Abstract
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,β-methylene-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.
Highlights
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 [6,7,8]
At the supraspinal level, we previously reported that the intracerebroventricular (i.c.v.) administration of adenosine 5'-triphosphate (ATP) and P2X receptor agonists produced mechanical and thermal antinociception in rats, suggesting that supraspinal P2X receptors play an inhibitory role in nociceptive transmission [13,14,15]
To clarify the involvement of P2X3/P2X2/3 receptors, we investigated the effect of i.c.v. pretreatment with A-317491, the novel non-nucleotide antagonist selective for P2X3/P2X2/3 receptors [16,17] and down-regulation of P2X3 receptors in the brain by antisense oligodeoxynucleotide (A-ODN) in rats
Summary
At the supraspinal level, we previously reported that the intracerebroventricular (i.c.v.) administration of ATP and P2X receptor agonists produced mechanical and thermal antinociception in rats, suggesting that supraspinal P2X receptors play an inhibitory role in nociceptive transmission [13,14,15]. To determine the roles of the endogenous purinergic system through supraspinal P2X3/P2X2/3 receptors in the exacerbated pain states, we examined the effect of A-317491 administered i.c.v. on the inflammatory nociceptive behaviors induced by chemical agents. The antinociceptive effect of α,β-methylene-ATP administered i.c.v. was measured by the paw pressure test, as previously described [13,14].
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