The actions of morphine on microglia and the underlying effects on associated adverse effects.

Morphine and other opioid receptor agonists are the gold-standard treatments for acute and chronic pain states due to their efficient and persistent analgesic effects. However, side effects limit the application of opioid drugs, with morphine misuse causing related deaths at an estimated incidence of 0.3% to 4%. Therefore, a comprehensive understanding of pharmacological actions of morphine, especially its adverse effects, may facilitate the exploration of potential treatments. Microglia, the predominant immune cells in the brain, regulate inflammation, synaptic plasticity, and pain, all of which affect morphine functions. Accumulating evidence has confirmed that morphine modulates the state of microglia and regulates the release of cell factors, thereby manipulating neuronal functions and influencing the related side effects. Here, we reviewed the regulatory effects of morphine on microglia from the perspective of the activation of microglial µ opioid receptor (MOR), δ opioid receptor (DOR), κ opioid receptor (KOR), and toll-like receptor 4 (TLR4). The associated side effects were also discussed. Studies to limit these adverse consequences by modulating microglial state and microglial endogenous opioid secretion (such as dynorphin and endorphin) were also collected. We further discussed the interactions between microglia and other glial cells in the development of morphine side effects. This review aims to deepen our understanding of opioid pharmacology and pave the way for promising therapies against adverse effects.