SYNERGISTIC EFFECT OF BICUCCULINE ON SPASTIC PARAPLEGIA INDUCED BY INTRATHECAL MORPHINE AFTER NON-INJURIOUS INTERVAL OF SPINAL CORD ISCHEMIA IN THE RAT

Abstract

S94 INTRODUCTION: We have recently found that intrathecal (IT)morphine after noninjurious interval of spinal ischemia in rodent model induced transient spastic paraplegia which lasted for a several hours corresponding to the duration of the effect of IT morphine [1]. We also reported repetitive morphine- induced irreversible paraplegia after non-injurious interval of spinal cord ischemia in the rat [2]. However, the mechanism of morphine-induced spastic paraplegia in this condition is not known. We hypothesized that morphine inhibits the GABAergic interneurons which control the tonus of spinal alpha-motoneurons, and that the disinhibition of alpha-motoneurons causes the spastic paraplegia. The purpose of this study is to analyze the interaction between GABAA antagonist and morphine on motor function after non-injurious interval of spinal cord ischemia in the rat. METHODS: Rats were implanted with chronic IT catheters (PE-10) 7 days prior to induction of spinal ischemia. Under halothane (1.0-2.0%) anesthesia, 6 min of ischemia was induced by the placement and subsequent inflation of a 2F Fogarty catheter which was inserted the descending thoracic aorta and combined with systemic hypotension (40mmHg) produced by withdrawal of the arterial blood from the left carotid artery [3]. After ischemia all intravascular catheters were removed and rats were allowed to recover for 3days. During this period the recovery of motor function (motor deficit index: MDI) was assessed periodically using a 6 point grading scale (6=complete paraplegia, 0=normal motor function). Thirty minutes after reperfusion, drugs were injected through IT catheter, and ED50 value of morphine or bicucculine alone was determined by the dose-response curve from the respective area under the curve of MDI. In order to evaluate the ED50 values of the dose combinations, dose response curve for the combination were generated using three dose levels in a constant dose ratio based on the ED50 values of each agent administrated separately (Table 1). The isobolograms were constructed by plotting the ED50 values of the single agents on X and Y axis, and by plotting the experimentally derived ED50 values of the combination dosage on the same axis.Table 1RESULTS: Intrathecal administration of morphine or bicucculine alone produced dose-dependent increase of motor deficit index, with the order of potency (ED50 micro-g.) being: morphine (10.28), bicucculine (3.24). In the isobologramic analysis, the experimental combinative value of ED50 fell below theoretical additive line, indicating a multiplicative interaction. (Figure 1).Figure 1CONCLUSION: Our results suggest that the synergistic interaction between morphine with bicucculine to the spastic paraplegia may depend upon events that occur as a result of functional interaction between two separate systems influenced by the two classes of receptors.