Jd. Kristensen et al., SPINAL-CORD MORPHOLOGY AND ANTINOCICEPTION AFTER CHRONIC INTRATHECAL ADMINISTRATION OF EXCITATORY AMINO-ACID ANTAGONISTS IN THE RAT, Pain, 54(3), 1993, pp. 309-316
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 possi
ble neurotoxicologic side effects following chronic intrathecal (i.t.)
application of two NMDA receptor antagonists: 3-(2-carboxypiperazin-4
-yl)propyl-1-phosphonic acid (CPP) and kynurenic acid (KYN). Rats equi
pped with i.t. catheters were injected twice a day for 2 weeks with sa
line, 2 nmol (0.5 mug) CPP or 2 10 nmol (40 mug) KYN, where the doses
of CPP and KYN were chosen on the basis of similar analgesic effects a
fter one administration. Antinociception was tested daily using the ta
il-flick and hot-plate tests. The antinociceptive effect was similar i
n CPP- and KYN-treated rats on days 1 and 2. The effect of CPP decreas
ed 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 vol
ume was applied as a sensitive variable of spinal cord neurotoxicity.
Morphologic and ultrastructural analyses of the spinal cord segment ad
jacent to the tip of the catheter showed normal appearance with no dif
ferences between the groups. Furthermore, no differences in cell numbe
r or cell volume in the dorsal horn were found between the groups. In
conclusion, chronic i.t. administration of pharmacologically active do
ses of CPP and KYN in rats did not produce neurotoxic effects in the s
pinal cord. It was also found that CPP, in contrast to KYN, appears to
induce tolerance to antinociception.