Inhibition of α5 subunit‐containing GABA_A receptors facilitated spinal nociceptive transmission and plasticity

Abstract

Background: c-Aminobutyric acid (GABA) type A receptors (GABA A Rs) locate at both synaptic and extrasynaptic membrane, which generate phasic and tonic inhibition, respectively. In spinal cord dorsal horn, the phasic inhibition produced by transient activation of synaptic GABA A Rs plays an important role in the gating control over nociceptive conveyance. Although extrasynaptic GABA A Rs that contain a5 subunits (a5-GABA A Rs) are also detectable in spinal dorsal horn, much less is known about the function of these receptors. Methods: The C fibre-evoked field potentials were recorded in superficial dorsal horn of spinal cord, and the effects of a5-GABA A R inverse agonist L-655708 on basal synaptic transmission and long-term potentiation (LTP) of C-fibre responses were examined. The possible changes of glutamate receptor function and pain sensitivity after a5-GABA A R inhibition were investigated by western blot and behavioural tests. Results: Inhibition of a5-GABA A Rs by L-655708 boosted the basal synaptic transmission and facilitated the induction of N-methyl-D-aspartate subtype glutamate receptors (NMDARs)-dependent LTP. L-655708 was found to enhance the phosphorylation and synaptic accumulation of NMDARs and a-Amino-3-hydroxy-5-methylisoxazole-4-propionic Acid receptors (AMPARs). Intrathecal L-655708 injection also decreased the pain thresholds of intact mice in a dose-dependent manner. Conclusions: a5-GABA A Rs were critical for the tonic inhibition of glutamatergic neurotransmission and plasticity in spinal dorsal horn. Significance: Tonic inhibition generated by a5-GABA A Rs is important for information processing. However, whether and how a5-GABA A Rs regulate the conveyance of nociceptive signals in spinal cord is largely unknown. Here, we revealed a negative control by a5-GABA A Rs over nociceptive transmission and plasticity.

Sex‐dependent pronociceptive role of spinal α5‐GABAA receptor and its epigenetic regulation in neuropathic rodents

“…Accordingly, α 5 ‐GABA A receptors have shown to contribute to GABA A receptor‐mediated tonic inhibition switching to excitation or loss of inhibition (Bravo‐Hernández et al., 2016; Loeza‐Alcocer et al., 2013). Our results agree with previous findings from our laboratory (Bravo‐Hernández et al., 2016; De la Luz‐Cuellar et al., 2019; Hernández‐Reyes et al, 2019) and other report showing that L‐655,708 increases basal synaptic transmission, facilitates long term potentiation, and generates hypersensitivity on intact mice (Xue et al., 2017). In naïve animals, spinal α 5 ‐GABA A receptors might tonically reduce excitability of projection neurons and primary afferent fibers (Hernández‐Reyes et al, 2019), although this has been disputed (Munro et al., 2011; Perez‐Sanchez et al., 2017).…”

“…In (f) *p < .05, **p < .01 versus 7 days (7) group, as determined by unpaired Student t-test. 7D:7 days long term potentiation, and generates hypersensitivity on intact mice (Xue et al, 2017). In naïve animals, spinal α 5 -GABA A receptors might tonically reduce excitability of projection neurons and primary afferent fibers (Hernández-Reyes et al, 2019), although this has been disputed (Munro et al, 2011;Perez-Sanchez et al, 2017).…”

“…Particularly, extrasynaptic GABA A receptors containing α 5 subunit (α 5 ‐GABA A receptors) are localized in dorsal root ganglia (DRG) and spinal cord (Loeza‐Alcocer, Andrés, Aguilar, Felix, & Delgado‐Lezama, 2014). Converging evidence has suggested a role for α 5 ‐GABA A receptor in the pathophysiology of pain (Bohlhalter, Weinmann, Mohler, & Fritschy, 1996; Lorenzo et al., 2014; Paul, Zeilhofer, & Fritschy, 2012; Perez‐Sanchez et al., 2017; Persohn, Malherbe, & Richards, 1991), either as antinociceptive (Perez‐Sanchez et al., 2017; Xue et al., 2017) or pronociceptive (Bravo‐Hernández et al., 2014, 2016; De la Luz‐Cuellar et al., 2019; Hernández‐Reyes et al., 2019). Interestingly, a recent work from our group found a sex‐difference in the extent of the antiallodynic effect induced by the specific α 5 ‐GABA A receptor inverse agonist, L‐655,708, in dysfunctional pain (De la Luz‐Cuellar et al., 2019).…”

Facilitation of Social Support through Negative Allosteric Modulation of α5-Associated GABAA Receptors: A Novel Mechanism for the Treatment of Depression, Agitation, and Aggression in the Elderly

“…The levels of AMPA receptor GluA1 were also enhanced [50] with AMPA potentiation being known as a core antidepressant mechanism and one associated with the actions of ketamine [55]. An integral role of 5-containing GABA A receptors is shown by the fact that L-655,708 can augment induction of NMDA-dependent long-term potentiation and the phosphorylation and synaptic addition of NMDA and AMPA receptors [56]. In turn, AMPA receptor potentiation feeds forward to further enrich synaptic α5-GABA A receptors [57].…”

β-elemene relieves neuropathic pain in mice through the regulation on C-X-C motif chemokine receptor 3 and GABAA receptor

“…N-methyl-D-aspartate receptors (NMDARs), for example, play critical roles in the transmission of excitatory synaptic, plasticity, and excitotoxicity in the CNS (Cull-Candy et al 2001). On the contrary, the gamma-aminobutyric acid A (GABAA) receptors are a major sort of inhibitory receptors which play an important role in the control of nociceptive conveyance (Xue et al 2017). Neuropathic pain also demands specific concerns, and both pharmacological and nonpharmacological strategies might be involved (Dworkin et al 2013;Finnerup et al 2015).…”