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.
Department of Pharmacology, School of Medicine, University of Pittsburgh, Pennsylvania.
M
M
Yoshiyama
J R
JR
Roppolo
W C
WC
de Groat
D000818:Animals; D003655:Decerebrate State; D016291:Dizocilpine Maleate / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D007278:Injections, Spinal; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D001743:Urinary Bladder / Q000187:drug effects* / Q000502:physiology
D016291:Dizocilpine Maleate