Abstract
The pro-inflammatory (M1) and anti-inflammatory (M2) status of microglial determines the outcome of neuroinflammation, which contributes to the pathogenesis of chronic morphine tolerance. Studies report that α2-adrenoceptor agonist dexmedetomidine exerts anti-inflammatory effects in inhibiting morphine tolerance in normal and neuropathic pain animals, which has not been studied in cancer pain. Therefore, we investigate the effect of intrathecal DEX on morphine tolerance in cancer pain, and whether dexmedetomidine functions via modulating microglial activation and M1/M2 polarization. 54 Wistar rats with intrathecal catheterization were treated by morphine for 10 days. Test groups received intrathecal α2-adrenoceptor agonist dexmedetomidine or antagonist MK-467. The mRNA levels of TLR4 and NF-κB were tested by RT-PCR. The protein levels of TLR4, NF-κB, Iba-1, iNOS, CD206 were quantifed using Western blotting, and IL-10 and TNF-α were examined by ELISA. Dexmedetomidine attenuates mechanical threshold and thermal latency, and increased the expression of TLR4 and NF-κB in morphine tolerance of cancer pain. Dexmedetomidine attenuates mechanical and thermal nociception in morphine tolerance in cancer pain rats. Intrathecal DEX pre-treatment significantly increased the protein levels of microglia maker Iba-1, M2 marker CD206 and anti-inflammatory factor IL-10, while had no evident influence on the pro-inflammatory factor TNF-α and M1 marker iNOS in morphine tolerance. Our findings suggest that intrathecal dexmedetomidine attenuates morphine tolerance in cancer pain via α2-adrenoceptor pathway. Furthermore, dexmedetomidine upregulates TLR4/NF-κB pathway and induces microglia activation in chronic morphine tolerance of cancer pain. The anti-inflammatory effect of dexmedetomidine might be exerted by inducing microglia M2 polarization and increasing anti-inflammatory factor IL-10.
Antinociception occurs with a reversal in α2-adrenoceptor regulation of TNF production by peripheral monocytes/macrophages from pro- to anti-inflammatory
