A type-5 metabotropic glutamate receptor-perineuronal net axis shapes the function of cortical GABAergic interneurons in chronic pain

Abstract

Parvalbumin-positive (PV⁺) interneurons (basket and chandelier cells) regulate the firing rate of pyramidal neurons in the cerebral cortex and play a key role in the generation of network oscillations in the cerebral cortex. A growing body of evidence suggest that cortical PV⁺ interneurons become overactive in chronic pain and contribute to nociceptive sensitization by inhibiting a top-down analgesic pathway. Here, we provide further support to this hypothesis showing that intracortical infusion of the GABA_A receptor antagonist, bicuculline, caused analgesia in a mouse model of chronic inflammatory pain, although it reduced pain thresholds in healthy mice. We propose that mGlu5 metabotropic glutamate receptors and perineuronal nets (PNNs) shape the activity of PV⁺ interneurons in chronic pain, generating a form of maladaptive plasticity that enhances behavioural pain responses. mGlu5 receptors might be locally targeted by drugs activated by light delivered in cortical regions of the pain matrix, whereas the density of PNNs enwrapping PV⁺ interneurons might be reduced by local activation of PNN-degrading enzyme, such as type-9 matrix metalloproteinase. These strategies, which may require invasive treatments, might be beneficial in the management of severe pain which is refractory to conventional pharmacological and non-pharmacological interventions.

Keywords: Metabotropic glutamate receptors 5; Pain; Perineuronal nets.

Fig. 1

Activation of mGlu5 receptors and formation of PNNs may caused a novel activity of PV⁺ interneurons, which in turn inhibit a top-down analgesic pathway originated from layer 5 of SSCtx. The interconnection between activation of mGlu5 receptors and formations of PNNs remains to be elucidated

Fig. 2

Increased density of WFA⁺ PNNs in the SSCtx of mice developing chronic inflammatory pain. Representative images showing the increased density of WFA⁺ PNNs (green) and PV⁺ neurons (red) in the contralateral SSCtx associated with chronic inflammatory pain (Mascio et al., [60]). Scale bar 100 µm

Fig. 3

Effect of intracortical infusion of bicuculline on pain thresholds in mice injected with CFA or vehicle. Mice were anaesthesized with isoflurane and stereotaxically implanted with a 27-gauge injection cannula in the SCCtx (AP: 0, L: 3, DV 2.2 mm), fixed with acrylic cement. Three days later, mice were injected with CFA or vehicle in the hindlimb contralateral to the injection cannula. Bicuculline (Tocris Cookson Ltd., Bristol, UK) was dissolved into saline and infused in the SSCtx contralateral to CFA or vehicle with a 5-µl Hamilton syringe connected by a catheter to the injection cannula. Mice were infused with 0.5 µl of bicuculline solution (20 ng/µl) or saline in 90 s. Mechanical thresholds were measured 1 h prior to and 5 min after intracortical infusions. Values are means ± SEM of 4–6 mice per group. *Significantly different vs. the respective values obtained 1 h prior to bicuculline infusion. The experimental protocol was approved by the Italian Ministry of Health, 1135/2020-PR