Gut-brain communication: nerve circuits and chemical messengers of colorectal motility and defecation control.

Recent advances and foundational knowledge are integrated to provide a comprehensive description of brain-gut signaling relevant to colorectal motility, with an emphasis on defecation. We discuss molecular targets of therapeutic potential. We identify four levels of neural control: 1) cortical and hypothalamic centers; 2) pontomedullary cell groups; 3) the lumbosacral defecation centers; and 4) the enteric nervous system (ENS). The critical role of central nervous system (CNS) input is evidenced by the constipation that follows spinal cord injury or during Parkinson's disease. The constipation of spinal cord injury suggests that propulsive reflexes generated by the ENS require augmentation from the CNS. Conversely, the crucial role of the ENS is revealed by the failed defecation in Hirschsprung and Chagas diseases. Spinal descending pathways receive inputs from the cortex and hypothalamus, and converge on a common efferent neuronal link between the CNS and the ENS: parasympathetic preganglionic neurons (PPG neurons) that connect with ENS directly or via pelvic ganglia. CNS pathways respond to the urge to defecate, to stress or alarm, and to signals from the large intestine. The ENS responds to signals from its lumen, commonly mediated through the release of local hormones, and to signals from the CNS. PPG neurons, the CNS to ENS link, express a wide range of amine and peptide receptors that are potential targets for the treatment of constipation. Important among targets are ghrelin, dopamine, and serotonin receptors. The receptors within the colon that connect luminal signals with propulsive contractile activity also represent potential therapeutic targets.