Inhibition of Bladder Activity by 5-Hydroxytryptamine₁ Serotonin Receptor Agonists in Cats with Chronic Spinal Cord Injury

Abstract

The serotonin (5-hydroxytryptamine 1A ) 5-HT 1A receptor agonist 8-OH-DPAT [(R)-(ϩ)-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-HT 1B and 5-HT 1D receptors but also at the 5-HT 1A receptor. Chloraloseanesthetized cats were catheterized through the bladder dome for saline-filling cystometry. Dose-response curves for i.v. 8-OH-DPAT (0.3-30 g/kg) and GR-46611 (0.03-300 g/kg) were followed in three cases each by 5-HT 1A antagonist WAY-100635 [N-tert-butyl-3-(4-(2-methoxyphenyl)-piperazin-1-yl)-2-phenylpropanamide] at 300 g/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 Ն10 g/kg for 8-OH-DPAT and at Ն3 g/kg for GR-46611. Effects of 8-OH-DPAT but not GR-46611 were largely reversed by WAY-100635. Both 5-HT 1A and 5-HT 1B/1D agonists may offer a promising means of reducing bladder hyperactivity and increasing bladder capacity in patients with chronic SCI.With spinal cord injury (SCI) rostral to the lumbosacral level, the most common constellation of lower urinary tract symptoms is loss of voluntary control of micturition, bladder hyperactivity mediated by spinal reflex pathways, and hyperreflexia or spasticity of the external urethral sphincter (EUS), with bladder and EUS activity commonly being dyssynchronous (bladder-sphincter dyssynergia) (Arnold, 1999;Madersbacher et al., 1999;Yoshimura et al., 2000). The patient is thus left in a state of unbalanced reflex incontinence, for which the management of choice is currently intermittent self-catheterization (Madersbacher et al., 1999). Pharmacotherapy that reduces bladder hyperactivity, improves EUS function, and increases functional bladder capacity could be beneficial in maintaining continence between catheterizations, reducing kidney damage that results from high intravesical pressure, and reducing autonomic dysreflexia associated with bladder hyperreflexia.Primary afferent C fibers and the second order neurons with which they communicate are attractive targets for pharmacotherapy. Whereas mechanoreceptive A␦ fibers participate in the normal spinobulbospinal micturition reflex, C fibers are generally silent during bladder filling in normal animals and are activated only in nociceptive conditions (de Groat et al., 1990). In chronic SCI, the spinobulbospinal reflex is lost and C fibers participate in the purely spi...

Characterization of Prejunctional Serotonin Receptors Modulating [3H]Acetylcholine Release in the Human Detrusor

“…This may represent an additional mechanism to prevent involuntary leakages due to sphincter incompetence and, in turn, stress UI. The same peripheral mechanism might be partly involved in the increased bladder capacity caused by 8-hydroxy-2-dipropylaminotetralin, a 5-HT 1A agonist, in cats with spinal cord injury (Gu et al, 2004).…”

Role of 5-HT1A receptors in control of lower urinary tract function in anesthetized rats

“…For example, in the cat, activation of 5-HT 1A receptors inhibits the parasympathetic excitatory input to the urinary bladder (14,15,27,31,36). On the other hand, in the rat, activation of 5-HT 1A receptors enhances reflex activity of the bladder and sphincter (1,2,12,20), whereas block of 5-HT 1A receptors suppresses bladder and sphincter activity, suggesting that endogenous 5-HT exerts a tonic influence on the neural pathways controlling the lower urinary tract (1,9,17,19,26,32).…”

Neural Control of the Lower Urinary Tract

“…The drug also has a facilitatory effect on activity of the EUS. 8-OH-DPAT also inhibits reflex bladder activity in awake or chloralose-anesthetized, chronic spinal cordinjured cats, but does not alter the somato-bladder excitatory reflex induced in spinal cats by tactile stimulation of the perigenital region (246). The effects of 8-OH-DPAT are blocked by WAY 100635, a 5-HT 1A receptor antagonist, which alone has no effect.…”