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  • Title: Spinal interleukin-10 produces antinociception in neuropathy through microglial β-endorphin expression, separated from antineuroinflammation.
    Author: Wu HY, Mao XF, Tang XQ, Ali U, Apryani E, Liu H, Li XY, Wang YX.
    Journal: Brain Behav Immun; 2018 Oct; 73():504-519. PubMed ID: 29928964.
    Abstract:
    Interleukin 10 (IL-10) is antinociceptive in various animal models of pain without induction of tolerance, and its mechanism of action was generally believed to be mediated by inhibition of neuroinflammation. Here we reported that intrathecal IL-10 injection dose dependently attenuated mechanical allodynia and thermal hyperalgesiain male and female neuropathic rats, with ED50 values of 40.8 ng and 24 ng, and Emax values of 61.5% MPE and 100% MPE in male rats. Treatment with IL-10 specifically increased expression of the β-endorphin (but not prodynorphin) gene and protein in primary cultures of spinal microglia but not in astrocytes or neurons. Intrathecal injection of IL-10 stimulated β-endorphin expression from microglia but not neurons or astrocytes in both contralateral and ipsilateral spinal cords of neuropathic rats. However, intrathecal injection of the β-endorphin neutralizing antibody, opioid receptor antagonist naloxone, or μ-opioid receptor antagonist CTAP completely blocked spinal IL-10-induced mechanical antiallodynia, while the microglial inhibitor minocycline and specific microglia depletor reversed spinal IL-10-induced β-endorphin overexpression and mechanical antiallodynia. IL-10 treatment increased spinal microglial STAT3 phosphorylation, and the STAT3 inhibitor NSC74859 completely reversed IL-10-increased spinal expression of β-endorphin and neuroinflammatory cytokines and mechanical antiallodynia. Silence of the Bcl3 and Socs3 genes nearly fully reversed IL-10-induced suppression of neuroinflammatory cytokines (but not expression of β-endorphin), although it had no effect on mechanical allodynia. In contrast, disruption of the POMC gene completely blocked IL-10-stimulated β-endorphin expression and mechanical antiallodynia, but had no effect on IL-10 inhibited expression of neuroinflammatory cytokines. Thus this study revealed that IL-10 produced antinociception through spinal microglial β-endorphin expression, but not inhibition of neuroinflammation.
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