NMDA Receptors and Chronic Pain

NMDA Receptors Regulate Spinal Cord Hyperexcitability

NMDA receptors (NMDARs) are critical regulators of neuroplasticity and excitability in the spinal dorsal horn.13 NMDARs are abundant in the dorsal horn, with GluN1 and GluN2A subunits expressed throughout the gray matter, whereas GluN2B subunits are distributed mainly in laminae I–II.14 Repeatedly stimulating C fibers results in a phenomenon called “windup” in which depolarization of neurons in the dorsal horn increases in amplitude.15 Both non-competitive (MK-801) and a competitive (D-CPP) NMDAR antagonists block windup.16Subcutaneous injection of formalin, a model of chronic pain, results in a biphasic pain response in animals. Neural activity generated during the first phase produces changes in CNS function that influence pain processing in the second phase.17 The increased excitability in the spinal dorsal horn caused by formalin can be blocked by NMDAR antagonists.18  Local injection of an adeno-associated virus into the dorsal horn of the spinal cord that results in >80% of NR1 NMDA receptor subunit expression and a corresponding loss of NMDA, but not AMPA currents, almost completely blocked pain hypersensitivity caused by formalin in mice.19 Moreover, NR1 subunit knockdown using intrathecal viral injections blocks the induction of pain hypersensitivity caused by formalin injection, but does not affect pain thresholds in the absence of injury.20 These results indicate that NMDA receptors are critical for central hypersensitivity.

Presynaptic NMDA receptors

Postsynaptic NMDA receptors are blocked by Mg2+ at rest, which is displaced with glutamate binding and neuronal depolarization. Presynaptic NMDA receptors are able to achieve tonic neurotransmitter release without neuronal depolarization.21,22 Unlike classical postsynaptic NMDA receptor, magnesium ions do not inhibit spontaneous neurotransmitter release brought on by presynaptic terminals exposed to glutamate and in the absence of neuronal depolarization.23,24 Consequently, presynaptic NMDARs become tonically active. In opioid-induced hyperalgesia and chronic neuropathic pain conditions, endogenous glutamate activates presynaptic NMDARs.25 Spinal nerve ligation, a model of neuropathic pain, increased evoked EPSC amplitudes compared to sham and increased the probability of neurotransmitter release from presynaptic terminals.26 Activation of presynaptic NMDA receptors increases the release of substance P, the frequency of miniature EPSCs, and pain hypersensitivity in chronic constriction injury and spinal nerve ligation models and a model of calcineurin inhibitor-induced pain syndrome27-29 but does not affect glutamate release in in sham-treated animals. Thus, neuropathic injury changes the regulation of presynaptic NMDA receptors to enhance glutamate release and drive excitability in the spinal dorsal horn. This is consistent with formalin-induced pain discussed above—NMDA receptor antagonism blocks phase 2 of the pain reaction but does not affect phase 1. Furthermore, selective knockdown of primary afferent NMDA receptors does not affect phase 1 of the formalin model of pain, only phase 2.30Likewise, local injections of NMDA receptor antagonists, namely dextrorphan, ketamine and memantine, inhibits phase 2 but not phase 1 response to subcutaneous formalin.31,32

NMDA Receptor-mediated Excitotoxicity Leads to Chronic Neuropathic Pain

Afferent signals from injured nerves cause apoptosis in dorsal horn neurons via glutamate excito-toxicity.33 Peripheral nerve injury leads to an irreversible loss of GABAergic interneurons, which in turn leads to persistent pain hypersensitivity. Targeted deletion of NMDA receptors using a spatially restricted Grin1 knockout or proapoptotic Bcl2-associated X (Bax) knockout prevents this loss of GABAergic inhibition.34 These findings indicate that NMDA receptor-mediated excitotoxicity leads to chronic neuropathic pain, and neuroprotection through genetic alteration of the NMDA receptor blocks the transition to chronic pain.

NMDA Receptors Affect Higher Pain Processing Centers in the Brain

Part of the survival benefit of pain is that it creates a persistent memory of the pain-inducing event. Painful stimuli can be used in mammalian fear conditioning to study learning and memory. The more painful the unconditioned stimulus, the fewer presentations of the stimulus are required to create an aversive association.35 Likewise, extinguishing the conditioned stimulus is critical to overcome the fear associated with conditioned stimuli. Indeed, disorders such as PTSD, specific phobia, social anxiety disorder, and chronic pain have been conceptualized as disorders of impaired fear extinction.36,37 The NMDA receptor is critical to the formation and extinction of fear memories.38-42