Introduction

Hippocampal long-term potentiation (LTP) is a well investigated form of synaptic plasticity in the central nervous system. In the hippocampus, LTP is an activity-dependent form of synaptic plasticity in which increased synaptic transmission follows brief, high-frequency stimulation of input pathways. Three different major types of glutamate receptors have been found in the hippocampus: N-methyl-d-aspartic acid (NMDA), α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) and metabotropic glutamate receptors (mGluRs). While AMPA receptors (AMPARs) mediate normal synaptic transmission, activation of NMDA receptors (NMDARs) is required for the induction of LTP. Pre-treatment with the NMDAR antagonist d-2-amino-5-phosphonopentanoic acid (AP5) prevents the induction of LTP. Subsequent pharmacological and genetic studies have confirmed that NMDAR LTP in the hippocampus play important roles in spatial memory of the hippocampus [1]. New mechanism for the synaptic plasticity in the hippocampus has been cumulatively reported (for example, see [2]). In this article that contributes to the special issue for the discovery of NMDAR LTP by Prof. Graham Collingridge, we will review the roles of NMDAR LTP in pain systems, especially in the condition of chronic pain.

Basic Circuitry of Pain: From Periphery to the Cortex

Glutamate is the fast excitatory transmitter of first sensory synapses. Peripheral noxious stimuli activate nociceptive afferent fibers (Aδ and C fibers) and incoming action potentials trigger a release of glutamate in the spinal dorsal horn. In addition, some neuropeptides such as substance P (SP) and neurokinin A (NKA) are also released in the spinal dorsal horn. Glutamate and neuropeptides activate spinal dorsal horn neurons, including those that send projection terminals to supraspinal structures. Neurons in the thalamus play key roles in relaying these ascending inputs to different cortical area. Among them, anterior cingulate cortex (ACC) and insular cortex (IC) are believed to be critical the unpleasantness of pain. As protective responses to noxious stimuli, endogenous pain modulatory systems are also activated. Descending modulatory systems are biphasic, including descending inhibitory and facilitatory systems. LTP has been reported in synapses located in spinal cord dorsal horn and cortex that are related to pain.

NMDAR LTP in Spinal Dorsal Horn

Glutamate is a major transmitter between primary afferent fibers and spinal dorsal horn neurons, whereas neuropeptides (e.g., SP and NKA) mediate slow excitatory postsynaptic potentials (EPSPs) at synapses between small-myelinated Aδ and unmyelinated C fibers and dorsal horn neurons [3,4,5,6]. Fast excitatory synaptic transmission is mainly mediated by AMPAR and kainate receptor (KAR) [7]. In some synapses (or called silent synapses), synaptic responses can be mediated by pure NMDARs [4].

Unlike with the hippocampus, studies of spinal LTP are limited by the technical difficulty of spinal cord slices and the complexity of the spinal local neuronal network. Electrophysiological experiments using intracellular or whole-cell patch-clamp recordings from the spinal dorsal horn neurons generate some important findings related to spinal LTP. Strong tetanic stimulation (100 Hz, 1 s for three times at 10 s intervals) of the dorsal root induces long-lasting enhancement of synaptic responses to presynaptic stimulation [8, 9]. The enhancement is relatively long-lasting (ranging from 25 to 90 min) and input specific. Postsynaptic depolarization of dorsal horn neurons is critical for the induction of spinal LTP. Pairing postsynaptic depolarization with synaptic activity also induces long-lasting enhancement of synaptic responses. Interestingly, the level of postsynaptic depolarization may be important in determining whether synaptic transmission will be potentiated or depressed. In some experiments, synaptic depression can also be induced by pairing synaptic activity with modest postsynaptic depolarization. The induction of spinal LTP requires activation of NMDARs and/or the SP (NK1) receptors. Activation of NMDARs in spinal dorsal horn neurons leads to increases in intracellular Ca2+ [10]. Pre-treatment of spinal cord slices with an NMDAR antagonist AP5 prevents the induction of LTP. The contribution of neuropeptide SP to spinal LTP may act by enhancing NMDAR mediated currents in spinal dorsal projecting neurons [8]. The intracellular signal pathways of spinal LTP remain to be fully mapped. Evidence from other studies indirectly indicates that several protein kinases may be important for spinal LTP, such as phospholipid-dependent protein kinase C (PKC). Phorbol ester induces long-lasting facilitation of evoked EPSPs or EPSCs (excitatory postsynaptic currents) amplitude to stimulation of presynaptic fibers [11, 12]. One possible mechanism for PKC-dependent spinal LTP is through the recruitment of spinal silent synapses or the insertion of AMPARs. Brain-derived neurotrophic factor (BDNF) can induce NMDAR LTP in spinal dorsal horn via different signaling pathways [13].

Early Genetic Studies of NMDAR GluN2B (Also Known as NR2B) in Pain-Related Cortex

In addition to the spinal cord, early studies suggest that NMDAR in supraspinal structures may contribute to persistent or chronic pain. Direct evidence for the contribution of NMDARs in forebrains to behavioral nociceptive responses comes from genetic studies of NMDAR GluN2B transgenic mice. Tang et al. generated transgenic mice with forebrain-targeted GluN2B overexpression, and the normal developmental change in NMDAR kinetics was reversed [14]. GluN2B subunit expression was observed extensively throughout the cerebral cortex including the ACC and IC. In both the ACC and IC, GluN2B expression was significantly increased, and NMDAR mediated responses were enhanced [15]. Interestingly, while transgenic mice and wild-type mice were indistinguishable in tests of acute nociception, GluN2B transgenic mice exhibited enhanced behavioral responses after peripheral inflammation. These findings provide the first genetic evidence that forebrain NMDARs play a critical role in chronic pain.

NMDAR Dependent Postsynaptic LTP (Post-LTP) in the ACC

Stimulation Protocols

Among sensory-related cortical areas, LTP is well investigated in the ACC. In the ACC slices of adult animals, different stimulation protocols can be used to induce LTP using field recording and whole-cell patch-clamp recording techniques [16, 17]. For field recording from adult rat or mouse ACC slices, glutamatergic synapses in the ACC can undergo LTP in response to theta burst stimulation (TBS), a paradigm more closely to the activity of the ACC neurons. The potentiation lasted for at least 40–120 min [18]. Unlike the hippocampus, strong tetanic stimulation in the ACC did not cause reliable LTP. Whole-cell patch-clamp recordings allow better investigation of synaptic mechanisms for LTP in the ACC [16]. LTP can be induced using three different protocols, including the pairing training protocol, the spike-timing (spike-EPSPs) protocol, and TBS protocol [16, 19]. LTP induced by the pairing protocol is mainly triggered by the activation of NMDARs, but not through L-type voltage-gated calcium channels (L-VGCCs) [16].

NMDAR Dependent ACC LTP

In the ACC, NMDAR containing GluN2A or GluN2B subunits contribute to most NMDAR currents [16]. Bath application of a NMDAR GluN2A antagonist (NVP-AAM077) and GluN2B antagonist (ifenprodil/Ro compounds) produce almost completely blockade of NMDAR mediated EPSCs. Application of NMDAR GluN2A or GluN2B antagonist reduces ACC LTP, without complete abolishment of LTP. LTP is only abolished after the co-application of both inhibitors [16]. It is noted that LTP induced by spike-timing protocol seems to be more sensitive to NMDAR GluN2B blockade as compared with effects on LTP induced by pairing training protocol [16].

NMDAR Dependent Calcium Influx

Calcium (Ca2+) signaling is critical for the induction of NMDAR LTP [16, 20]. Using the two-photon imaging method, it has been shown that NMDARs contribute to postsynaptic Ca2+ signal increases induced by different synaptic stimulation in ACC pyramidal neurons. Furthermore, LTP inducing protocols also triggered postsynaptic Ca2+ influx, which were NMDAR dependent [19]. These studies provide the first direct study of Ca2+ signals in the ACC and demonstrate that NMDARs play important roles in postsynaptic Ca2+ signals (see Fig. 1). As a result of postsynaptic increase of Ca2+, Ca2+ binds to calmodulin (CaM) and leads to activation of Ca2+-stimulated signaling pathways [21]. In support of the role of Ca2+ in LTP, postsynaptic injection of 1,2-bis(o-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid (BAPTA) completely blocked the induction of LTP [16]. Furthermore, a study using electroporation of mutant CaM in the ACC suggests that Ca2+ binding sites of CaM are critical for the induction of cingulate LTP [21].

Fig. 1
figure 1

Reproduced with permission from Li et al. [19] and Wu et al. [51]

NMDAR dependent LTP in the ACC. A Neurons in the ACC receive sensory afferents from the thalamus. Synaptic LTP is believed to be the key cellular mechanism for chronic pain in the ACC. LTP can be blocked by NMDAR antagonist AP5. B NMDAR mediated postsynaptic calcium signals in the ACC neurons. Representative calcium transient waveforms and average traces of fluorescence changes (ΔF/F) in responsive spines evoked by puff-application of glutamate in the control artificial cerebro-spinal fluid (ACSF), presence of CNQX (20 µM), and AP5 (50 µM) in the ACC, respectively. C ACC microinjection NMDAR antagonists reduced chronic pain. The NR2B receptor antagonists Ro 25-6981 and Ro 63-1908 microinjected into the ACC significantly reduced mechanical allodynia in the CFA injection 3 days mice.

Full size image

Downstream Intracellular Signaling Pathways

Cyclic AMP (cAMP) signaling pathways are important signaling pathways in biological systems. Among more than 10 adenylyl cyclase (AC) subunits, AC subtype 1 (AC1) and subtype 8 (AC8) are two AC subtypes that respond positively to Ca2+–CaM [

Abbreviations

AC:

Adenylyl cyclase

ACC:

Anterior cingulate cortex

AMPA:

α-Amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid

AP5:

d-2-Amino-5-phosphonopentanoic acid

BAPTA:

1,2-Bis(o-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid

BDNF:

Brain-derived neurotrophic factor

CaM:

Calmodulin

cAMP:

Cyclic AMP (cAMP)

CNQX:

6-Cyano-7-nitroquinoxaline-2,3-dione

CP-AMPARs:

Ca2+ permeable AMPA receptors

CPP:

3-(R-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid

CTA:

Conditioned taste aversion

EPSCs:

Excitatory postsynaptic currents

EPSPs:

Excitatory postsynaptic potentials

IC:

Insular cortex

KAR:

Kainate receptor

LTP:

Long-term potentiation

mGluRs:

Metabotropic glutamate receptors

NAPSM:

1-Naphthyl acetyl spermine

NKA:

Neurokinin A

NMDA:

N-Methyl-d-aspartate

PDZ:

Postsynaptic density-95/Discs large/zona occludens-1

PKC:

Protein kinase C

PKMζ:

Protein kinase Mζ

PPF:

Paired-pulse facilitation

SP:

Substance P

ZIP:

ζ-Pseudosubstrate inhibitory peptide

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Authors and Affiliations

  1. Center for Neuron and Disease, Frontier Institute of Science and Technology, **’an Jiaotong University, **’an, 710049, Shaanxi, China

    Xu-Hui Li & Min Zhuo

  2. Department of Physiology, Faculty of Medicine, University of Toronto, Medical Science Building, 1 King’s College Circle, Toronto, ON, M5S 1A8, Canada

    Xu-Hui Li, Hui-Hui Miao & Min Zhuo

  3. Department of Physiology, Faculty of Medicine, University of Toronto, Medical Science Building, Room #3328, 1 King’s College Circle, Toronto, ON, M5S 1A8, Canada

    Min Zhuo

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Li, XH., Miao, HH. & Zhuo, M. NMDA Receptor Dependent Long-term Potentiation in Chronic Pain. Neurochem Res 44, 531–538 (2019). https://doi.org/10.1007/s11064-018-2614-8

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