Effect of 5-Hydroxytryptamine₁ Serotonin Receptor Agonists on Noxiously Stimulated Micturition in Cats With Chronic Spinal Cord Injury

Purpose: The serotonin 5-hydroxytryptamine_1A/7 receptor agonist (R)-8-OH-DPAT (8-hydroxy-2-(di-n-propylamino)tetralin) (Sigma®) and the 5-hydroxytryptamine_1A/1B/1D agonist GR-46611 (3-[3-(2-dimethylaminoethyl)-1H-indol-5-yl]-N-(4-methoxybenzyl)acrylamide) (Tocris Cookson, Ellisville, Missouri) inhibit bladder activity during saline infusion into the bladder of cats with chronic spinal cord injury (saline infused, spinal cord injured cats), suggesting an effect on mechanosensitive bladder afferent C fibers or their targets. We investigated the effects of (R)-8-OH-DPAT and GR-46611 on bladder activity in chronic spinal cord injured cats during infusion of dilute acetic acid into the bladder to stimulate chemosensitive bladder afferent C fibers (acid infused, spinal cord injured cats). Materials and Methods: Chloralose anesthetized, spinal cord injured cats were catheterized through the bladder dome for filling cystometry during 0.5% acetic acid infusion. Dose-response curves for (R)-8-OH-DPAT (0.3 to 30 μg/kg intravenously) or GR-46611 (0.03 to 300 μg/kg intravenously) were followed by the 5-hydroxytryptamine_1A antagonist WAY-100635 (N-tert-butyl-3-(4-(2-methoxyphenyl)-piperazin-1-yl)-2-phenylpropanamide) (Sigma) (300 μg/kg). Threshold volume, bladder capacity, residual volume, micturition volume and arterial pressure were measured and external urethral sphincter electromyogram was recorded. Results: Acid infused, spinal cord injured cats responded to (R)-8-OH-DPAT but not to GR-46611 with dose dependent increases in threshold volume, capacity and residual volume (significant above 3 μg/kg). Effects of (R)-8-OH-DPAT were largely reversed by WAY-100635. Neither (R)-8-OH-DPAT nor GR-46611 augmented external urethral sphincter electromyogram activity. Conclusions: Based on differences in the response to GR-46611 in saline vs acid infused, spinal cord injured animals it is tempting to speculate that 2 distinct populations of bladder afferent C fibers (1 chemosensitive and 1 mechanosensitive) can initiate spinal bladder reflexes. Because 5-hydroxytryptamine_1A receptor agonists increased bladder capacity under saline or acid infused conditions, they are promising candidates for decreasing bladder hyperactivity and increasing bladder capacity in patients with chronic spinal cord injury.