Microglial ablation does not affect opioid-induced hyperalgesia in rodents

Opioids are the frontline analgesics in pain management. However, chronic use of opioid analgesics causes paradoxical pain that contributes to the decrease of their efficacy in pain control and the escalation of dose in long-term management of pain. The underling pathogenic mechanism is not well understood. Microglia have been commonly believed to play a critical role in the expression of opioid-induced hyperalgesia in animal models. We performed microglial ablation experiments using either genetic (CD11b-diphtheria toxin receptor transgenic mouse) or pharmacological (colony-stimulating factor-1 receptor inhibitor PLX5622) approaches. Surprisingly, ablating microglia using these specific and effective approaches did not cause detectable impairment in the expression of hyperalgesia induced by morphine. We confirmed this conclusion with a behavioral test of mechanical and thermal hyperalgesia, in male and female mice, and with different species (mouse and rat). These findings raise caution about the widely assumed contribution of microglia to the development of opioid-induced hyperalgesia.