Abstract.We investigated the roles of β-and α 2 -adrenoceptors within the central nucleus of the amygdala (CeA) in the negative affective and sensory components of visceral pain in rats. We observed a dose-dependent reduction of intraperitoneal acetic acid-induced conditioned place aversion by bilateral injections of timolol, a β-adrenoceptor antagonist, or clonidine, an α 2 -adrenoceptor agonist, without reducing writhing behaviors. These data suggest a pivotal role of intra-CeA adrenoceptors in the negative affective, but not sensory, component of visceral pain.

Abstract. We reported previously that intracerebroventricular (i.c.v.) administration of P2X-receptor agonists produced antinociception and the effect was attenuated by i.c.v. pretreatment with b 2 -adrenergic receptor antagonists. The present study examined the involvement of noradrenergic neurons arising from the locus coeruleus (LC) in the supraspinal antinociception by the P2X-receptor agonist a ,b-methylene-ATP in rats. We found that pretreatment with DSP-4 (50 mg / kg, i.p.), which is a neurotoxin to selectively disrupt noradrenergic neurons arising from the LC, significantly attenuated the antinociception by i.c.v. administration of a ,b -methylene-ATP (10 nmol / rat). Microinjection of a ,b-methylene-ATP (0.1 and 1 nmol / side) into the bilateral LC significantly elevated the nociceptive threshold more potently than the i.c.v. administration at a dose of 10 nmol / rat. The antinociception by intra-LC injection of a ,b -methylene-ATP (1 nmol / side) was significantly attenuated by co-injection of pyridoxal-phosphate-6-azophenyl-2',4'-disulphonic acid (1 nmol / side), a non-selective P2X-receptor antagonist. These results suggest that noradrenergic neurons arising from the LC are involved in the supraspinal antinociception by a ,b -methylene-ATP through P2X receptors in the LC.

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 dosedependently 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 β 2-adrenergic receptor is involved in the antinociceptive effect of i.c.v. administered α ,β -methylene-ATP.