Dopamine and dobutamine induce hypokalemia in anesthetized dogs

Epinephrine-induced hypokalemia appears to be mediated by beta 2-agonist activation of Na+/K+ ATPase. To determine whether dopamine and dobutamine induce hypokalemia, eight adult mongrel dogs were anesthetized and studied in random crossover fashion. Potassium [K+] was measured with an ion-selective microelectrode, and central hemodynamics were measured continuously. After stabilization, dopamine and dobutamine were infused at doses of 2, 4, 8, and 20 micrograms/kg/min (15-min increments/dose), and 0.9% NaCl was infused at equivalent volumes, with a 1-h washout between treatments. The mean change in [K+] at each infusion rate was compared between treatments among dogs with an adequate hemodynamic response. Among dopamine responders (n = 5), [K+] decreased from 3.74 +/- 0.42 mEq/L at baseline to 3.63 +/- 0.51 at 2 micrograms/kg/min (p less than 0.02) and was not significantly different at higher doses. Among dobutamine responders (n = 7), [K+] decreased from 3.52 +/- 0.74 at baseline to 3.31 +/- 0.87 at 8 micrograms/kg/min (p less than 0.02) and 3.25 +/- 0.86 at 20 micrograms/kg/min (p less than 0.02), and was not significantly different at lower doses. We conclude that dopamine and dobutamine induce significant hypokalemia, consistent with their adrenergic agonist activity, and this may be related to the known arrhythmogenicity of these agents.     

Effects of apomorphine on urinary bladder motility in anesthetized rats

We studied the effects of apomorphine (AM) on bladder motility in anesthetized rats in which Tyrode's solution was continuously infused into the bladder at a constant rate, including an almost constant rate of bladder contraction accompanying micturition. AM at a dose of 1 mg/kg, i.v., caused a hyperactive bladder response, during which micturition disappeared. AM (12.5 micrograms for intracerebroventricular (i.c.v.) injection or 50 micrograms for intrathecal (i.t.) injection also caused a hyperactive response in about half of the rats. Supersensitization to AM appeared in reserpine-treated rats (2.5 mg/kg, i.p., 48 and 24 hr before the experiment). Haloperidol (1 mg/kg, i.v.) or SCH 23390 (5 mg/kg, i.v.) completely suppressed the hyperactive bladder response induced by AM (5 mg/kg, i.v.), and then the bladder contraction accompanying micturition reappeared after administration of these drugs. Pretreatment with sulpiride (100 mg/kg, i.p.) for 60 min, which hardly affected the bladder contraction induced by infusion of Tyrode's solution, suppressed the hyperactive bladder response induced by AM. These results suggest that the hyperactive bladder response induced by i.v.-injected AM results from synchronous stimulation of the micturition reflex centers in the brain stem and sacral cord and that the hyperactive bladder response is elicited via both D1 and D2 receptors.     

Dopamine D1 receptor agonists induce penile erections in rats

The dopamine receptor agonist apomorphine has been recently introduced in the treatment of erectile dysfunction. While it is well established that dopamine D2-like receptors play a crucial role in this effect, conflicting result are reported in the literature as for the role of dopamine D1-like receptors. The aim of this study was to determine the effect of systemic administration of dopamine D1-like receptor agonists on penile erection in rats. Male Wistar rats were treated with three different, and not structurally related, dopamine D1-like receptor agonists: the partial agonists SKF38393 ((+) 2,3,4,5-tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine) and CY 208-243 ((-)-4,6,6a,7,8,12b-exahydro-7-methylindole [4,3-ab]fenantridine), and the full agonist A 77636 ((-)-(1R,3S)-3-Adamantyl-1-(aminomethyl)-3,4-dihydro-5,6-dihydroxy-1H-2-benzopyran hydrochloride). All three compounds dose-dependently increased the number of penile erections, with the full agonist A77636 showing a more pronounced effect with respect to the other two. Moreover, the dopamine D1-like receptor antagonist SCH 23390 ((R)-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine) dose-dependently antagonised A77636 effect. These results show that systemic administration of dopamine D1-like receptor agonists induce penile erection in rats. This observation suggests that dopamine D1-like receptor agonists might be considered as a possible alternative to apomorphine in the treatment of erectile dysfunction, thus avoiding the typical side effects related to the stimulation of dopamine D2-like receptors such as nausea.     

Tachykinin NK1 receptor subtypes in the rat urinary bladder.

1. Following the recent proposal that the selective agonist septide, ([pGlu6,Pro9]SP(6-11)), acts on a novel tachykinin receptor distinct from the ''classical'' NK1 receptor, the aim of the study was to investigate the possible heterogeneity of tachykinin NK1 receptors in the rat urinary bladder. 2. The synthetic tachykinin receptor agonists, septide (pD2 7.87) and [Sar9]substance P (SP) sulphone (pD2 7.64) produced concentration-dependent contractions of the rat isolated urinary bladder. 3. The NK1 receptor antagonists GR82,334, (+/-)-CP96,345, and RP67,580 competitively antagonized (slopes of Schild plot not significantly different from unity) the response to septide with the rank order of potency (pKB values in parentheses): RP 67,580 (7.57) > GR 82,334 (7.01) > (+/-)-CP 96,345 (6.80). The same antagonists were significantly less potent when tested against [Sar9]SP sulphone, while maintaining the same rank order of potency: RP 67,580 (7.00) > GR 82,334 (5.93) > (+/-)-CP 96,345 (< 6). The antagonists did not affect the concentration-response curve to bombesin. 4. To exclude the involvement of the NK2 receptor, a second series of experiments was performed in the presence of the potent nonpeptide NK2 receptor antagonist, SR 48,968. SR 48,968 (1 microM) produced a rightward shift of the concentration-response curve to the NK2 receptor selective agonist, [beta Ala8]neurokinin A (NKA) (4-10). SR 48,968 did not significantly modify the response to SP, NKA, neurokinin B (NKB), neuropeptide K (NPK), neuropeptide gamma (NP gamma), SP(4-11), SP(6-11), septide or [Sar9]SP sulphone.(ABSTRACT TRUNCATED AT 250 WORDS)     

Characterization of the muscarinic receptor subtypes in the rat urinary bladder

We investigated the nature of the muscarinic receptors present in the rat urinary bladder by performing binding studies with various selective (pirenzepine, AF-DX 116, hexahydrosiladifenidol, benzhexol, 4-diphenyl-acetoxy-N-methyl piperidine methiodide, dicyclomine, secoverine) and classical (N-methylscopolamine, atropine) antagonists. Competition experiments were carried out against [3H]N-methyl scopolamine at 30 degrees C in Na+/Mg2+ HEPES buffer; non-specific binding was determined in the presence of 1 microM 3-quinuclidinyl benzilate. Of all the antagonists examined, only AF-DX 116 exhibited a heterogeneous binding profile (nH less than 1). Computer-assisted analysis showed that the data fitted best to a two-binding site model, revealing the existence of high and low affinity receptors. The affinity values of AF-DX 116, determined in binding experiments carried out in heart and gland homogenates, allowed us to classify the rat urinary bladder receptors into cardiac and glandular subtypes. We suggest that the glandular receptor subtype is involved in smooth muscle contraction, since AF-DX 116 was equally potent in inhibiting smooth muscle contraction and the secretion of saliva.     

Pharmacological characterization of the muscarinic receptor subtypes responsible for the contractile response in the rat urinary bladder

1 Contractile responses of smooth muscle from the Wistar rat urinary bladder were studied with the use of muscarinic agonists and antagonists. 2 McN-A-343 induced only weak contractile responses of the bladder muscle. In contrast, oxotremorine showed higher potency than either acetylcholine or bethanechol in inducing a contractile response (the respective pD₂ values were 6.38 ± 0.25, 4.82 ± 0.24 and 4.42 ± 0.14). 3 The M₂ antagonists, methoctramine (10^?9m to 10^?5m ) and gallamine (10^?9m to 10^?5m ), did not reduce acetylcholine-induced (10^?5m ) contractions of the bladder muscle strip. On the other hand, 4-diphenyl-acetoxy-N-methyl piperidine methiodide (4-DAMP, 10^?10m to 10^?7m ), an M₃ receptor blocker, effectively antagonized the acetylcholine-induced contractions in a concentration-dependent manner. 4-DAMP had a similar pA₂ value to those of the non-selective antagonists, atropine and scopolamine (pA₂ values were 8.26 ± 0.05, 8.36 ± 0.05 and 8.41 ± 0.11, respectively). Pirenzepine, an M₁ blocker, antagonized the contractions at higher concentrations (10^?8m to 10^?5m , pA₂= 6.23 ± 0.04). 4 It is concluded that (1) the dominant muscarinic receptor subtype responsible for smooth muscle contraction in the rat urinary bladder is M₃; and (2) the muscarinic agonist oxotremorine was more potent than acetylcholine and bethanechol in inducing a contractile response.     

Opioid receptor subtypes involved in the central inhibition of urinary bladder motility

Intracerebroventricular morphine consistently inhibited spontaneous urinary bladder contractions recorded from the anesthetized rat. This effect was reversed by naloxone and appeared to be exerted within the forebrain. Neither dynorphin-(1-13) nor U-50, 488 (kappa-agonists) affected bladder motility. Ethylketocyclazocine inhibited contractions only at higher doses, possibly due to mu-receptor interactions. Bladder activity was consistently inhibited by the mu-agonists morphiceptin and [D-Ala2, MePhe4, Gly-(ol)5]enkephalin (DAGO) and by [D-Ala2, D-Leu5]enkephalin (DADLE, delta-agonist). DAGO was the most potent compound tested. These observations support the involvement of mu- and possibly delta-receptors in the centrally mediated inhibition of urinary bladder motility by opioids.     

Effects of ageing on muscarinic receptor subtypes and function in rat urinary bladder

We compared the density and function of M₂ and M₃ muscarinic acetylcholine receptor subtypes in the urinary bladder of young adult (3 months) and old (23 months) male Wistar rats. Old rats had a reduced density of muscarinic receptors (96±10 vs. 156±21 fmol/mg protein), but competition experiments with the M₃-selective darifenacin did not indicate alterations in the relative roles of M₂ and M₃ receptors, with the former being more abundant. The amount of immunodetectable -subunits of various G-proteins potentially linked to muscarinic receptor function was unchanged. The potency of carbachol to contract bladder strips was also unaltered; its maximum effects as well as those of a single KCl concentration were unchanged if raw data or those corrected for strip length were analysed, but somewhat reduced when those corrected for strip weight were analysed. Antagonistic effects of atropine, the M₂-selective Ro 320–6206 and the M₃-selective darifenacin were unchanged. Agonistic effects of the M₃-sparing agonist 4-(2-oxo-2,3-dihydro-benzoimidazol-1-yl)-[1,4]bipiperidinyl-1-carboxylic acid ethyl ester were similarly poor in young and old rats. Additional experiments were concomitantly performed in submandibular glands from the same animals. While total muscarinic receptor density in submandibular glands was not significantly affected by age (56±5 vs. 61±4 fmol/mg protein), the relative contribution of M₃ receptors significantly declined from 68±3% to 57±2% based upon darifenacin competition curves. We conclude that aged Wistar rats express fewer muscarinic receptors in their urinary bladder, but there is no change in the relative abundance of M₂ and M₃ receptors; this is accompanied by only minor if any alterations in receptor responsiveness. In contrast, submandibular gland expresses similar receptor numbers in young and old rats, but slightly fewer M₃ receptors in old animals.     

Dopamine antagonists induce gastric lesions in rats

Gastric lesions were provoked in all rats that had received intraperitoneally a single dose of the dopamine antagonists haloperidol, metoclopramide or domperidone 24 h before. Dose-dependence was demonstrated for haloperidol. This drug induced gastric lesions as early as 90 min after its application. The ulcerogenic effect of haloperidol was completely prevented or markedly reduced by simultaneous applications of dopamine agonists bromocriptine or L-dopa. We conclude that the model of gastric lesions induced by dopamine antagonists could be successfully applied in further investigations of the role of dopamine in the pathogenesis of ulcer disease.     

多沙唑嗪对映体对大鼠血压和排尿功能的影响

目的观察十二指肠给予多沙唑嗪(rac-DOX)及其对映体(S-DOX、R-DOX)对麻醉大鼠血压和膀胱排尿功能的影响。方法采用八道生理仪记录麻醉大鼠颈总动脉血压、心率以及膀胱排尿压、排尿间隔,并测量排尿量。结果十二指肠给予S-DOX、R-DOX和rac-DOX均可剂量依赖性降低颈总动脉收缩压、舒张压和平均动脉压,1.0mg.kg-1时3者对平均动脉压的降低幅度分别达到23.5%±4.6%、38.5%±8.9%和42.6%±7.5%,3者降低平均动脉压的ED30值依次为(2.0±0.8)、(0.6±0.7)、(0.6±0.5)mg.kg-1。S-DOX降低收缩压、舒张压和平均动脉压的作用均弱于rac-DOX和R-DOX(P<0.05),rac-DOX与R-DOX的降压作用差异无显著性(P>0.05)。rac-DOX在0.1～3.0mg.kg-1剂量范围内剂量依赖性抑制麻醉大鼠心率,而S-DOX和R-DOX仅在3.0mg.kg-1剂量时对心率有抑制作用。十二指肠给予S-DOX、R-DOX和rac-DOX均剂量依赖性降低麻醉大鼠膀胱排尿压,3种药物对排尿压的最大降低幅度分别为13.4%±5.7%、14.5%±11.0%和10.9%±7.6%,3者降低排尿压的作用差异无显著性(P>0.05)。与S-DOX相比,R-DOX可缩短排尿间隔并减少排尿量(P<0.05),而S-DOX和rac-DOX对排尿间隔和排尿量无影响。结论与R-DOX和rac-DOX相比,S-DOX保留了对麻醉大鼠膀胱排尿压的有利作用,减轻了对血压、心率和膀胱排尿间隔的不良影响。     

The effect of baclofen on the urinary bladder contraction accompanying micturition in anesthetized rats

We studied the effects of baclofen on the bladder contraction induced by infusion of Tyrode's solution into the urinary bladder in anesthetized rats. Baclofen (5 mg/kg, i.v.) completely inhibited bladder contraction and abolished the efferent discharges recorded from the left pelvic nerve, causing the bladder pressure to rise until solution leaked from the penis. The inhibitory effect of baclofen (5 mg/kg, i.v.) could not be reversed by picrotoxin (1 mg/kg, i.v., twice with an interval of 10 min) or naloxone (1 mg/kg, i.v.). In parallel with convulsion, strychnine (1 mg/kg, i.v.) contracted the bladder which had been inhibited by baclofen and generated electrical activities consisting of efferent discharges and electromyograms. The dose of intracerebroventricularly or intrathecally injected baclofen which completely inhibited the bladder contraction was 0.1 or 10 micrograms, respectively. After the inhibition of bladder contraction by i.v. injection of baclofen, electrical stimulation of the sacral cord could contract the bladder and cause a fall in bladder pressure to around the level existing after micturition. From these results, the active site of baclofen which is related to the inhibition of bladder contraction is thought to be the micturition center in the brain stem.     

Dopamine receptor subtypes in the human pulmonary arterial tree

Dopamine induces vasorelaxation of pulmonary artery primarily through an endothelium-dependent mechanism, but dopamine receptor subtypes involved in these mechanisms have not been identified yet. The expression and localization of dopamine D1-like (D1 and D5) and D2-like (D2, D3 and D4) receptors were investigated in hilar, lobar and intrapulmonary branches of human pulmonary artery by immunoblotting and immunohistochemistry. Pulmonary artery expresses dopamine D1, D2, D4 and D5 receptor subtypes, but not the D3 receptor subtype. Dopamine D1 and to a lesser extent D5 receptors were accumulated primarily in the endothelium of extrapulmonary branches of pulmonary artery. A faint dopamine D1 and D5 receptor immunoreactivity was found in the inner media of extrapulmonary and of large sized intrapulmonary branches of pulmonary artery, but not in medium- or small-sized intrapulmonary artery branches. Dopamine D2 and to a lesser extent D4 receptor immunoreactivity co-localized with the tyrosine hydroxylase-immunoreactive sympathetic plexus supplying pulmonary artery was found in the adventitia and in the adventitia-media of both extra- and different-sized intrapulmonary branches of pulmonary artery. These findings suggest the possible role of dopamine receptors in the pulmonary endothelium-dependent vasorelaxing activity. The D1 receptor subtype seems to be the most involved in this mechanism. Dopamine D2-like receptors are prejunctional and are located at the level of sympathetic neuroeffector plexus. The heterogeneous distribution and density of dopamine receptor subtypes along the human pulmonary arterial tree may be related to the different functional roles of dopamine at various levels of the pulmonary circulation.     

Dopamine receptor subtypes and formalin test analgesia.

The role played by dopamine D1 and D2 receptors in formalin test analgesia was explored by challenging D-amphetamine- and morphine-induced analgesia with mixed and selective D1 and D2 antagonists, and by examining the relative analgesic activity of mixed and selective D1 and D2 agonists. The mixed D1/D2 dopamine antagonist cis-flupenthixol (0.5 mg/kg), the D2 antagonist pimozide (0.5 mg/kg), and the D1 antagonist SCH 23390 (0.1 mg/kg) attenuated both D-amphetamine and morphine analgesia. The mixed D1/D2 agonist apomorphine and the selective D2 agonist quinpirole produced dose-dependent analgesia while the selective D1 agonist SKF 38393 was without effect. These data suggest that D1 receptors play an "enabling" role in D2 receptor-mediated analgesia in the formalin test.     

Muscarinic receptor subtypes and signalling involved in the attenuation of isoprenaline-induced rat urinary bladder relaxation

β-Adrenoceptors are important mediators of smooth muscle relaxation in the urinary bladder, but the concomitant presence of a muscarinic agonist, e.g., carbachol, can attenuate relaxation responses by reducing potency and/or efficacy of β-adrenoceptor agonists such as isoprenaline. Therefore, the present study was designed to explore the subtypes and signalling pathways of muscarinic receptors involved in the attenuation of isoprenaline-induced isolated rat detrusor preparations using novel subtype-selective receptor ligands. In radioligand binding studies, we characterized BZI to be a M₃-sparing muscarinic agonist, providing selective M₂ stimulation in rat bladder, and THRX-182087 as a highly M₂-selective antagonist. The use of BZI and of THRX-182087 in the presence of carbachol enabled experimental conditions with a selective stimulation of only M₂ or M₃ receptors, respectively. Confirming previous findings, carbachol attenuated isoprenaline-induced detrusor relaxation. M₂-selective stimulation partly mimicked this attenuation, indicating that both M₂ and M₃ receptors are involved. During M₃-selective stimulation, the attenuation of isoprenaline responses was reduced by the phospholipase C inhibitor U 73,122 but not by the protein kinase C inhibitor chelerythrine. We conclude that both M₂ and M₃ receptors contribute to attenuation of β-adrenoceptor-mediated relaxation of rat urinary bladder; the signal transduction pathway involved in the M₃ component of this attenuation differs from that mediating direct contractile effects of M₃ receptors.     

Chiral selective effects of doxazosin enantiomers on blood pressure and urinary bladder pressure in anesthetized rats

AIM: To study chiral selective effects of doxazosin enantiomers on blood pressure and urinary bladder pressure in anesthetized rats. METHODS: In anesthetized rats, the carotid blood pressure, left ventricular pressure of the heart and the urinary bladder pressure were recorded. RESULTS: Administration of S-doxazosin at 0.25, 2.5, 25, and 250 nmol/kg iv produced a dose-dependent decrease in blood pressure, but its depressor effect was significantly weaker than that induced by R-doxazosin and racemic-doxazosin (rac-doxazosin), and the ED(30) values (producing a 30% decrease in mean arterial pressure) of R-doxazosin, rac-doxazosin and S-doxazosin were 15.64, 45.93, and 128.81, respectively. Rac-doxazosin and its enantiomers administered cumulatively in anesthetized rats induced a dose-dependent decrease in the left ventricular systolic pressure and +/-dp/dt(max), and the potency order of the 3 agents was R-doxazosin > rac-doxazosin > S-doxazosin. Rac-doxazosin and its enantiomers decreased the vesical micturition pressure dose-dependently at 2.5, 25, and 250 nmol/kg, and the inhibitory potency among the 3 agents was not significantly different. CONCLUSION: S-doxazosin decreases the carotid blood pressure and left ventricular pressure of the heart less than R-doxazosin and rac-doxazosin, but its effect on the vesical micturition pressure is similar to R-doxazosin and rac-doxazosin, indicating that S-doxazosin has chiral selectivity between cardiovascular system and urinary system in anesthetized rats.     

Beta-adrenoceptor subtypes in the detrusor of guinea-pig urinary bladder.

beta-Adrenoceptors have been demonstrated in the urinary bladders of many animals including the guinea pig. However, there is little information on the subtypes involved in the antispasmodic activity of beta-adrenoceptor activation in the guinea-pig detrusor. The present study uses the non-selective beta-agonist isoproterenol, the antagonist nadolol, the beta 2-selective agonists salbutamol and terbutaline, the antagonist ICI 118551, and the beta 1-selective antagonist metoprolol, to demonstrate functionally the subtypes existing in the guinea-pig detrusor. Isoproterenol dose-dependently reduces the myogenic activity in the guinea-pig detrusor induced by mild depolarization with 20 mM potassium in the tissue bath. At the supramaximal concentration of 30 microM, isoproterenol achieves 73 +/- 2% of the reference maximal response. This activity of isoproterenol is reduced to 9 +/- 5, 24 +/- 6 and 54 +/- 1% in the total blockade of beta, beta 1 and beta 2 with nadolol, metoprolol and ICI 118551, respectively. Consistently, salbutamol and terbutaline at the same concentration produce only 35 +/- 1 and 38 +/- 4% of the response, respectively. Thus, both beta 1- and beta 2-adrenoceptors are present in the detrusor of the guinea-pig urinary bladder. Although activation of either subtype results in antispasmodic action, the larger portion of the antispasmodic activity appears to be associated with the activation of the beta 1-subtype.     

Dopamine receptor subtypes: in vivo biochemical evidence for functional interaction

SKF 38393, a selective D-1 dopamine (DA) agonist, enhanced the ability of spiperone, a D-2 antagonist, to increase rat striatal DA metabolite concentrations. Conversely, SKF 38393 reduced the abilities of pergolide and LY 171555, D-2 agonists, to decrease striatal DA metabolite concentrations. These findings are discussed in terms of a possible functional interaction between D-1 and D-2 DA receptors.     

Effects of propiverine hydrochloride (P-4) and its metabolites on urinary bladder function in anesthetized rats

The effects of P-4 and its active metabolites, 1-methyl-4-piperidyl diphenylpropoxyacetate N-oxide[P-4(N----O)], 1-methyl-4-piperidyl benzilate N-oxide [DPr-P-4 (N----O)] and 1-methyl-4-piperidyl benzilate hydrochloride (DPr-P-4), on urinary bladder function were investigated in urethane anesthetized rats. By cystometrography, P-4 (2, 4 mg/kg, i.v.) and P-4 (N----O) (4 mg/kg, i.v.), which have direct action on smooth muscles, significantly increased the maximum vesical volume. As for rhythmic bladder contractions, P-4 (1,2,4 mg/kg, i.v.) and P-4 (N----O) (2, 4 mg/kg, i.v.) significantly decreased the frequency with a slight decrease in the amplitude. On the other hand, DPr-P-4 (N----O) (0.1, 0.5 mg/kg, i.v.) and DPr-P-4 (0.01, 0.05 mg/kg, i.v.), which have anticholinergic effects, significantly inhibited the maximum vesical pressure on the cystometrograms, and DPr-P-4 (N----O) (0.1, 0.5 mg/kg, i.v.) and DPr-P-4 (0.005, 0.05 mg/kg, i.v.) significantly inhibited the amplitude of the rhythmic bladder contractions. The effects of flavoxate and papaverine were similar to those of P-4 and P-4 (N----O), but the effects of propantheline and atropine were similar to those of DPr-P-4 (N----O) and DPr-P-4 in these two experimental methods. These results suggest that the clinical effects of P-4 are based not only on the actions of P-4 itself but also on those of its active metabolites.     

Central effects of baclofen on thel-dopa induced hyperactive urinary bladder of the rat

Summary Cystometric recordings were performed in pentobarbitone anaesthetized rats and the effects of baclofen on urinary bladder function were evaluated as their influence on bladder hyperactivity induced by 1-dihydroxyphenylalanine (l-dopa) after peripheral decarboxylase inhibition. The bladder response was inhibited by intracerebroventricularly (i.c.v., 4th ventricle, 0.1 g) as well as by systemically administered (10 mg/kg i.v.) baclofen. Intravenous naloxone but not i.v. bicuculline i.c.v. substance P or i.c.v. glutamate antagonized the inhibitory actions of i.c.v. or/and i.v. baclofen.It is suggested that baclofen depresses the hyperactive bladder by a central action that is unrelated to bicuculline sensitive gamma aminobutyric acid mechanisms, substance P or glutamate neurotransmission but that is possibly related to interference with opioid mechanisms.