LASER-DOPPLER EVALUATION OF SPINAL-CORD BLOOD-FLOW AFTER INTRATHECAL ADMINISTRATION OF AN N-METHYL-D-ASPARTATE ANTAGONIST IN RATS

The N-methyl-D-aspartate (NMDA) receptor antagonist 3-(2-carboxypipera zin-4-yl)propyl-1-phosphonic acid (CPP), which produces antinociceptio n in experimental animal models after spinal administration, may be of value in clinical pain treatment. Safety screening of drugs intended for spinal administration includes evaluation of the drug's effect on spinal cord blood flow (SCBF). In the present study laser-Doppler flow -metry technique was used to assess SCBF in an experimental model usin g anesthetized, spontaneously breathing rats. Methodologic aspects of the experimental set-up were studied, and the effects on SCBF were eva luated after intrathecal (IT) administration of saline or CPP in a dos e range of 1-100 nmol. The spontaneously breathing rats, anesthetized with enflurane/N2O had stable mean arterial blood pressure values thro ughout the study, and no difference was found in arterial blood gas va lues or acid-base status measured either before or after the 80-min ob servation period. A reproducible increase in SCBF of approximately 10% during an 80-min measuring period was found in saline-treated rats. T he trauma of the IT injection procedure gave a disturbance in the regi stered SCBF that lasted less than 10 min. No difference was found in S CBF between rats injected IT with either saline or CPP in a dose range from 1 nmol, i.e., a pharmacologically active dose, to 100 nmol, i.e. , a provocative dose 400-fold the smallest dose that produces antinoci ception. When acidic solutions were injected, the SCBF increased in in verse proportion to pH. CPP in doses between 1 and 100 nmol did not af fect SCBF, indicating that neither antinociception nor neurotoxicity a re likely to occur as a result of vasoconstriction of spinal cord micr ocirculation. Our findings do not contraindicate the use of CPP in cli nical practice.