The intrathecal administration of excitatory amino acid receptor antagonists selectively attenuated carrageenan-induced behavioral hyperalgesia in rats

Abstract

A single unilateral injection of carrageenan (4.5–6.0 mg in 0.15–0.20 ml saline) into the rat hindpaw induced behavioral hyperalgesia as evidenced by a significant reduction in hindpaw withdrawal latency to a noxious thermal stimulus. The involvement of N-methyl-D-aspartate (NMDA) receptors in this model of hyperalgesia was examined by intrathecal administration of the selective excitatory amino acid (EAA) receptor antagonists: (±)-2-amino-5-phosphonopentanoic acid (AP-5), (±)-3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP), ketamine hydrochloride (ketamine), 7-chlorokynurenic acid (7-Cl kynurenic acid), and 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX). The effects of dizocilpine maleate (MK-801) were studied under the same conditions and published previously (Ren et al., 1992) and the data are presented for comparison. While the withdrawal latencies of the non-injected paws and of the paws of naive rats were not significantly affected by application of the EAA receptor antagonists at doses tested, the paw withdrawal latencies of the carrageenan-injected paws were elevated dose dependently. The rank order of potency of these agents to reduce hyperalgesia was: MK-801 ≥ AP-5 ≥ CPP = 7-Cl kynurenic acid = ketamine ⪢ CNQX > 0. In contrast, intrathecal injection of the opioid receptor agonists, [D-Ala 2,MePhe 4,Gly-ol 5]enkephalin (DAMGO, μ-selective) and [D-Pen 2,D-Pen 5] enkephalin (DPDPE, δ-selective), produced antinociception in both injected and non-injected paws. DAMGO was much more potent, while DPDPE was less potent, than MK-801. It is concluded that NMDA receptors are involved in the development of carrageenan-induced thermal hyperalgesia.