Although opioid analgesics exhibit potent antinociceptive effects, various side effects including antinociceptive tolerance limit their effective clinical use. Our previous studies show that neuronal receptor transporter protein 4 (RTP4), one of the receptor chaperone proteins, contributes to the mechanism of development of morphine tolerance. Although, studies suggest that glial as well as neuronal cells contribute to antinociceptive tolerance, the role of glial RTP4 on opiate induced tolerance has not yet been elucidated. Here, we examined the changes in RTP4 levels in microglial cells after morphine exposure.
We find that morphine treatment (1 mM, 24-hr) significantly up-regulates RTP4 mRNA levels in a microglial cell line, SIM-A9 cell. This up-regulation was not reversed by naltrexone, a mu opioid receptor antagonist, while it was significantly inhibited by a neutralizing antibody targeting toll-like receptor 4 (TLR4) and by a janus kinase (JAK) inhibitor. Furthermore, interferon (IFN)-β mRNA levels were increased by morphine treatment.
These findings suggest that in microglial cells, morphine activates TLR4, leading to type I IFN production, IFN receptor and JAK activation, and finally to RTP4 gene induction.