The role of glutamate release mediated by extrasynaptic P2X7 receptors in animal models of neuropathic pain

Purinergic signaling represents a major non-synaptic signaling mechanism in the normal and pathological nervous system. The expression of the purinergic ligand gated ion channel P2X7 receptor (P2rx7) has been described on nerve terminals as well as in non-neuronal cells, such as astrocytes and microglia. The activation of P2rx7s results in Ca2+ influx and increased transmitter release in the brain. P2rx7s previously suggested having a pivotal role in different pain modalities, including neuropathic pain. Here we investigated whether the activation of P2rx7 leads to increased glutamate release from the spinal cord in an experimental model of neuropathic pain (partial nerve ligation of the sciatic nerve, PNL). One week after surgery, we studied the effects of PNL on tactile allodynia using aesthesiometry, in parallel with the in vitro release of [3H]glutamate from lumbar spinal cord slices. The observed allodynia in wild-type (P2rx7+/+) mice one week after PNL surgery was lower that was observed in P2rx7 deficient (P2rx7−/−) animals. Perfusion of spinal cord slices with ATP (10 mM) elicited [3H]glutamate release in both sham operated and neuropathic P2rx7+/+ animals. The ATP-induced [3H]glutamate release was absent in P2rx7−/− mice. Electrically evoked release of [3H]glutamate from spinal cord slices was not significantly altered in PNL animals and in P2rx7−/− mice. The results suggest that activation of P2rx7 by ATP releases glutamate in the spinal cord, which might contribute to mechanical allodynia following PNL. On the other hand, this release does not contribute to glutamate efflux evoked by conventional neuronal activity, which is consistent with the idea that P2X7 receptors are either extrasynaptic or expressed on non-neuronal cells.This article is part of a Special Issue entitled ‘Extrasynaptic ionotropic receptors’.

► Neuropathic pain is alleviated in the absence of P2X7 receptors.
► The activation of P2X7 receptors releases glutamate from spinal cord slices.
► Extrasynaptic P2X7 receptors mediate the facilitation of glutamate release.