Serotonergic modulation of visceral sensation: upper gastrointestinal tract. (Visceral Perception).

Agents that modify serotonergic function have therapeutic potential for the treatment of visceral hypersensitivity, either through a direct effect on perception or through modulation of visceral tone or motility. Administration of selective serotonin reuptake inhibitors reduces oesophageal sensitivity to distension but not gastric sensitivity to distension. 5-HT ligands may also influence gastric mechanosensitivity by altering tone. Although the exact role of 5-HT receptors in the control of gastrointestinal functions remains unknown, 5-HT is generally considered to be the main candidate involved in the modulation of motor and sensory function from the gastrointestinal tract. Hence serotonergic modulation of upper gut sensitivity appears to be promising for the development of novel approaches to the treatment of functional disorders of the upper gastrointestinal tract.

SUMMARY

Agents that modify serotonergic function have therapeutic potential for the treatment of visceral hypersensitivity, either through a direct effect on perception or through modulation of visceral tone or motility. Administration of selective serotonin reuptake inhibitors (SSRIs) reduces oesophageal sensitivity to distension but not gastric sensitivity to distension. Administration of amitriptyline to patients with functional dyspepsia has no effect on sensitivity to gastric distension but may provide symptomatic benefit. The 5-[HT.sub.3] antagonist ondansetron partly reverses sensitisation to gastric distension during duodenal lipid infusion. 5-HT ligands may also influence gastric mechanosensitivity by altering tone. cisapride, a 5-[HT.sub.4] agonist/weak 5-[HT.sub.3] antagonist induces a small degree of gastric contraction in the fasting state but postprandially it markedly enhances gastric accommodation. Similarly, the SSRI paroxetine enhances relaxation in response to a liquid meal and may provide symptoma tic benefit for patients with impaired gastric accommodation. The 5-[HT.sub.1p] receptor agonist sumatriptan activates intrinsic inhibitory neurones in the stomach. The resulting gastric relaxation has been shown to reduce postprandial symptoms in patients with functional dyspepsia caused by hypersensitivity. Buspirone, a 5-[HT.sub.1A] agonist, reduces cholinergic tone to the stomach, thereby increasing the threshold for discomfort and reducing the severity of dyspeptic symptoms.

INTRODUCTION

Serotonin and the gastrointestinal tract

Serotonin (5-hydroxytryptamine; 5-HT) is a neurotransmitter in the central nervous system (CNS). The presence of 5-HT in the gastrointestinal tract has been demonstrated immunohistochemically in enterochromaffln (EC) cells and also in enteric neurones. (1-3) Release of 5-HT and other paracrine messengers from EC cells act as chemical and mechanical transducers for the initiation of local reflexes (for example, peristalsis) and for activation of afferent projections to the CNS. (4-6)

Accumulating evidence supports the hypothesis that 5-HT is a neurotransmitter in the enteric nervous system (ENS). (4 5) However, due to the presence of multiple 5-HT receptor subtypes, and the lack of suitable ligands that can be safely used in vivo, the physiological role of neuronal 5-HT in the gastrointestinal tract remains unclear. (4 5 7)

Visceral sensation is modulated at different levels of the brain-gut axis. The neuroanatomical pathways involved in this process have been reviewed extensively. (6 8-10) The gastrointestinal tract can respond to different sensory modalities, including chemo-, thermo-, and mechanosensitivity. Of these, only visceral mechanosensitivity has been studied in depth. Under normal…