Table 3.
Pharmacological Agents Modulating Serotonin-mediated Mechanisms in Disorders of Gut-Brain Interactions
| Drug name | Mechanisms of action | Clinical outcome |
|---|---|---|
| TCA | TCA has 5-HT and NA reuptake inhibition properties, primarily used for anti-depressant and analgesic. | Affect gut motility through anticholinergic and serotonergic mechanisms. Reduces visceral hypersensitivity, intestinal pain sensitivity, mediated either in peripheral nerves or the CNS.147 |
| Their mode of action involves mechanisms beyond 5-HT and NA, like blockage of voltage-gated ion channels, opioid receptor activation and also modulates neuroimmune anti-inflammatory effects. | ||
| Tetracyclic antidepressant | Boosts both 5-HT and NA neurotransmission, not by blocking their reuptake pumps, but by blocking presynaptic α2-noradrenergic receptors on NA and 5-HT neurons, resulting in an increased noradrenergic and serotonergic activity | Upregulates the levels of orexigenic hormones and downregulated the levels of anorexigenic hormones. |
| Reduce colonic hypersensitivity and improve gastric emptying.148 | ||
| SSRI | SSRIs are characterized by selective blockade of the presynaptic 5-HT transporter, boosting 5-HT neurotransmission. | Increase colonic contractility and reduce colonic tone during fasting conditions and reduce the colonic tone increase. Decrease IBS scores for abdominal pain and bloating independent of anxiety, depression and colonic sensorimotor function.149 |
| SNRI | Primarily block both 5-HT and NA reuptake, boosting 5-HT and NA neurotransmission. | Increase compliance, relax tone and reduce the postprandial colonic contraction and increase sensory thresholds in response to balloon distensions.149 |
| Considering the central roles of 5-HT and NA in the descending modulatory nerve pathways, SNRIs are better pharmacological agents to modulate pain sensation. | ||
| 5-HT4R agonist | 5-HT4R agonist target 5-HT4R to promote peristalsis and secretion through enhanced release of acetylcholine from excitatory motor neurons and interneurons. | Improves GI motility.57,150 |
| 5-HT3R antagonist | Abnormal neurotransmission of 5-HT via the 5-HT3R has been reported in IBS-D patients. Blocking 5-HTR receptors is of clinical relevance in chronic diarrhea as this leads to reduced contractility, slows colonic transit, and increases fluid absorption. | Global improvement in IBS symptoms and relieve abdominal pain and discomfort, improve stool consistency and bowel movements.150,151 |
| 5-HT1AR agonist | Activation of 5-HT1AR at the level of the CNS increases gastric tone and decrease gastric sensitivity to distension. | Enhances fundus relaxation, gastric accommodation and improves postprandial symptoms independently from its anxiolytic effect.152 |
| Peripheral inhibitory effect exerted by the 5-HT1AR agonist improve gastric accommodation. |
TCA, tricyclic antidepressant; 5-HT, 5-hydroxytriptamine; NA, noradrenaline; CNS, central nervous system; SSRI, serotonin reuptake inhibitor; IBS, irritable bowel syndrome; SNRI, serotonin norepinephrine reuptake inhibitor; 5-HTR, 5-hydroxytriptamine receptor; GI, gastrointestinal; IBS-D, diarrhea-predominant IBS.