Effects of GABA_B receptor activation on excitability of IB4-positive maxillary trigeminal ganglion neurons: Possible involvement of TREK2 activation

Abstract

IB4-positive maxillary trigeminal ganglion (TG) neurons are a subtype of afferent neurons involving nociception in orofacial regions, and excitability of these neurons is associated with orofacial nociceptive sensitivity. TREK-2 channel is a member of two-pore domain potassium (K2P) channel family mediating leak K+ currents. It has been shown previously that TREK-2 channel activity can be enhanced following GABAB receptor activation, leading to a reduction of cortical neuron excitability. In the present study, we have characterized TREK-2 channel expression on maxillary TG neurons and investigated the effect of the GABAB agonist baclofen on electrophysiological properties of small-sized maxillary TG neurons of rats. We show with immunohistochemistry that TREK-2 channels are predominantly expressed in small-sized IB4-positive maxillary TG neurons. Patch-clamp recordings on neurons in ex vivo TG preparations show that baclofen hyperpolarizes resting membrane potentials, increases outward leak currents, and decreases input resistances in IB4-positive maxillary TG neurons. Moreover, baclofen significantly reduces action potential (AP) firing in IB4-positive maxillary TG neurons. In contrast, baclofen shows no significant effect on electrophysiological properties of small-sized nociceptive-like and non-nociceptive-like maxillary trigeminal neurons that are IB4-negatve. Our results suggest that TREK-2 channel activity can be enhanced by baclofen, leading to reduced excitability of IB4-positive maxillary TG neurons. This finding provides new insights into the role of TREK-2 and GABAB receptors in controlling nociceptive sensitivity in orofacial regions, which may have therapeutic implications.

Role of common and rare genetic variants in the aetiology of trigeminal neuralgia

“…For example, the Potassium Two Pore Domain Channel Subfamily K Member 10 gene (KCNK10) suggested by our GWAS acts as an open rectifier ion channel which primarily passes outward current under physiological K+ concentrations (Stelzer et al, 2016). It appears to play a role in the excitability of trigeminal Formatted for: medRxiv Draft of 16 July 2024 ganglion neurons (Chang et al, 2021) and its expression in axotomized rat primary sensory neurons reduced neuropathic pain behavior (Messina et al, 2022). Our evidence suggests that that SNPs located >145 kbp from the LRP1B gene are strongly association with TN1.…”

Non-nociceptive and nociceptive-like trigeminal Aβ-afferent neurons of rats: Distinct electrophysiological properties, mechanical and chemical sensitivity

“…Ex vivo TG preparation and patch-clamp recordings were performed in a manner similar to our previous studies ( Chang et al 2021 ; Okutsu et al 2021 ). In brief, rats were anesthetized and decapitated, and trigeminal ganglia (TG) were bilaterally dissected out and submerged in ice cold Krebs solution in a 35 mm Petri dish containing (in mM): 117 NaCl, 3.6 KCl, 1.2 Na 2 PO 4 , 2.5 CaCl 2 , 1.2 MgCl 2 , 25 NaHCO 3 , and 25 glucose.…”

Disinhibition Is an Essential Network Motif Coordinated by GABA Levels and GABA B Receptors

“…At the same time, the RGS protein increases the GTPase activity of the Gα subunit, causing rapid desensitization of the K + current [38], which reduces neuronal excitability and inhibits action potential backpropagation. Furthermore, GABA B Rs activate a two-pore domain K + channel (TREK2, also called KCNK10 [39,40]). In the dendrites, the joint activation of GIRK, TREK2, and VGCC and the inhibition of action potential backpropagation [41] reduce the generation of Ca 2+ spikes (Figure 1A).…”