Evidence suggests that activity in the anterior cingulate cortex (ACC) contributes to acute and chronic pain. In this article, Zhuo and colleagues review the different types of synaptic plasticity observed in the ACC and the implications of these forms of plasticity for pain processing.

Synaptic plasticity in the anterior cingulate cortex in acute and chronic pain

The prefrontal cortex (PFC) is not only important in executive functions, but also pain processing. The latter is dependent on its connections to other areas of the cerebral neocortex, hippocampus, periaqueductal gray (PAG), thalamus, amygdala, and basal nuclei. Changes in neurotransmitters, gene expression, glial cells, and neuroinflammation occur in the PFC during acute and chronic pain, that result in alterations to its structure, activity, and connectivity. The medial PFC (mPFC) could serve dual, opposing roles in pain: (1) it mediates antinociceptive effects, due to its connections with other cortical areas, and as the main source of cortical afferents to the PAG for modulation of pain. This is a 'loop' where, on one side, a sensory stimulus is transformed into a perceptual signal through high brain processing activity, and perceptual activity is then utilized to control the flow of afferent sensory stimuli at their entrance (dorsal horn) to the CNS. (2) It could induce pain chronification via its corticostriatal projection, possibly depending on the level of dopamine receptor activation (or lack of) in the ventral tegmental area-nucleus accumbens reward pathway. The PFC is involved in biopsychosocial pain management. This includes repetitive transcranial magnetic stimulation, transcranial direct current stimulation, antidepressants, acupuncture, cognitive behavioral therapy, mindfulness, music, exercise, partner support, empathy, meditation, and prayer. Studies demonstrate the role of the PFC during placebo analgesia, and in establishing links between pain and depression, anxiety, and loss of cognition. In particular, losses in PFC grey matter are often reversible after successful treatment of chronic pain.

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Role of the Prefrontal Cortex in Pain Processing.

Only humans can report feeling pain. In contrast, pain in animals is typically inferred on the basis of nonverbal behaviour. Unfortunately, these behavioural data can be problematic when the reliability and validity of the behavioural tests are questionable. The thesis proposed here is based on the bioengineering principle that structure determines function. Basic functional homologies can be mapped to structural homologies across a broad spectrum of vertebrate species. For example, olfaction depends on olfactory glomeruli in the olfactory bulbs of the forebrain, visual orientation responses depend on the laminated optic tectum in the midbrain, and locomotion depends on pattern generators in the spinal cord throughout vertebrate phylogeny, from fish to humans. Here I delineate the region of the human brain that is directly responsible for feeling painful stimuli. The principal structural features of this region are identified and then used as biomarkers to infer whether fish are, at least, anatomically capable of feeling pain. Using this strategy, I conclude that fish lack the necessary neurocytoarchitecture, microcircuitry, and structural connectivity for the neural processing required for feeling pain.

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Why fish do not feel pain

An increasing body of neuroimaging and electrophysiological studies of the brain suggest that the insular cortex (IC) integrates multimodal salient information ranging from sensation to cognitive-affective events to create conscious interoception. Especially with regard to pain experience, the IC has been supposed to participate in both sensory-discriminative and affective-motivational aspects of pain. In this review, we discuss the latest data proposing that subregions of the IC are involved in isolated pain networks: the posterior sensory circuit and the anterior emotional network. Due to abundant connections with other brain areas, the IC is likely to serve as an interface where cross-modal shaping of pain occurs. In chronic pain, however, this mode of emotional awareness and the modulation of pain are disrupted. We highlight some of the molecular mechanisms underlying the changes of the pain modulation system that contribute to the transition from acute to chronic pain in the IC.

Insular Cortex is Critical for the Perception, Modulation, and Chronification of Pain.

To what degree are non-human animals conscious? We propose that the most meaningful way to approach this question is from the perspective of functional neurobiology. Here we focus on subjective experience, which is a basic awareness of the world without further reflection on that awareness. This is considered the most basic form of consciousness. Tellingly, this capacity is supported by the integrated midbrain and basal ganglia structures, which are among the oldest and most highly conserved brain systems in vertebrates. A reasonable inference is that the capacity for subjective experience is both widespread and evolutionarily old within the vertebrate lineage. We argue that the insect brain supports functions analogous to those of the vertebrate midbrain and hence that insects may also have a capacity for subjective experience. We discuss the features of neural systems which can and cannot be expected to support this capacity as well as the relationship between our arguments based on neurobiological mechanism and our approach to the "hard problem" of conscious experience.

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Insects have the capacity for subjective experience

Long-term potentiation of glutamatergic transmission has been observed after physiological learning or pathological injuries in different brain regions, including the spinal cord, hippocampus, amygdala, and cortices. The insular cortex is a key cortical region that plays important roles in aversive learning and neuropathic pain. However, little is known about whether excitatory transmission in the insular cortex undergoes plastic changes after peripheral nerve injury. Here, we found that peripheral nerve ligation triggered the enhancement of AMPA receptor (AMPAR)-mediated excitatory synaptic transmission in the insular cortex. The synaptic GluA1 subunit of AMPAR, but not the GluA2/3 subunit, was increased after nerve ligation. Genetic knock-in mice lacking phosphorylation of the Ser845 site, but not that of the Ser831 site, blocked the enhancement of the synaptic GluA1 subunit, indicating that GluA1 phosphorylation at the Ser845 site by protein kinase A (PKA) was critical for this upregulation after nerve injury. Furthermore, A-kinase anchoring protein 79/150 (AKAP79/150) and PKA were translocated to the synapses after nerve injury. Genetic deletion of adenylyl cyclase subtype 1 (AC1) prevented the translocation of AKAP79/150 and PKA, as well as the upregulation of synaptic GluA1-containing AMPARs. Pharmacological inhibition of calcium-permeable AMPAR function in the insular cortex reduced behavioral sensitization caused by nerve injury. Our results suggest that the expression of AMPARs is enhanced in the insular cortex after nerve injury by a pathway involving AC1, AKAP79/150, and PKA, and such enhancement may at least in part contribute to behavioral sensitization together with other cortical regions, such as the anterior cingulate and the prefrontal cortices.

https://www.jneurosci.org/content/jneuro/34/40/13505.full.pdf

GluA1 Phosphorylation Contributes to Postsynaptic Amplification of Neuropathic Pain in the Insular Cortex

To mimic multilevel nerve root compression and intervertebral foramina stenosis in human, we established a new animal model of the chronic compression of unilateral multiple lumbar DRGs (mCCD) in the rat. A higher occurrence of signs of spontaneous pain behaviors, such as wet-dog shaking and spontaneous hind paw shrinking behaviors, was firstly observed from day 1 onward. In the meantime, the unilateral mCCD rat exhibited significant bilateral hind paw mechanical and cold allodynia and hyperalgesia, as well as a thermal preference to 30°C plate between 30 and 35°C. The expression of activating transcription factor 3 (ATF3) was significantly increased in the ipsilateral and contralateral all-sized DRG neurons after the mCCD. And the expression of CGRP was significantly increased in the ipsilateral and contralateral large- and medium-sized DRG neurons. ATF3 and CGRP expressions correlated to evoked pain hypersensitivities such as mechanical and cold allodynia on postoperative day 1. The results suggested that bilateral neuropathy of primary sensory neurons might contribute to bilateral hypersensitivity in the mCCD rat.

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Bilateral Neuropathy of Primary Sensory Neurons by the Chronic Compression of Multiple Unilateral DRGs

The anterior cingulate cortex (ACC) serves as a critical hub for the anxiety and pain perception. The large-conductance Ca2+-activated potassium channels, or BKCa channels, are ubiquitously expressed throughout the central nervous system including the cingulate cortex. However, what changes of cortical BKCa channels undergo in the ACC remains unknown in pain-related anxiety. In the present study, a significant upregulation of synaptic and non-synaptic BKCa channel accessory β4 subunits in the ACC was accompanied with pain-associated anxiety-like behaviors in the chronic compression of multiple dorsal root ganglia (mCCD) of the rat. NS1619, an opener of BKCa channels, significantly rescued the alteration of fAHP and AP duration of ACC pyramidal neurons in mCCD rats. The mRNA expression of BKCa β4 subunits was extremely upregulated in the ACC after mCCD with the increased amount of both synaptic and non-synaptic BKCa β4 subunit protein. Meanwhile, NS1619 reversed the enhanced AMPA receptor-mediated spontaneous excitatory postsynaptic current (sEPSC) frequency and the attenuated PPR of ACC neurons in mCCD rats. Local activation of BKCa channels in the ACC reversed mechanical allodynia and anxiety-like behaviors. These results suggest that the upregulation of postsynaptic and presynaptic BKCa β4 subunit may contribute to neuronal hyperexcitability and the enhanced synaptic transmission in the ACC in neuropathic pain state, and then may result in anxiety-like behavior induced by neuropathic pain.

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Ming Zhang

Papers

Insular Cortex is Critical for the Perception, Modulation, and Chronification of Pain.

GluA1 Phosphorylation Contributes to Postsynaptic Amplification of Neuropathic Pain in the Insular Cortex

Bilateral Neuropathy of Primary Sensory Neurons by the Chronic Compression of Multiple Unilateral DRGs

Upregulation of Beta4 subunit of BKCa channels in the anterior cingulate cortex contributes to mechanical allodynia associated anxiety-like behaviors