Korean J Physiol Pharmacol.  2022 Mar;26(2):69-75. 10.4196/kjpp.2022.26.2.69.

Altered synaptic connections and inhibitory network of the primary somatosensory cortex in chronic pain

• Kim YR
• Kim SJ

• KMID: 2526726
• DOI: http://doi.org/10.4196/kjpp.2022.26.2.69

Abstract

Chronic pain is induced by tissue or nerve damage and is accompanied by pain hypersensitivity (i.e., allodynia and hyperalgesia). Previous studies using in vivo two-photon microscopy have shown functional and structural changes in the primary somatosensory (S1) cortex at the cellular and synaptic levels in inflammatory and neuropathic chronic pain. Furthermore, alterations in local cortical circuits were revealed during the development of chronic pain. In this review, we summarize recent findings regarding functional and structural plastic changes of the S1 cortex and alteration of the S1 inhibitory network in chronic pain. Finally, we discuss potential neuromodulators driving modified cortical circuits and suggest further studies to understand the cortical mechanisms that induce pain hypersensitivity.

Keyword

Chronic pain; Cortical circuit; Inhibitory network; Neuropathic pain; Primary somatosensory cortex

Figure

• 

  Fig. 1 Local inhibitory circuits are modified in chronic pain. (A) Under normal conditions, pyramidal neurons (PN) are appropriately modulated by mainly somatostatin (SOM) and parvalbumin (PV)-expressing inhibitory neurons. Vasoactive intestinal polypeptide (VIP)-expressing inhibitory neurons primarily inhibit other subtypes of inhibitory neuron, and preferentially suppresses SOM activity. SOM and PV neurons contribute to tuft dendritic and perisomatic inhibition of pyramidal neurons, respectively. (B) Tissue or nerve injury alters local inhibitory circuits towards hyperactivity of pyramidal neurons, leading to chronic pain. Enhanced VIP activity reduces SOM and PV activities and ultimately enhances PN hyperactivity.

• 

  Fig. 2 Potential local circuit plasticity evoked by cholinergic and noradrenergic inputs in chronic pain. (A) Acetylcholine is the one of the potential neuromodulators that drives circuit changes in chronic pain. Cholinergic input from basal forebrain projection neurons can differentially target each subtype of cortical GABAergic neurons. Vasoactive intestinal polypeptide (VIP) neurons are mainly located in L1 and L2/3, and, in particular, exhibit a higher expression of nicotinic receptors compared to other subtypes. In chronic pain, VIPs expressing nicotinic acetylcholine receptors (nAChR) can be driven by cholinergic inputs and reduce the net inhibitory effects on pyramidal neurons. Along with the action on nAChRs in VIP neurons, the activation of presynaptic nAChRs in thalamocortical neurons may modulate thalamocortical transmission in layer 4 of the S1 cortex in chronic pain. (B) Another potential factor is noradrenergic action of the S1 cortex during chronic pain conditions. Noradrenergic inputs projected from the locus coeruleus may exert layer-specific modulation by the action of different types of adrenergic receptors in the S1 cortex. Norepinephrine (NE) regulates the excitability of L1 and L2/3 excitatory neurons via presynaptic alpha-1 and alpha-2/beta-adrenergic receptors, respectively, on inhibitory neurons. In addition, NE modulates the synaptic responsiveness of L5 pyramidal neurons via alpha-1 receptors. NE may also act on presynaptic thalamocortical neurons, resulting in local circuit plasticity.

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