Pain-induced Synaptic Plasticity in anterior cingulate cortex


Synaptic plasticity refers to the molecular mechanisms that produce long-term changes in the central nervous systemin. These synaptic changes are believed to mediate the modification of various behavioural responses. Interestingly, pain perception is also accompanied by synaptic plasticity in the somatosensory and limbic cortices of the brain. The synaptic changes especially in the anterior cingulate cortex (ACC) are associated with the perception of the chronic neuropathic pain[1]. The inhibition of Protein Kinase M Zeta (PKMζ) in ACC by ζ-pseudosubstrate inhibitory peptide (ZIP) erase synaptic potentiation, and decrease the behavioral response to neuropathic pain in mice. These findings suggest that modification of LTP in ACC can be potential therapeutic treatments for patients suffering from chronic neuropathic pain[2] .

1.0 Negative affective processing of pain in anterior cingulate cortex

The anterior cingulate cortex(ACC) is a region that is located directly above the corpus callosum. The neurons in layer Ⅱ/Ⅲ within the ACC increase in glutamatergic activity after an injury to the peripheral nervous system [3]. This glutamatergic activity is sustained over a period of time even in the absence of the noxious stimulus[3]. Surgical ablation of this area results in analgesic effects in animals with peripheral nerve injury, while the animal’s ability in sensory perception of the stimulus remains intact. This illustrates that the glutamatergic activity in ACC is responsible for the emotional aspects of pain, which is distinct from the sensory component of pain[1].



1. 1 LTP in ACC

1.1 a : mechanisms of LTP

NR2B_subunit_insertion_into_NMDA.jpg
Figure 3. Addition of NR2B subunits to postsynaptic NMDA receptors occur via CREB activation in ACC.

The ACC is an area that receives direct and indirect inputs from other cortices including thalamus, hippocampus and amygdala[1]. The signaling pathways for synaptic long-term potentiation (LTP) in the ACC begins with glutamatergic excitation from an injury . Glutamate is the major excitatory neurotransmitter in ACC. When glutamate binds to postsynaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors (AMPAr), the AMPAr undergo conformational changes to form Na+ channels. This opening of Na+ channels by conformational changes of AMPAr causes influx of Na+, and creates excitatory postsynaptic potentials (EPSPs). When enough EPSPs summate and depolarize the postsynaptic membrane,The magnesium block on the N-methyl-D-aspartate (NMDA) receptor is removed, and NMDA receptors are activated. The activated NMDA receptors allow influx of Ca2+. The intracellular Ca2+ binds to Calmodulin (CaM) and activates CaM- stimulated adenylyl cyclae (AC1) and Ca2+/CaM dependent protein kinases such as PKC, CaMKⅡ, and CaMKⅣ[3]. These Ca2+/CaM dependent protein kinases contribute to the AMPA receptor trafficking and phosphorylation, thus increasing the sensitivity of AMPA receptors to the extracellular glutamate[3]. Activation of CaMKIV, a kinase expressed predominantly in the nuclei, triggers CREB signaling pathways. In addition, activation of calcium-stimulated adenylyl cyclase subtype 1 (AC1) leads to activation of PKA and subsequently CREB activity. This activation AC1 increases both presynaptic release of glutamate release and postsynaptic AMPA-receptor medated responses in peripheral nerve injuries . The increase in CREB activity also produces NR2B subunits, and they become incorporated to the postsynaptic NMDA receptors. This increase in NR2B and NR2A subunits amplifies the induction of the LTP[1] .

LTP_in_ACC.jpg
(a): intracellular Ca2+ activating various Ca2+/CaM dependent protein kinases and adenylyl cyclases, which subsequently activate CREB cycle. (b): increase in presynaptic glutamate release probability and GluR1 subunit addition to postsynaptic AMPA receptors via AC1 signaling cascade.

1.2 PKMz

PKMz is a protein kinase C isoform, which maintains the LTP. Blockade of PKMz in ACC signifiacantly reduces postsynaptic GluR1 insertion and alleviates mechanical allodynia and pain-induced aversive behavior[2].

1.2 a: AC1 triggers the release of PKMz in a transcription independent pathway.

In the ACC, blockade of AC1 results in absence of LTP as well as PKMz.. However, when cell permeable AC activator is applied to brain slices of ACC, there is an immediate increase of PKMz level within 5 minutes, which suggests that cAMP signaling cascade may be the trigger to release PKMz for the sustained LTP. The immediate increase in the level of PKMz shows that the release of PKMz is transcription independent pathway [1] [5].


1.2 b PKMz and maintenance of L-LTP

The potentiation of EPSCs and maintenance of LTP by PKMz appear to occur by increasing the number of AMPA receptors (AMPARs) at the synapses in the ACC. Inducing LTP by theta burst stimulation(TBS), and subsequently blocking PKMz by ZIP results in a significant decrease in evoked- EPSCs (eEPSCs) amplitude. This decrease in amplitude of eEPSCs may be due to decrease in conductance of the AMPA receptor and number of active channels. PKMζ may exert its effects by increasing the number of active postsynaptic AMPA receptors by reducing GluR1 subunits[2]. Application of ZIP after 3 hours of TBS induction still had robust effects in reducing the L-LTP, demonstrating that PKMz, in addition to AC1, is required for sustaining L-LTP in the ACC[7]


1.3 Analgesia from modifying LTP in ACC

1.3 a: Microinjection of ZIP

Synaptic plasticity in ACC is believed to be important for the processing of emotional processing of pain. The investigation of molecular mechanism responsible for maintaining injury-related plastic changes gives an insight into a potential therapeutic treatment for chronic pain using PKMz. Inhibiting PKMz using ZIP produces analgesic effects in animal models of chronic pain, which lasts for at least 2 hours. This analgesic effect is regionally specific; ZIP infusion into the primary somatosensory cortex or dorsal horn do not produce any notable analgesic effects. Another remarkable feature of it is its modality-specificity. The animals experiencing analgesia showed neither memory impairment, nor any deficit in locomotion and sensory perception [2], .

contextual_fear_conditioning.png
Contextual fear conditioning showed no memory impairment in ZIP infused mice.

1.3 b: Direct inhibition of ACC from motor cortex

One of the common treatment for patients suffering from phantom pain is rTMS in motor cortex. This rTMS is a technique that induces noninvasive stimulation, causing plastic changes in the brain. Studies from direct motor cortex stimulation (MCS) suggest that motor cortex stimulation may directly induce inhibition in ACC or other structures responsible for decoding the painful information[8] .

Rtms.jpg
Modulation of the primary motor cortex with excitability-enhancing high-frequency rTMS induces modification in the pain neural network, thereby alleviating chronic pain.



References

This activation of calcium-stimulated adenylyl cyclase subtype 1 (AC1) increases both presynaptic release of glutamate release and postsynaptic glutamate AMPA-receptor medated responses after a peripheral nerve injury

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  2. ^ Li, XY., et al. Alleviating Neuropathic Pain Hypersensitivity by Ihibiting PKMz in the Anterior Cingulate Cortex. Science . 330 :1400-1404 (2010).
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  4. ^ Xu, H., et al. Presynaptic and postsynaptic amplifications of neuropathic pain in the anterior cingulate cortex. J Neurosci . 28 (29):7445-53. (2008).
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  6. ^ Zhao, MG., et al. Roles of NMDA NR2B subtype receptor in prefrontal long-term potentiation and contextual fear memory. Neuron. 47(6):859–872. (2005).
  7. ^ Li, XY., et al. Erasing injury-related cortical synaptic potentiation as anew treatment for chronic pain. J Mol Med . 89:847-855. (2011).
  8. ^ Leung, A., et al. rTMS for Suppressing Neuropathic Pain: A Meta-Analysis. J Pain . 10 (12):1205-16. (2009).