Involvement of Spinal Microglial P2X ₇ Receptor in Generation of Tolerance to Morphine Analgesia in Rats

Abstract

Morphine loses analgesic potency after repeated administration. The underlying mechanism is not fully understood. Glia are thought to be involved in morphine tolerance, and P2X ₇ purinergic receptor (P2X ₇R) has been implicated in neuron–glia communication and chronic pain. The present study demonstrated that P2X ₇R immunoreactivity was colocalized with the microglial marker OX42, but not the astrocytic marker GFAP, in the spinal cord. The protein level of spinal P2X ₇R was upregulated after chronic exposure to morphine. Intrathecal administration of Brilliant Blue G (BBG), a selective P2X ₇R inhibitor, significantly attenuated the loss of morphine analgesic potency, P2X ₇R upregulation, and microglial activation. Furthermore, RNA interference targeting the spinal P2X ₇R exhibited a similar tolerance-attenuating effect. Once morphine analgesic tolerance is established, it was no longer affected by intrathecal BBG. Together, our results suggest that spinal P2X ₇R is involved in the induction but not maintenance of morphine tolerance.