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 P2Y 12,13 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 P2Y 1 receptor antagonist 2′-deoxy-N 6-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 P2X 1 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 P2Y 12 and P2Y 13 receptors are expressed in the brainstem, whereas P2Y 13 but not P2Y 12 receptor mRNA is present in the dorsal root ganglion and spinal cord. P2Y 1 receptor expression in the spinal cord is also demonstrated at the protein level. In conclusion, inhibitory P2Y and facilitatory P2X 1-like receptors, involved in the regulation of glutamate (P2Y 13 and/or P2Y 1) and noradrenaline (P2Y 13 and/or P2Y 1, P2Y 12) release have been identified, which provide novel target sites for analgesics acting at the spinal cord level.
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