Emodin suppresses oxaliplatin-induced neuropathic pain by inhibiting COX2/NF-κB mediated spinal inflammation.

Oxaliplatin (OXA) is a common chemotherapy drug for colorectal, gastric, and pancreatic cancers. The anticancer effect of OXA is often accompanied by neurotoxicity and acute and chronic neuropathy. The symptoms present as paresthesia and pain which adversely affect patients' quality of life. Herein, five consecutive intraperitoneal injections of OXA at a dose of 4 mg/kg were used to mimic chemotherapy. OXA administration induced mechanical allodynia, activated spinal astrocytes, and increased inflammatory response. To develop an effective therapeutic measure for OXA-induced neuropathic pain, emodin was intrathecally injected into OXA rats. Emodin developed an analgesic effect, as demonstrated by a significant increase in the paw withdrawal threshold of OXA rats. Moreover, emodin treatment reduced the pro-inflammatory cytokines (tumor necrosis factor-α and interleukin-1ß) which upregulated in OXA rats. Furthermore, autodock data showed four hydrogen bonds were formed between emodin and cyclooxygenase-2 (COX2), and emodin treatment decreased COX2 expression in OXA rats. Cell research further proved that emodin suppressed nuclear factor κB (NF-κB)-mediated inflammatory signal and reactive oxygen species level. Taken together, emodin reduced spinal COX2/NF-κB mediated inflammatory signal and oxidative stress in the spinal cord of OXA rats which consequently relieved OXA-induced neuropathic pain.

SIRT1 activation by SRT1720 attenuates bone cancer pain via preventing Drp1-mediated mitochondrial fission.

Bone cancer pain (BCP) is the pain induced by primary bone cancer or tumor metastasis. Increasing evidence and our previous studies have shown that mammalian silent information regulator 2 homolog (SIRT1) is involved in periphery sensitization and central sensitization of BCP, and the underlying mechanism of SIRT1 in bone cancer pain may provide clues for pain treatment. Dynamin-related protein 1 (Drp1) is an essential regulator for mitochondrial fission. In this research, BCP model rats were established by injecting MRMT-1 rat mammary gland carcinoma cells into the left tibia of female Sprague-Dawley rats and validated by tibia radiographs, histological examination and mechanical pain test. As a result BCP rats exhibited bone destruction and sensitivity mechanical pain. BCP increased inflammatory cells infiltration and apoptosis, reduced SIRT1 protein expression and phosphorylation, and elevated Drp1 expression in spinal cord. An agonist of SIRT1 named SRT1720 intrathecal treatment in BCP rats increased SIRT1 phosphorylation, reduced the up-regulated Drp1 expression, and reversed pain behavior. SRT1720 also regulated Bcl-2/BAX and cleaved caspase-3 expressions, and inhibited mitochondrial apoptosis in spinal cord of BCP rats. For in vitro research, SRT1720 treatment decreased Drp1 expression in a dose-dependent manner, blocked CCCP-induced mitochondrial membrane potential change, consequently reduced apoptosis and promoted proliferation. These data suggest that SIRT1 activation by SRT1720 attenuated bone cancer pain via preventing Drp1-mediated mitochondrial fission. Our results provide new targets for therapeutics of bone cancer pain.

Prokineticin 2 suppresses GABA-activated current in rat primary sensory neurons.

Prokineticin 2 (PK2) is a newly identified regulatory protein, which is involved in a wide range of physiological processes including pain perception in mammals. However, the precise role of PK2 in nociception is yet not fully understood. Here, we investigate the effects of PK2 on GABA(A) receptor function in rat trigeminal ganglion neurons using whole-cell patch clamp technique. PK2 reversibly depressed inward currents produced by GABA(A) receptor activation (I(GABA)) with an IC50 of 0.26 ± 0.02 nM. PK2 appeared to decrease the efficacy of GABA to GABA(A) receptor but not the affinity. The maximum response of the GABA dose-response curve decreased to 71.2 ± 7.0% of control after pretreatment with PK2, while the threshold value and EC50 of curve did not alter significantly. The effects of PK2 on I(GABA) were voltage independent. The PK2-induced inhibition of I(GABA) was removed by intracellular dialysis of either GDP-ß-S (a non-hydrolyzable GDP analog), EGTA (a Ca²+ chelator) or GF109203X (a selective protein kinase C inhibitor), but not by H89 (a protein kinase A inhibitor). These results suggest that PK2 down-regulates the function of the GABA(A) receptor via G-protein and protein kinase C dependent signal pathways in primary sensory neurons and this depression might underlie the hyperalgesia induced by PK2.