Proof-of-Concept of Acute Drug-Elicited Defecatory Behaviors in Spinal Cord-Transected Animals: A Model for Identifying Centrally-Acting Prokinetic Agents

Abstract

No cure and no safe or acceptable treatment exist yet against bowel problems and chronic constipation in spinal cord-injured (SCI) patients. Although some non-central nervous system (CNS)-acting drugs have already been identified and used clinically as symptomatic treatment, most have been associated with significant side effects and deleterious complications. To ease basic research aimed at identifying new drug candidates against bowel control problems, we developed a standardized approach and corresponding assays for quantitatively measuring prokinetic and acute defecatory effects in paraplegic animals. Following a period of acclimation, a single subcutaneous injection of 0.5 ml of vehicle (sterile water) was performed in normal animals or in early chronic (> 7 days post-surgery) low-thoracically (Th9/10)-transected (Tx) mice. A 30 minute-period of observation of freely moving animals using a transparent Plexiglas arena was used to subsequently measure timing (latency of each episode), amounts (fecal pellets in mg) and frequency (number of episodes/30 min). Residual activity levels, clearly determined in control animals, were used as baseline level to determine statistically greater effects induced by compounds of potential interest. Tests with SR57227 (5-HT3 receptor agonist) and quipazine (5-HT2/3 receptor agonist) revealed that only quipazine acutely elicited significantly greater amounts of fecal pellets in Tx mice. Using this straightforward and reliable method, future drug screening experiments that may yield the identification and development of new potent and safe centrally acting-drug treatments (e.g., upon the Lumbosacral Defecation Center) for potent ‘on-demand’ facilitation or induction of reflex bowel control and acute episodes of defecation in patients with SCI.