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Cortical integration and control of spontaneous neuropathic pain-like behaviour in mice. BACKGROUND: Spontaneous pain is commonly reported in patients with nerve injuries, posing a great challenge to physicians. However, the mechanisms underlying spontaneous pain remain largely unknown in comparison to evoked pain (e.g. allodynia and hyperalgesia). Cortical processing is vital in coding nociception, and dysfunction of anterior cingulate cortex might facilitate pain hypersensitivity. This indicates a distinct pattern of ensemble activity during spontaneous pain-like behaviour. METHODS: Combining in vivo calcium imaging and ex vivo electrophysiological recording, we explored the maladaptive changes of cortical neurones at individual and population levels induced by several models of neuropathic pain in mice. We also examined the role of the anterior cingulate cortex in the regulation of spontaneous pain-like behaviour using optogenetic methods. RESULTS: We identified a common status of cortical hyperactivity in pyramidal neurones and neural ensembles recorded in the anterior cingulate cortex. Optogenetic inhibition of the anterior cingulate cortex inhibited spontaneous pain-like behaviour, while optogenetic activation restored it. In addition, the cortical representation of spontaneous behaviour was inhibited by nerve injury, which conversely was restored with pain relief. In freely moving animals, we further demonstrated a stable mode of cortical integration in response to spontaneous grooming episodes, independent of the presence of pain, with a dynamic reconfiguration mechanism. CONCLUSIONS: Our data reveal an essential role of the anterior cingulate cortex in the processing and modulation of non-evoked reflex in distinct preclinical models of neuropathic pain in mice.