Inhibitory role of supraspinal P2X3/P2X2/3 subtypes on nociception 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 alpha,beta-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 alpha,beta-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.
Fukui
Masato
M
Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8501, Japan. masato.fukui@duke.edu
Nakagawa
Takayuki
T
Minami
Masabumi
M
Satoh
Masamichi
M
Kaneko
Shuji
S
D019342:Acetic Acid / Q000008:administration & dosage; D000255:Adenosine Triphosphate / Q000008:administration & dosage / Q000031:analogs & derivatives; D000700:Analgesics / Q000008:administration & dosage / Q000627:therapeutic use; D000818:Animals; D004305:Dose-Response Relationship, Drug; D005557:Formaldehyde / Q000008:administration & dosage; D008297:Male; D010146:Pain / Q000188:drug therapy; D010147:Pain Measurement; D010636:Phenols / Q000008:administration & dosage / Q000627:therapeutic use; D011083:Polycyclic Compounds / Q000008:administration & dosage / Q000627:therapeutic use; D058919:Purinergic P2 Receptor Antagonists; D051381:Rats; D017207:Rats, Sprague-Dawley; D018048:Receptors, Purinergic P2 / Q000502:physiology*; D058476:Receptors, Purinergic P2X2; D058477:Receptors, Purinergic P2X3
C470346:A-317491; D000700:Analgesics; D010636:Phenols; D011083:Polycyclic Compounds; D058919:Purinergic P2 Receptor Antagonists; D018048:Receptors, Purinergic P2; D058476:Receptors, Purinergic P2X2; D058477:Receptors, Purinergic P2X3; D005557:Formaldehyde; D000255:Adenosine Triphosphate; C002630:alpha,beta-methyleneadenosine 5'-triphosphate; D019342:Acetic Acid