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