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NEUROPHARMACOLOGY

The Role of Melanin-Concentrating Hormone-1 Receptors in the Voiding Reflex in Rats

Department of Target Discovery and Assessment, Lundbeck Research USA, Paramus, New Jersey

We have used the selective melanin-concentrating hormone-1 (MCH₁) receptor antagonist SNAP 7941 [((+)-methyl (4S)-3-{[(3-{4-[3-(acetylamino)phenyl]-1-piperidinyl}propyl) amino]carbonyl}-4-(3,4-difluorophenyl)-6-(methoxymethyl)-2-oxo-1,2,3,4-tetrahydro-5-pyrimidinecarboxylate hydrochloride)] to investigate the role of the hypothalamic neuropeptide MCH in the control of voiding in rats. Intravenous administration of SNAP 7941 (3 and 10 mg/kg i.v.) produced dose-related inhibition of rhythmic, distension-induced voiding contractions in anesthetized rats. In conscious rats in which repeated voiding cycles were evoked by continuous slow transvesicular infusion of saline, intragastric SNAP 7941 [0.03–1 mg/kg intragastrically (i.g.)] produced sustained increases in infusion capacity (maximum = 220% basal), comparable with the effects of the 5-hydroxytryptamine_1A antagonist WAY 100635 (N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinyl-cyclohexanecarboxamide maleate salt), and the muscarinic antagonist, oxybutynin (4-diethylaminobut-2-ynyl 2-cyclohexyl-2-hydroxy-2-phenylacetate hydrochloride). SNAP 7941 produced similar results when administered at a low dose (0.01 nmol) into the lateral ventricle (intracerebroventricular). The opposite effect was produced when MCH (20 nmol) was delivered intracerebroventricularly, resulting in a 34% decrease in apparent bladder capacity with increased urinary frequency. The effect of MCH was blocked by the prior intragastric administration of SNAP 7941 (0.1 mg/kg), but oxybutynin (1 mg/kg) was ineffective. Finally, in conscious spontaneously hypertensive rats, SNAP 7941 (0.1 mg/kg i.g.) produced a 31% reduction in micturition frequency, accompanied by a 36% increase in bladder capacity, with no effect on total volume voided over 6 h. The data indicate that MCH acts via MCH₁ receptors within the CNS to modulate the voiding reflex in rats. The striking effects of the MCH₁ antagonist SNAP 7941 to increase bladder capacity and reduce voiding frequency indicate that MCH₁ antagonists may offer a potential novel approach for treating overactive bladder syndrome.

Address correspondence to: Douglas A. Craig, Lundbeck Research USA, Inc., 215 College Road, Paramus, NJ 07652-1431. E-mail: dcraig1{at}optonline.net