Effect of selective antagonists of group I metabotropic glutamate receptors on the micturition reflex in rats.
OBJECTIVE
To investigate the role of Group I metabotropic glutamate (mGlu) receptor subtypes on reflex-induced micturition in anaesthetized and conscious rats using selective mGlu1 (NPS 2407 and R214127) and mGlu5 (MPEP, MTEP, and SIB1893) allosteric antagonists.


METHODS
The affinity of the compounds at mGlu1 and mGlu5 receptor subtypes was evaluated by displacement of tritiated R214127 and MPEP, respectively, from rat brain tissue. Effects of intravenous (i.v.) administration of the compounds on isovolumic bladder contractions were evaluated in anaesthetized rats. Effects of MPEP and NPS 2407 on bladder filling and voiding were evaluated by cystometry using saline or diluted (0.2%) acetic acid (MPEP only) infusion of bladders in conscious rats.


RESULTS
Binding studies confirmed the selectivity of the mGlu1 (NPS 2407 and R214127) and mGlu5 (MPEP, MTEP, and SIB1893) compounds. Isovolumic bladder contractions were blocked after i.v. administration of all compounds. However, the mGlu5 antagonists were generally more potent than mGlu1 antagonists. In conscious rats with bladders infused with saline, MPEP dose-dependently and significantly increased bladder capacity starting from oral administration of 10 mg/kg. Oral administration of NPS 2407 (up to 30 mg/kg) did not induce consistent changes in bladder capacity or micturition pressure. MPEP (10 mg/kg, orally) was also evaluated in conscious rats with bladders infused with diluted acetic acid. In this model, MPEP reduced bladder instability counteracting the decrease of bladder volume capacity induced by acetic acid. There were no consistent effects on bladder contractility.


CONCLUSIONS
The results indicate that i.v. and oral administration of selective mGlu5 antagonists, but not those selective for the mGlu1 subtype, have a marked inhibitory effect on reflex micturition pathways in the rat.
Guarneri
Luciano
L
Pharmaceutical R & D Division, RECORDATI S.p.A., Milano, Italy.
Poggesi
Elena
E
Angelico
Patrizia
P
Farina
Pierluigi
P
Leonardi
Amedeo
A
Clarke
David E
DE
Testa
Rodolfo
R
D000818:Animals; D005260:Female; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects* / Q000502:physiology; D011714:Pyrans / Q000737:chemistry / Q000494:pharmacology; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology; D011804:Quinolines / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors*; D013844:Thiazoles / Q000737:chemistry / Q000494:pharmacology; D001743:Urinary Bladder / Q000502:physiology*; D014554:Urination / Q000187:drug effects* / Q000502:physiology; D014563:Urodynamics / Q000502:physiology*
C472365:3-((2-methyl-1,3-thiazol-4-yl)ethynyl)pyridine; D011714:Pyrans; D011725:Pyridines; D011804:Quinolines; C473784:R 214127; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; C120148:SIB 1893; D013844:Thiazoles; C104077:metabotropic glutamate receptor type 1; C121465:6-methyl-2-(phenylethynyl)pyridine