Title Inhibitory role of supraspinal P 2 X 3 / P 2 X 2 / 3 subtypes onnociception in rats

Extracellular ATP is known to mediate synaptic transmission as a neurotransmitter or a neuromodulator via ionotropic P2X and metabotropic P2Y receptors. Several lines of evidence have suggested that ATP facilitates pain transmission at peripheral and spinal sites via the P2X receptors, in which the P2X3 subtype is considered as an important candidate for the effect. Conversely, we previously found that the activation of supraspinal P2X receptors evoked antinociception. However, the subtypes responsible for the antinociception via supraspinal P2X receptors remain unclear. In the present study, we showed that intracerebroventricular (i.c.v.) pretreatment with A-317491 (1 nmol), the novel non-nucleotide antagonist selective for P2X3 and P2X2/3 receptors, attenuated the antinociceptive effect produced by i.c.v. administered α,βmethylene-ATP (10 nmol), the P2X receptor agonist, in rats. Similarly, the abolishment of the P2X3 receptor mRNA in the brainstem by repeated i.c.v. pretreatments with antisense oligodeoxynucleotide for P2X3 gene once a day for 5 consecutive days diminished the antinociceptive effect of α,β-methylene-ATP. Furthermore, i.c.v. administration of A-317491 (1 and 10 nmol) significantly enhanced the inflammatory nociceptive behaviors induced by the intraplantar injection of formalin and intraperitoneal injection of acetic acid. Taken together, these results suggest that supraspinal P2X3/P2X2/3 receptors play an inhibitory role in pain transmission. Findings Extracellular ATP has been established as a signaling molecule that mediates diverse biological effects via P2 purinoceptors (P2Xn and P2Yn) in both the peripheral and central nervous systems [1,2]. A body of evidence indicates that ionotropic P2X receptors are involved in both peripheral and spinal pain transmission [3-5]. Of the seven P2X receptors identified to date, the expression of the P2X3 receptors appear selective for a subpopulation of small-diameter dorsal root ganglion neurons, which are probably associated with nociception [6-8]. In vivo studies have provided evidence that the activation of P2X receptors, especially the P2X3 subtype and P2X2/3 heteromer, contributes to an acute nociceptive behavior, hyperalgesia and allodynia [9-12]. These observations support the idea that the P2X3 and P2X2/3 receptors play a crucial Published: 05 June 2006 Molecular Pain 2006, 2:19 doi:10.1186/1744-8069-2-19 Received: 28 April 2006 Accepted: 05 June 2006 This article is available from: http://www.molecularpain.com/content/2/1/19 © 2006 Fukui et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Molecular Pain 2006, 2:19 http://www.molecularpain.com/content/2/1/19