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

Abstract

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.

The spinal microglial IL-10/β-endorphin pathway accounts for cinobufagin-induced mechanical antiallodynia in bone cancer pain following activation of α7-nicotinic acetylcholine receptors

“…Cancer pain particularly bone cancer pain remains to be one of the most challenging symptoms to control [36,51]. Current major drug treatment for advanced cancer pain is strong opioids, such as morphine, methadone, oxycodone, hydromorphone, and fentanyl [26].…”

The Expanding Therapeutic Potential of Neuronal KCC2

“…The latter is a downstream target of SIRT1 [123]. Resveratrol is known to be anti-nociceptive and inhibits neuropathic pain [124,125], and also appears to be anti-epileptic [126]. In these regards, its upregulation of KCC2 is in line with a general protection against the consequences of KCC2 dysfunction.…”

SIRT1: A promising therapeutic target for chronic pain

“…However, SRT1720 (an activator of SIRT1) treatment reverses pain behavior in BCP rats and upregulates SIRT1. 114,115 Neurons are metabolically active cells with high energy demands and are particularly dependent on mitochondrial function. 116 Dynamin-related protein 1 (Drp1), a cytosolic guanosine-5′-triphosphatase, migrates between the cytosol and mitochondrial network and binds to the mitochondrial outer membrane, driving mitochondrial fission.…”

“…SIRT1 expression and activity are lower in rats with BCP. However, SRT1720 (an activator of SIRT1) treatment reverses pain behavior in BCP rats and upregulates SIRT1 114,115 . Neurons are metabolically active cells with high energy demands and are particularly dependent on mitochondrial function 116 .…”