Intraperiaqueductal Gray Glycine and D-Serine Exert Dual Effects on Rostral Ventromedial Medulla ON- and OFF-Cell Activity and Thermoceptive Threshold in the Rat
Department of Experimental Medicine, Second University of Naples, Naples, Italy. Journal of Neurophysiology
(Impact Factor: 2.89).
09/2009; 102(6):3169-79. DOI: 10.1152/jn.00124.2009
We have studied the involvement of the N-methyl-D-aspartate receptor (NMDAR) glycine site and the strychnine-sensitive glycine receptor (GlyR) in the ventrolateral periaqueductal gray (VL-PAG) on nociceptive behavior (tail flick) and pain-related changes on neuronal activity in the rostral ventromedial medulla (RVM). Glycine or D-serine increased the tail-flick latency, reduced OFF-cell pause, and delayed its onset and increased the time between the onset of the OFF-cell pause and the tail withdrawal. Conversely, they decreased the ongoing activity of the ON cell, the tail-flick-induced ON-cell firing, whereas they delayed the onset of increased tail-flick-induced ON-cell firing. Also, glycine or D-serine reduced the interval between the onset of the increased ON-cell firing and tail withdrawal. Whereas 7-Cl-kynurenic acid (7-Cl-KYN) prevented such effects, strychnine did not do so. A higher dose of 7-Cl-KYN or strychnine was per se able to reduce or increase tail-flick latency and increase or reduce ON-cell activities, respectively. A higher dose of glycine was hyperalgesic in the presence of 7-Cl-KYN, whereas such an effect was prevented by strychnine. These data suggest 1) a dual role of glycine in producing hyperalgesia or analgesia by stimulating the GlyR or the NMDARs within the VL-PAG, respectively; 2) consistently that RVM ON and OFF cells display opposite firing patterns to the stimulation of the VL-PAG NMDAR glycine site and GlyR activation; and 3) a tonic role of these receptors within the VL-PAG-RVM antinociceptive descending pathway.
- "For example, a previous study has shown that the microinjection of glycine into the dorsal PAG of rats increases tail-flick latencies in a dose-dependent manner, and this hyponociceptive effect of glycine is reversed by coadministration with the specific inhibitor for NMDA receptor glycine site , suggesting that microinjected glycine acts on glycine-binding site of NMDA receptors to elicit hyponociception. In addition, a recent study has shown that the microinjection of glycine into the ventrolateral PAG of rats produces conflicting results, for example, hyperalgesia or analgesia . In this study, while the glycine-induced analgesia is blocked by the NMDA receptor antagonist, the glycine-induced hyperalgesia is blocked by the glycine receptor antagonist , suggesting that glycine acts as an excitatory transmitter, for example, coagonist for NMDA receptors, to increase the excitability of output PAG neurons. "
[Show abstract] [Hide abstract]
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.
Available from: PubMed Central
[Show abstract] [Hide abstract]
ABSTRACT: Neurons within the periaqueductal gray (PAG) have been implicated in the central regulation of pain signals by affecting the descending inhibitory pathway. Here we report on the functional role of presynaptic kainate receptors within the PAG. Using a conventional whole-cell patch clamp technique, we recorded GABAergic spontaneous miniature inhibitory postsynaptic currents (mIPSCs) from mechanically isolated rat PAG neurons in the presence of 300nM tetrodotoxin and 20microM DL-2-amino-5-phosphonovaleric acid under voltage-clamp conditions. Kainic acid at a 10microM concentration significantly increased the frequency of GABAergic mIPSCs without affecting their amplitude, suggesting that kainic acid acts presynaptically to enhance spontaneous GABA release. The kainic acid-induced increase in mIPSC frequency was completely blocked by CNQX, a selective AMPA/kainate receptor antagonist. While neither AMPA nor NMDA affected GABAergic mIPSC frequency, ATPA, a selective agonist of GluR5-containing kainate receptors, increased GABAergic mIPSC frequency in a concentration-dependent manner. The kainic acid-induced increase in mIPSC frequency was completely suppressed either in the presence of 100microM Cd(2+), a general voltage-dependent Ca(2+) channel (VDCC) blocker, or in the Na(+)-free external solution. These results suggest that presynaptic kainate receptors have a low permeability to Ca(2+), and that their activation elicits a presynaptic depolarization large enough to activate presynaptic VDCCs. Presynaptic kainate receptors on GABAergic nerve terminals appear to modulate GABAergic transmission, and in doing so may play an important role in the regulation of PAG neuron excitability.
Available from: Jozsef Toldi
[Show abstract] [Hide abstract]
ABSTRACT: Migraine is one of the commonest neurological disorders. Despite intensive research, its exact pathomechanism is still not fully understood and effective therapy is not always available. One of the key molecules involved in migraine is glutamate, whose receptors are found on the first-, second- and third-order trigeminal neurones and are also present in the migraine generators, including the dorsal raphe nucleus, nucleus raphe magnus, locus coeruleus and periaqueductal grey matter. Glutamate receptors are important in cortical spreading depression, which may be the electrophysiological correlate of migraine aura.
The kynurenine metabolites, endogenous tryptophan metabolites, include kynurenic acid (KYNA), which exerts a blocking effect on ionotropic glutamate and α7-nicotinic acetylcholine receptors. Thus, KYNA and its derivatives may act as modulators at various levels of the pathomechanism of migraine. They can give rise to antinociceptive effects at the periphery, in the trigeminal nucleus caudalis, and may also act on migraine generators and cortical spreading depression. The experimental data suggest that KYNA or its derivatives might offer a novel approach to migraine therapy.
Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed. The impact factor represents a rough estimation of the journal's impact factor and does not reflect the actual current impact factor. Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence agreement may be applicable.