Presynaptic Glycine Receptors Increase GABAergic Neurotransmission in Rat Periaqueductal Gray Neurons

Abstract

The periaqueductal gray (PAG) is involved in the central regulation of nociceptive transmission by affecting the descending inhibitory pathway. In the present study, we have addressed the functional role of presynaptic glycine receptors in spontaneous glutamatergic transmission. Spontaneous EPSCs (sEPSCs) were recorded in mechanically dissociated rat PAG neurons using a conventional whole-cell patch recording technique under voltage-clamp conditions. The application of glycine (100 µM) significantly increased the frequency of sEPSCs, without affecting the amplitude of sEPSCs. The glycine-induced increase in sEPSC frequency was blocked by 1 µM strychnine, a specific glycine receptor antagonist. The results suggest that glycine acts on presynaptic glycine receptors to increase the probability of glutamate release from excitatory nerve terminals. The glycine-induced increase in sEPSC frequency completely disappeared either in the presence of tetrodotoxin or Cd2+, voltage-gated Na+, or Ca2+ channel blockers, suggesting that the activation of presynaptic glycine receptors might depolarize excitatory nerve terminals. The present results suggest that presynaptic glycine receptors can regulate the excitability of PAG neurons by enhancing glutamatergic transmission and therefore play an important role in the regulation of various physiological functions mediated by the PAG.

Functional modulation of glycine receptors by the alkaloid gelsemine

“…The existence of presynaptic glycine receptors has been well demonstrated by several groups. Studies in several CNS regions have shown that the activation of presynaptic glycine receptors can enhance the frequency of synaptic events elicited by glutamate, GABA and glycine synaptic release in a neuron‐specific manner (Turecek and Trussell, ; Jeong et al ., ; Kunz et al ., ; Choi et al ., ). The increase on the neurotransmitter release is mainly due to a glycine‐evoked activation of chloride channels, which depolarizes the axon terminal (Turecek and Trussell, ).…”

“…Glycine receptors mediate fast synaptic inhibition in the spinal cord, brain stem and in some selected CNS areas (Zeilhofer et al ., 2012a,b). Additional evidence has shown that these receptors can also modulate neuronal excitability through tonic inhibition (Mitchell et al ., ; Xu and Gong, ; Salling and Harrison, ; Liu et al ., ) and presynaptic modulation (Turecek and Trussell, ; Jeong et al ., ; Kunz et al ., ; Choi et al ., ). Synaptic glycine receptors interact with the scaffolding protein gephyrin through molecular interactions of the β subunits with the E domain of gephyrin, allowing the formation and stabilization of inhibitory synapses at postsynaptic sites (Tyagarajan and Fritschy, ).…”

Neurochemical effects of motor cortex stimulation in the periaqueductal gray during neuropathic pain

“…Glycine may exert its inhibitory function through activation of specific postsynaptic receptors (GlyR) and an excitatory effect by acting as a coagonist of glutamate on the activation of N-methyl-d-aspartate (NMDA) receptors. 5,25 GlyRs are found mainly in dlPAG. 5,26 Additionally, a common vesicular transporter for both glycine and GABA, which would be responsible for their costorage in the same synaptic vesicle and subsequent corelease at mixed synapses of these inhibitory neurotransmitters, has been proposed.…”

“…5,25 GlyRs are found mainly in dlPAG. 5,26 Additionally, a common vesicular transporter for both glycine and GABA, which would be responsible for their costorage in the same synaptic vesicle and subsequent corelease at mixed synapses of these inhibitory neurotransmitters, has been proposed. It has been hypothesized that GABA and glycine are released by distinct populations of interneurons and not jointly in the PAG.…”

“…25 Data obtained from in situ hybridization and immunoreactivity studies indicate that glycine seems to play an important role in pain processing in the PAG. 5,31,33 In vivo microdialysis studies have shown that inflammatory pain markedly increases the glycine and glutamate levels and reduces GABA in the PAG. 31,39 However, microinjection of glycine in the dlPAG induces antinociception in rats, and this effect is anatomically specific to dlPAG.…”