Chronic Inflammatory Pain Impairs mGluR5-Mediated Depolarization-Induced Suppression of Excitation in the Anterior Cingulate Cortex

Abstract

The anterior cingulate cortex (ACC) is a critical hub for nociceptive perception and pain-related anxiety. Long-term synaptic plasticity in ACC was found to be important for chronic inflammatory pain and pain-related anxiety. As short-term synaptic plasticity, depolarization-induced suppression of excitation (DSE) is involved in several conditions, such as chronic stress, epilepsy, and autism. However, it is still unknown whether DSE in the ACC is involved in the central sensitization of pain and anxiety. Using a whole-cell patch clamp, calcium imaging, western blot, and behavioral testing, we found that DSE was induced by a 2 s depolarization in postsynaptic pyramidal cells in ACC. DSE was mediated by endocannabinoid signaling and modulated by metabotropic glutamate receptor 5 (mGluR5). DSE was impaired by decreasing expression and dysfunction of mGluR5 in a mouse model of inflammatory pain induced by complete Freund's adjuvant. CDPPB, an mGluR5-positive allosteric modulator, could rescue hypersensitivity and anxiety-like behavior in this pain model. Our results demonstrated that mGluR5-mediated short-term plasticity in ACC may be a critical mechanism for chronic pain, and mGluR5 may potentially serve as a target of pain therapy, including treatments for hyperalgesia and anxiety.

Tetrahydroxystilbene glucoside relieves the chronic inflammatory pain by inhibiting neuronal apoptosis, microglia activation, and GluN2B overexpression in anterior cingulate cortex

“…ACC could collect the nociceptive information from thalamus, amygdala, and other pain-related areas in the cortex. 25 , 26 Besides, peripheral nociceptive stimulation and/or injury models produce excitatory postsynaptic potentials in ACC. And related mechanism of excitatory synaptic transmission has been demonstrated.…”

Chronic inflammatory pain decreases the glutamate vesicles in presynaptic terminals of the nucleus accumbens

“…The open field test (OFT) was performed at day 8 after the injection as previously described. 20 The test was carried out as previously described. 21 Mice were placed in the center of a cubic chamber (40 × 40 × 40 cm).…”

Striatal Distribution and Cytoarchitecture of Dopamine Receptor Subtype 1 and 2: Evidence from Double-Labeling Transgenic Mice

“…The chamber was divided into an outer zone (10 cm from the walls) and a square center zone (20 cm × 20 cm). Total distance traveled was used for measuring locomotor activity, and distance traveled in the central zone was used for evaluating anxiety (Gubert et al, 2016 ; Guo et al, 2017 ). Two hours after the behavior test, these mice were sacrificed for c-fos immunostaining.…”