Spinal cord morphology and antinociception after chronic intrathecal administration of excitatory amino acid antagonists in the rat

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Abstract
Drugs that antagonize the action of excitatory amino acids on the NMDA receptor in the spinal cord are of interest in pain treatment. Before such drugs can be applied clinically, their potential toxicity should be studied. This study was performed in rats in order to reveal possible neurotoxicologic side effects following chronic intrathecal (i.t.) application of two NMDA receptor antagonists: 3-(2-carboxypiperazin-4-yl)propyl-l-phosphonic acid (CPP) and kynurenic acid (KYN). Rats equipped with i.t. catheters were injected twice a day for 2 weeks with saline, 2 nmol (0.5 μg) CPP or 210 nmol (40 μg) KYN, where the doses of CPP and KYN were chosen on the basis of similar analgesic effects after one administration. Antinociception was tested daily using the tail-flick and hot-plate tests. The antinociceptive effect was similar in CPP- and KYN-treated rats on days 1 and 2. The effect of CPP decreased during the following days, whereas that of KYN persisted for the 12-day testing period. The spinal cord was then removed and prepared for light and electron microscopic examination and a morphometric method using an unbiased stereological estimator of cell number and cell volume was applied as a sensitive variable of spinal cord neurotoxicity. Morphologic and ultrastructural analyses of the spinal cord segment adjacent to the tip of the catheter showed normal appearance with no differences between the groups. Furthermore, no differences in cell number or cell volume in the dorsal horn were found between the groups. In conclusion, chronic i.t. administration of pharmacologically active doses of CPP and KYN in rats did not produce neurotoxic effects in the spinal cord. It was also found that CPP, in contrast to KYN, appears to induce tolerance to antinociception.