Synaptic NMDA Receptors in Spinal Cord Pain Signalling

Michael Hildebrand

Carleton University

The inability to effectively treat and manage chronic pain is one of the major public health challenges facing Canada today. The spinal cord dorsal horn is an essential component of the pain transmission pathway, with an output to brain pain centers controlled by opposing excitatory and inhibitory inputs. For excitation, activation of NMDA receptors (NMDARs) determines both electrical integration and downstream biochemical signalling in CNS neurons, with functional specialization conferred by the GluN2 NMDAR subunit. A central tenet of glutamatergic transmission in the adult CNS is that GluN2A is the dominant mediator of synaptic NMDAR responses whereas GluN2B and GluN2C play minor roles and GluN2D none whatsoever. Using a spinal cord slice recording preparation, we discovered NMDAR-mediated synaptic responses in dorsal horn neurons that contravene this rule. Unlike the adult brain, we found that GluN2A-containing receptors contribute little to synaptic NMDAR responses while GluN2B and GluN2D dominate at synapses of the adult dorsal horn, providing the molecular underpinnings for the slow, prolonged and feedforward amplification that is a fundamental characteristic of pain. Moreover, we found that these synaptic NMDAR responses are potentiated through a BDNF disinhibition pathway in animal models of neuropathic pain. We propose that a removal of the inhibitory brakes for dorsal horn excitability (BDNF disinhibition) directly acts to facilitate dorsal horn excitation (NMDAR potentiation), leading to enhanced dorsal horn output and pain hypersensitivity. We have therefore identified specific NMDAR subunits and associated regulators that may constitute novel therapeutic targets for the treatment of chronic pain.