Abstract
The serotonin (5-hydroxytryptamine1A) 5-HT1A receptor agonist 8-OH-DPAT [(R)- (+)-8-hydroxy-2-(di-n-propylamino)tetralin] inhibits bladder activity under nociceptive but not innocuous conditions in cats with an intact spinal cord, suggestive of an effect on primary afferent C fibers or their targets. Because C fibers play a key role in reflex micturition in chronic spinal cord injury (SCI), we investigated the effect of 8-OH-DPAT on micturition in SCI cats. We also investigated GR-46611 (3-[3-(2-dimethylaminoethyl)-1H-indol-5-yl]-N-(4-methoxybenzyl)acrylamide), which has agonist activity predominantly at 5-HT1B and 5-HT1D receptors but also at the 5-HT1A receptor. Chloralose-anesthetized cats were catheterized through the bladder dome for saline-filling cystometry. Dose-response curves for i.v. 8-OH-DPAT (0.3-30 μg/kg) and GR-46611 (0.03-300 μg/kg) were followed in three cases each by 5-HT1A antagonist WAY-100635 [N-tert-butyl-3-(4-(2-methoxyphenyl)-piperazin-1-yl)-2-phenylpropanamide] at 300 μg/kg. Threshold volume, capacity, residual volume, micturition volume, and arterial pressure were measured. Intact cats showed few significant changes in cystometric variables. SCI cats responded to both 8-OH-DPAT and GR-46611 with dose-dependent increases in threshold volume, capacity, and residual volume, significant at ≥10 μg/kg for 8-OH-DPAT and at ≥3 μg/kg for GR-46611. Effects of 8-OH-DPAT but not GR-46611 were largely reversed by WAY-100635. Both 5-HT1A and 5-HT1B/1D agonists may offer a promising means of reducing bladder hyperactivity and increasing bladder capacity in patients with chronic SCI.
Footnotes
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Supported by a Veterans Affairs Merit Review Award and a grant from the Christopher Reeve Paralysis Foundation.
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doi:10.1124/jpet.103.063842.
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ABBREVIATIONS. SCI, spinal cord injury; EUS, external urethral sphincter; 5-HT1, 5-hydroxytryptamine1; EMG, electromyogram; 8-OH-DPAT, (R)-(+)-8-hydroxy-2-(di-n-propylamino)tetralin; GR-46611, 3-[3-(2-dimethylaminoethyl)-1H-indol-5-yl]-N-(4-methoxybenzyl)acrylamide; WAY-100635, N-tert-butyl-3-(4-(2-methoxyphenyl)-piperazin-1-yl)-2-phenylpropanamide.
- Received February 12, 2004.
- Accepted May 19, 2004.
- The American Society for Pharmacology and Experimental Therapeutics
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