Modulation of neurotransmitter release by P2X and P2Y receptors in the rat spinal cord

Attila Heinrich, A. Kittel, Cecilia Csölle, E. Vízi, B. Sperlágh

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

In this study, the P2 receptor-mediated modulation of [3H]glutamate and [3H]noradrenaline release were examined in rat spinal cord slices. Adenosine 5′-triphosphate (ATP), adenosine 5′-diphosphate (ADP), and 2-methylthioadenosine 5′-diphosphate (2-MeSADP) decreased the electrical stimulation-evoked [3H]glutamate efflux with the following order of potency: ADP > 2-MeSADP > ATP. The effect of ATP was antagonized by suramin (300 μM), the P2Y12,13 receptor antagonist 2-methylthioadenosine 5′-monophosphate (2-MeSAMP, 10 μM), and partly by 4-[[4-Formyl-5-hydroxy-6-methyl-3-[(phosphonooxy)methyl]-2-pyridinyl]azo]-1,3-benzenedisulfonic acid (PPADS, 30 μM) and the P2Y1 receptor antagonist 2′-deoxy-N6-methyladenosine 3′,5′-diphosphate (MRS 2179, 10 μM). ATP, ADP and 2-MeSADP also decreased evoked [3H]noradrenaline outflow; the order of agonist potency was ADP ≥ 2-MeSADP > ATP. The effect of ATP was reversed by 2-MeSAMP (10 μM), and partly by MRS 2179 (10 μM). By contrast, 2-methylthioadenosine-5′-triphosphate (2-MeSATP, 10-300 μM) increased resting and electrically evoked [3H]glutamate and [3H]noradrenaline efflux, and this effect was prevented by the P2X1 receptor selective antagonist 4,4′,4″,4″′-[carbonylbis[imino-5,1,3-benzenetriyl bis (carbonyl-imino)]] tetrakis (benzene-1,3-disulfonic acid) octasodium salt (NF449, 100 nM). Reverse transcriptase polymerase chain reaction (RT-PCR) analysis revealed that mRNAs encoding P2Y12 and P2Y13 receptors are expressed in the brainstem, whereas P2Y13 but not P2Y12 receptor mRNA is present in the dorsal root ganglion and spinal cord. P2Y1 receptor expression in the spinal cord is also demonstrated at the protein level. In conclusion, inhibitory P2Y and facilitatory P2X1-like receptors, involved in the regulation of glutamate (P2Y13 and/or P2Y1) and noradrenaline (P2Y13 and/or P2Y1, P2Y12) release have been identified, which provide novel target sites for analgesics acting at the spinal cord level.

Original languageEnglish
Pages (from-to)375-386
Number of pages12
JournalNeuropharmacology
Volume54
Issue number2
DOIs
Publication statusPublished - Feb 2008

Fingerprint

Adenosine Diphosphate
Neurotransmitter Agents
Glutamic Acid
Spinal Cord
Norepinephrine
Purinergic P2X1 Receptors
Adenosine Triphosphate
Purinergic P2Y1 Receptors
Diphosphates
Purinergic P2Y Receptor Antagonists
Suramin
Messenger RNA
Spinal Ganglia
Benzene
Reverse Transcriptase Polymerase Chain Reaction
Electric Stimulation
Brain Stem
Analgesics
Salts
Acids

Keywords

  • ATP
  • Glutamate
  • Noradrenaline
  • P2 receptors
  • Release
  • Spinal cord

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Drug Discovery
  • Pharmacology

Cite this

Modulation of neurotransmitter release by P2X and P2Y receptors in the rat spinal cord. / Heinrich, Attila; Kittel, A.; Csölle, Cecilia; Vízi, E.; Sperlágh, B.

In: Neuropharmacology, Vol. 54, No. 2, 02.2008, p. 375-386.

Research output: Contribution to journalArticle

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N2 - In this study, the P2 receptor-mediated modulation of [3H]glutamate and [3H]noradrenaline release were examined in rat spinal cord slices. Adenosine 5′-triphosphate (ATP), adenosine 5′-diphosphate (ADP), and 2-methylthioadenosine 5′-diphosphate (2-MeSADP) decreased the electrical stimulation-evoked [3H]glutamate efflux with the following order of potency: ADP > 2-MeSADP > ATP. The effect of ATP was antagonized by suramin (300 μM), the P2Y12,13 receptor antagonist 2-methylthioadenosine 5′-monophosphate (2-MeSAMP, 10 μM), and partly by 4-[[4-Formyl-5-hydroxy-6-methyl-3-[(phosphonooxy)methyl]-2-pyridinyl]azo]-1,3-benzenedisulfonic acid (PPADS, 30 μM) and the P2Y1 receptor antagonist 2′-deoxy-N6-methyladenosine 3′,5′-diphosphate (MRS 2179, 10 μM). ATP, ADP and 2-MeSADP also decreased evoked [3H]noradrenaline outflow; the order of agonist potency was ADP ≥ 2-MeSADP > ATP. The effect of ATP was reversed by 2-MeSAMP (10 μM), and partly by MRS 2179 (10 μM). By contrast, 2-methylthioadenosine-5′-triphosphate (2-MeSATP, 10-300 μM) increased resting and electrically evoked [3H]glutamate and [3H]noradrenaline efflux, and this effect was prevented by the P2X1 receptor selective antagonist 4,4′,4″,4″′-[carbonylbis[imino-5,1,3-benzenetriyl bis (carbonyl-imino)]] tetrakis (benzene-1,3-disulfonic acid) octasodium salt (NF449, 100 nM). Reverse transcriptase polymerase chain reaction (RT-PCR) analysis revealed that mRNAs encoding P2Y12 and P2Y13 receptors are expressed in the brainstem, whereas P2Y13 but not P2Y12 receptor mRNA is present in the dorsal root ganglion and spinal cord. P2Y1 receptor expression in the spinal cord is also demonstrated at the protein level. In conclusion, inhibitory P2Y and facilitatory P2X1-like receptors, involved in the regulation of glutamate (P2Y13 and/or P2Y1) and noradrenaline (P2Y13 and/or P2Y1, P2Y12) release have been identified, which provide novel target sites for analgesics acting at the spinal cord level.

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