CENTRAL-NERVOUS-SYSTEM EFFECTS OF INTRATHECAL MUSCLE-RELAXANTS IN RATS

When given for a sufficient time and dose intravenously, neuromuscular blocking drugs eventually can enter the cerebrospinal fluid (CSF). To study the potential pharmacologic consequences of neuromuscular block ing drugs in the CSF, a model was developed in the rat by using an int rathecal infusion of these drugs. A cannula was stereotaxically implan ted in a lateral cerebral ventricle of anesthetized male Sprague-Dawle y rats (250-300 g). Several days later, the effects of an intraventric ular infusion (5 muL/min) of atracurium (0.804 mumol/mL), pancuronium (0.172 mumol/mL), and vecuronium (21.978 mumol/mL) were studied in una nesthetized rats. These rats (n = 6 in each group) exhibited dose-depe ndent hyperexcitability during drug infusion, with seizures occurring at threshold doses of (mean), 0.12, 0.26, and 0.065 +/- 0.010 and 3.32 mumol/kg of atracurium, pancuronium, and vecuronium, respectively. Th e neuromuscular ED50 (intravenous dose required to produce a 50% depre ssion of twitch tension) in rats determined by other investigators are 0.408, 0.115, and 0.352 mumol/kg for atracurium, pancuronium, and vec uronium, respectively. Therefore, seizure threshold doses were not rel ated to the potencies of these drugs as neuromuscular blocking drugs. Based on these data, central nervous system effects were studied over the subseizure dose range approximating 1/100, 1/10, and 1/5 of the cu mulative dose causing seizures for each drug (n = 5 for each dose). At 1/100 of seizure dose, decreased locomotor activity and piloerection occurred. At 1/10 to 1/5 of seizure dose, agitation, shivering, splaye d limbs, and whole body shaking resulted. We have demonstrated also th at at concentrations similar to those in the CSF at seizure threshold doses, atracurium, pancuronium, and vecuronium produce increases in in tracellular calcium in rat cortical brain slices in vitro, suggesting a possible mechanism for seizure activity. We conclude that neuromuscu lar blocking drugs injected directly into the CSF cause dose-dependent central nervous system excitation and seizures. Although species and possible dosage differences prevent any clinical applications, we prop ose that these results in rats indicate that possible central nervous system effects of neuromuscular blocking drugs in patients receiving t hese drugs for several days deserves exploration.