Nonionotropic NMDA receptor activity enables reversal of pathological pain in mice

Current treatments for chronic pain tend to conceal and dampen nociceptive processing rather than target its root causes. Many forms of chronic pain are thought to involve sensitization of spinal pain networks. Sensitization of nociceptive pathways shares several mechanisms with the strengthening of neuronal pathways in the brain which gives rise to memory. Like memory traces in the brain, it has previously been shown that sensitized nociceptive pathways can be destabilized and modified upon reactivation. However, the cellular mechanisms underlying the destabilization of ‘pain memory traces’ in the spinal cord are poorly understood. UTCSP member Dr. Rob Bonin and his colleagues performed a battery of behavioural, molecular, and electrophysiological experiments in mice to study the cellular mechanisms involved in the reversal of pain hypersensitivity.

To selectively reverse mechanical hypersensitivity in commonly used mouse models of pain, the authors of this study leveraged parallels between pain and memory by focusing on a nonionotropic form of NMDA receptor-mediated signaling involved in the weakening of synaptic connections in the brain. They found that reactivating sensitized sensory pathways, while pharmacologically inducing nonionotropic NMDA receptor activity, reverses mechanical hypersensitivity. Similarly, potentiated spinal cord pathways can be reactivated and weakened ex vivo by nonionotropic NMDA receptor activity. The authors identified specific synaptic proteins that are degraded to reduce mechanical hypersensitivity upon reactivation, many of which are also degraded during memory modification.

The results of this study published in Science Advances reveal a unique signaling pathway which enables reversal of pathological pain in mice by targeting its underlying cellular causes. Ultimately, gaining a better understanding of the dynamic regulation of pathological pain could lead to new therapeutic options for treating chronic pain conditions in humans.

The results of this study published in Science Advances reveal a unique signaling pathway which enables reversal of pathological pain in mice by targeting its underlying cellular causes.