Microglial ablation does not affect opioid-induced hyperalgesia in rodents

Abstract

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 thought to play a critical role in the expression of opioid-induced hyperalgesia (OIH) in animal models. We performed microglial ablation experiments using either a 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 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 OIH.

Development of opioid-induced hyperalgesia depends on reactive astrocytes controlled by Wnt5a signaling

“…Microglia were suggested to modulate neuronal activity via BDNF during OIH expression 11 . However, other studies raise questions about the role of microglia 4, 12 . Astrogliosis is associated with various chronic pain conditions, including OIH models, but its pathogenic contribution has not been tested conclusively 9, 16 .…”

“…1A-1B), consistent with previous observations 35,36 . A critical role of microglia in OIH was proposed in an early study 11 , but inconsistent findings were reported later 4,12 . In this study, we aimed to examine the potential role of reactive astrocytes in OIH development.…”

“…In addition to neuronal malplasticity, opioids also induce reactions of glia, including microglia and astrocytes 9 . Microglia were reported to play a critical role in OIH 11 [but see recent studies by Liu et al 12 ]. Astrocytes are activated in the spinal cords following different paradigms of opioid administration 13, 14 .…”