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. 2009 Oct;104(8):1163-9.
doi: 10.1111/j.1464-410X.2009.08515.x. Epub 2009 Mar 30.

Effects of cholinesterase inhibition in supraspinal and spinal neural pathways on the micturition reflex in rats

Hitoshi Masuda  1 , Michel B Chancellor, Kazunori Kihara, Yasuyuki Sakai, Fumitaka Koga, Hiroshi Azuma, William C de Groat, Naoki Yoshimura
Affiliations

Effects of cholinesterase inhibition in supraspinal and spinal neural pathways on the micturition reflex in rats

Hitoshi Masuda et al. BJU Int. 2009 Oct.

Abstract

Objective: To investigate whether activation of brain and spinal cholinergic pathways affects the micturition reflex in rats.

Materials and methods: The effects of intracerebroventricular (i.c.v.) or intrathecal (i.t.) administration of neostigmine as a cholinesterase inhibitor and oxotremorine-M (OXO-M) as a muscarinic acetylcholine receptor (mAChRs) agonist, on the micturition reflex were evaluated by infusion cystometrography (CMG) in urethane-anaesthetized untreated rats or rats pretreated with capsaicin.

Results: Neostigmine injected i.c.v. increased bladder capacity (BC) and pressure threshold (PT) dose-dependently, with an increase in maximum voiding pressure (MVP) and a decrease in voiding efficiency (VE) at higher doses. Also, neostigmine injected i.t. increased the BC and PT dose-dependently without changing MVP or VE, and these effects were not apparent in capsaicin-pretreated rats. In both routes, atropine as an antagonist of mAChRs, but not mecamylamine as a nicotinic-AChR antagonist, almost completely antagonized the effects of neostigmine. The rank order of potencies of the antagonists for increasing effects of BC induced by 1 nmol of neostigmine was: pirenzepine (an M(1) mAChR antagonist) = atropine > 4-DAMP (an M(3) mAChR antagonist) " methoctramine (an M(2) mAChR antagonist) and tropicamide (an M(4) mAChR antagonist) via the i.c.v. route; and atropine > methoctramine > pirenzepine > tropicamide and 4-DAMP via the i.t. route, respectively. OXO-M injected via i.c.v. and i.t. had the same effects on BC, PT, MVP and VE as neostigmine by i.c.v. and i.t., respectively.

Conclusions: These results indicate that activation of muscarinic cholinergic mechanisms by the cholinesterase inhibitor in the brain and spinal cord can inhibit the micturition reflex, mainly by affecting afferent pathways. These mAChR-induced inhibitory effects seem to be mediated through M(1)/M(3) receptor subtypes in the brain, while in the spinal cord, the M(1)/M(2) receptor subtypes might be involved in inhibitory effects, which are mediated via inhibition of mechanoceptive C-fibre afferent pathways.

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Conflict of interest statement

CONFLICT OF INTEREST: None declared.

Figures

FIG. 1
FIG. 1
Effects of i.c.v. (A,B) and i.t. (C–E) applications of neostigmine (NEO, 1 nmol) with or without pretreatment with a muscarinic M1 receptor antagonist, pirenzepine (PZ, 3 nmol) or a muscarinic M2 receptor antagonist, methoctramine (MET, 10 nmol) on bladder activity in urethane-anaesthetized rats with or without pretreatment with capsaicin (E). Arrows indicate the timing of drug administration. RU; residual urine.
FIG. 2
FIG. 2
Dose–response curves showing the effects of increasing doses of neostigmine (NEO, square i.t., six or seven rats in each dose: circle, i.c.v., six or seven rats at each dose; triangle, i.t. in eight rats pretreated with capsaicin, CAP). Abscissa: dose of neostigmine (nmol/rat); C, control (before administration); V, vehicle. Ordinates: (A) increase in BC (% of control); (B) increase in PT (% of control); (C) increase in MVP (% of control); and (D) VE (%). Each data point represents the mean (sem). Individual doses were compared with vehicle treatment using repeated-measures ANOVA (*P < 0.05, **P < 0.01).
FIG. 3
FIG. 3
Effects of i.c.v. pretreatment with atropine sulphate (A-S, 0.1–10 nmol), pirenzepine (P, 0.1–3 nmol), methoctramine (MET, 30 nmol), 4-DAMP (1–30 nmol), tropicamide (TRO, 30 nmol) or mecamylamine (MEC, 30 nmol) on the changes in BC elicited by i.c.v. injected neostigmine (NEO, 1 nmol). V; vehicle (PBS) pretreatment. Each histogram represents the mean (sem) from five or six different rats. *P < 0.05, **P < 0.01 vs vehicle treatment.
FIG. 4
FIG. 4
Effects of i.t. pretreatment with atropine sulphate (A-S, 0.3–10 nmol), pirenzepine (P, 1–30 nmol), methoctramine (MET, 1–30 nmol), 4-DAMP (10–30 nmol), tropicamide (TRO, 3–30 nmol) or mecamylamine (MEC, 30 nmol) on the changes in BC elicited by i.t. injected neostigmine (NEO, 1 nmol). V, vehicle (PBS) pretreatment. Each histogram represents the mean (sem) from five or six different rats. *P < 0.05, **P < 0.01 compared with vehicle treatment.
FIG. 5
FIG. 5
Dose–response curves showing the effects of increasing doses of OXO-M (square, i.t., six or seven rats at each dose; circle, i.c.v., six or seven rats at each dosel triangle, i.t. in six rats pretreated with capsaicin, CAP). Abscissa: the doses of OXO-M (nmol/rat); V, vehicle. Ordinates: (A) increase in BC (% of control)l (B) increase in PT (% of control); (C) increase in MVP (% of control); and (D) VE (%). Each data point represents the mean (sem). Individual doses were compared with vehicle treatment using repeated-measures ANOVA (*P < 0.05, **P < 0.01).
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