The α5 subunit containing GABAA receptors contribute to chronic pain

Abstract

It has been recently proposed that α5-subunit containing GABAA receptors (α5-GABAA receptors) that mediate tonic inhibition might be involved in pain. The purpose of this study was to investigate the contribution of α5-GABAA receptors in the loss of GABAergic inhibition and in formalin-, Complete Freund’s adjuvant (CFA)- and L5/L6 spinal nerve ligation-induced long-lasting hypersensitivity. Formalin or CFA injection and L5/L6 spinal nerve ligation produced long-lasting allodynia and hyperalgesia. Moreover, formalin injection impaired the rate-dependent depression (RDD) of the Hofmann reflex. Peripheral and intrathecal pre-treatment or post-treatment with the α5-GABAA receptor antagonist, L-655,708 (0.15–15 nmol) prevented and reversed, respectively, these long-lasting behaviors. Formalin injection increased α5-GABAA receptors mRNA expression in the spinal cord and dorsal root ganglia (DRG) mainly at 3 days. α5-GABAA receptors were localized in the dorsal spinal cord and DRG co-labeling with NeuN, CGRP and IB4 suggesting their presence in peptidergic and non-peptidergic neurons. These receptors were found mainly in small- and medium-size neurons. Formalin injection enhanced α5-GABAA receptors fluorescence intensity in spinal cord and DRG at 3 and 6 days. Intrathecal administration of L-655,708 (15 nmol) prevented and reversed formalin-induced impairment of RDD. These results suggest that α5-GABAA receptors play a role in the loss of GABAergic inhibition and contribute to long-lasting secondary allodynia and hyperalgesia.

Heteromeric α/β glycine receptors regulate excitability in parvalbumin‐expressing dorsal horn neurons through phasic and tonic glycinergic inhibition

“…In contrast, some work suggests that tonic GABAergic currents can contribute to more chronic forms of pain following inflammation and nerve injury (Bravo‐Hernández et al . ). Less work has assessed the properties and roles of tonic glycinergic currents in the dorsal horn and thus the potential for different receptor stoichiometry between extrasynaptic versus synaptic GlyR pools has remained unresolved.…”

“…; Bravo‐Hernández et al . ; Perez‐Sanchez et al . ), tonic rather than synaptic inhibition is responsible for the major effect of neurosteroids on GABA A receptors (Mitchell et al .…”

“…GABAergic, as well as glycinergic, tonic currents have also been described within the spinal dorsal horn (Takahashi et al 2006;Takazawa & MacDermott, 2010). For tonic GABAergic currents, it has been confirmed that both δ and α5 subunit-containing receptors are crucial (Bonin et al 2011;Bravo-Hernández et al 2016;Perez-Sanchez et al 2017), tonic rather than synaptic inhibition is responsible for the major effect of neurosteroids on GABA A receptors (Mitchell et al 2007), and that each receptor type is functionally relevant for nociceptive processing. This work suggests tonic GABAergic currents play roles in normal resolution of hyperalgesia following acute inflammation (Perez-Sanchez et al 2017), as well as limiting acute nociception and central sensitization (Bonin et al 2011).…”

“…This work suggests tonic GABAergic currents play roles in normal resolution of hyperalgesia following acute inflammation (Perez-Sanchez et al 2017), as well as limiting acute nociception and central sensitization (Bonin et al 2011). In contrast, some work suggests that tonic GABAergic currents can contribute to more chronic forms of pain following inflammation and nerve injury (Bravo-Hernández et al 2016). Less work has assessed the properties and roles of tonic glycinergic currents in the dorsal horn and thus the potential for different receptor stoichiometry between extrasynaptic versus synaptic GlyR pools has remained unresolved.…”

Effects of niflumic acid on γ-aminobutyric acid-induced currents in isolated dorsal root ganglion neurons of neuropathic pain rats

“…It has previously been demonstrated that GABA type A receptors (GABA A Rs) are involved in the transmission of pain (5,6). GABA A Rs are ligand-gated chloride ion channel receptors (5,6).…”