(+)-Naloxone inhibits morphine-induced chemotaxis via prevention of heat shock protein 90 cleavage in microglia

Abstract

Microglia have a crucial role in maintaining neuronal homeostasis in the central nervous system. Immune factors released from microglia have important roles in nociceptive signal transduction. Activation of microglia seems to be a shared mechanism in pathological pain and morphine tolerance because pharmacological attenuation of microglia activation provides satisfactory management in both situations. Methods: In the present study, we investigated the effect of 1nM (+)-naloxone, which is not an opioid receptor antagonist, on morphine-induced activation of microglia EOC13.31 cells. Results: Our results showed that 1μM morphine enhanced microglia activation and migration, decreased α-tubulin acetylation, and induced heat shock protein 90 (HSP90) fragmentation and histone deacetylase 6 (HDAC6) expression. Morphine-induced α-tubulin deacetylation and HSP90 fragmentation were HDAC6-dependent. Pretreatment with (+)-naloxone (1nM) inhibited morphine-evoked microglia activation and chemotaxis and prevented α-tubulin deacetylation and HSP90 fragmentation by inhibiting HDAC6 expression. Conclusion: Based on the findings of the present study, we suggest that (+)-naloxone inhibits morphine-induced microglia activation by regulating HDAC6-dependent α-tubulin deacetylation and HSP90 fragmentation.

Keywords

• cytoskeleton
• morphine tolerance
• neuroinflammation
• protrusion
• ruffling