Supraspinal antinociception by intracerebroventricular administration of P2 purinoceptor agonists in rats

Extracellular ATP has been reported to play facilitative roles in nociceptive transmission at peripheral and spinal sites. We examined the effects of ATP and its analogues administered intracerebroventricularly on nociceptive thresholds in rats. Intracerebroventricular (i.c.v.) administration of ATP (10 and 100 nmol/rat), α,β-methylene-ATP (1 – 30 nmol/rat) and 2', 3'-O-(4-benzoylbenzoyl)-ATP (1 – 30 nmol/rat) transiently and dose-dependently elevated the mechanical nociceptive threshold in the paw pressure test. However, i.c.v. administration of β,γ-methylene-ATP (1 – 30 nmol/rat) and UTP (10 and 100 nmol/rat) had no significant effects on the mechanical nociceptive threshold. We also examined the effect of α,β-methylene-ATP on the mechanical hyperalgesia. I.c.v. administration of α,β-methylene-ATP (0.1 – 10 nmol/rat) at 3 hr after intraplantar (i.pl.) injection of 2% carrageenan ⁄ kaolin dose-dependently elevated the mechanical nociceptive threshold of the ipsilateral and contralateral hind paws. The effect was also transient with similar to the effect in normal rats. Antinociceptive effect of α,β-methylene-ATP (10 nmol/rat) was significantly attenuated by subcutaneous (s.c.) pretreatment with propranolol, but not phentolamine or methysergide, at a dose of 10 mg/kg. I.c.v. pretreatment with propranolol, butoxamine, and ((±)-1-[2,3-(dihydro-7-methyl-1H-inden-4-yl)oxy]-3-[(1-methylethyl)amino]- 2-butanol) hydrochloride but not atenolol (100 nmol/rat) significantly attenuated the antinociceptive effect of α,β-methylene-ATP. However, i.c.v. pretreatment with atenolol (100 nmol/rat) and intrathecal (i.t.) pretreatment with propranolol (100 nmol/rat) and phentolamine (100 nmol/rat) did not show any significant effects. Since α,β-methylene-ATP and Bz-ATP are reported to be selective to P2X purinoceptor, these results suggest that P2X purinoceptors play an inhibitory role in nociceptive transmission in the brain. Furthermore, supra­spinal β2-adrenergic receptor is involved in the antinociceptive effect of i.c.v. administered α,β-methylene-ATP.