Effects of cholinesterase inhibition in supraspinal and spinal neural pathways on the micturition reflex in rats
- Hitoshi Masuda
- Michel B. Chancellor
- Kazunori Kihara
- Yasuyuki Sakai
- Fumitaka Koga
- Hiroshi Azuma
- William C. de Groat
- Naoki Yoshimura
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 M1 mAChR antagonist) = atropine > 4-DAMP (an M3 mAChR antagonist) >> methoctramine (an M2 mAChR antagonist) and tropicamide (an M4 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 M1/M3 receptor subtypes in the brain, while in the spinal cord, the M1/M2 receptor subtypes might be involved in inhibitory effects, which are mediated via inhibition of mechanoceptive C-fibre afferent pathways.