ3Z cancer cells. Bone resorption and tumour mass growth (measured by in vivo X-ray and fluorescence imaging), as well as mechanical nociceptive thresholds (von Frey device) and dynamic functionality (rotarod machine), were evaluated during the following 4 weeks. Acute resveratrol (100 mg/kg i.p.) and/or selisistat (10 mg/kg s.c.) were administered on day 14. Chronic resveratrol (100 mg/kg i.p., daily) and/or selisistat (0.5 µg/h s.c., Alzet pump) were administered between days 14 and 20. KEY FINDINGS: Tumour growth gradually incremented until day 31, while mechanical hyperalgesia started on day 3 after cancer cell injection. Acute resveratrol increased the mechanical threshold of pain (peaking at 1.5 h), while the dynamic functionality decreased. Chronic resveratrol produced a sustained antinociceptive effect on mechanical hyperalgesia and improved the loss of dynamic functionality induced by the bone cancer tumour. Selisistat prevented all the effects of resveratrol. CONCLUSIONS: Acute and chronic resveratrol induces antinociceptive effect in the model of metastatic osseous oncological pain, an effect that would be mediated by SIRT1 molecular signalling.

Chronic toxicity study of neosaxitoxin in rats.

Neosaxitoxin (NeoSTX) is a specific reversible blocker of voltage gated sodium channels on excitable cells. In the last decade, it has been tested in a number of interesting clinical trials, however there is still little information available on mammalian toxicity. Rats were treated for 12 weeks with doses of 1, 3 or 6 µg/kg of subcutaneous NeoSTX. At weeks 12 and 17, animals were sacrificed and blood samples collected for hematological and biochemical analysis. Organs were harvested for weight determination and histopathological assessments. The lowest acute toxicity via the intraperitoneal (ip) route was (30.35 µg/kg) and there was no significant difference between intramuscular and subcutaneous routes (11.4 and 12.41 µg/kg). The NeoSTX adiministration did not produce lethality at week 12 and after five weeks of suspension. NeoSTX 6 µg/kg ip produced reductions (p < 0.05) in body weight and food intake, and increased blood level of total and direct bilirubin, GGT and SGOT at week 12; all of these were reversed in the recovery period. NeoSTX 1 and 3 µg/kg ip did not show significant changes with the control group. Histopathological presentations were normal in all groups. This study revealed that NeoSTX is safe in vivo, giving a reliable security margin for its use like a local anesthetic.