Effects of MK-801 on the micturition reflex in the rat--possible sites of action.

The i.v. administration of MK-801 (dizocilpine), a noncompetitive N-methyl-D-aspartate receptor antagonist, depresses reflex bladder contractions in the rat, suggesting that glutamatergic transmission may have an important role in the micturition reflex pathway. The site of action of MK-801 was analyzed in the present experiments by studying the effects of the drug in the following urethane-anesthetized preparations: 1) intact rats, 2) decerebrate rats, 3) chronic spinal rats with transection at the T6-T8 segment and 4) intact rats in which the drug was administered via an intrathecal (i.t.) catheter at the L6-S1 spinal cord segments. Reflex bladder activity was monitored by measuring intravesical pressure under isovolumetric conditions and during a cystometrogram where the bladder outlet was open and voiding occurred. MK-801 (0.001-3 mg/kg i.v.) administered to the intact rats produced a dose-dependent suppression of the amplitude of reflex bladder contractions recorded during a cystometrogram. The ED50 and dose to produce maximal inhibition were 0.36 mg/kg and 3 mg/kg i.v., respectively. Doses of 0.3 to 1 mg/kg i.v. doubled the volume threshold for inducing micturition and decreased by 80% the voided volume in the intact rats. In decerebrate rats, reflex bladder contractions were also inhibited by MK-801 (ED50 = 0.055 mg/kg i.v.); however, in chronic spinal animals, even large doses of MK-801 (3-30 mg/kg i.v.) did not inhibit reflex bladder activity. MK-801 (6-78 micrograms) administered i.t. in the intact rats produced a dose-dependent suppression of the amplitude of reflex bladder contractions (ED50 = 13 micrograms). These results suggest that the inhibition of micturition reflex by MK-801 is mediated at least in part by an action on the lumbosacral spinal cord and is dependent on an intact pathway between the brain and spinal cord.