Enteric Nervous System Pharmacology Flashcards
What is the enteric nervous system?
- Branch of the peripheral nervous system (mostly autonomous) responsible for the range between the oesophagus and anus
- Controls digestion
What are the clinically prevalent disorders of the GI system?
- IBS
- Diabetes
- Crohn’s disease
(all have links to AD and Parkinson’s)
What is the basic structure of the enteric nervous system?
2 sheets of neurons inside the gut
myenteric plexus - outside muscle layer controls motility
submucosal plexus - close to lumen, regulates digestive secretions and water balance
What is the hierarchy of the enteric nervous system?
Plexus
Ganglia and Internodal strands
Neurons and glial cells + bundles of axons
What types of motor neuron signalling to the smooth muscle are present in the myenteric plexus?
Excitatory - Ach
Inhibitory - NO, ATP, VIP
What are the non-motor neurons found in the myenteric plexus? What are their neurotransmitters?
Intrinsic Primary Afferent Neurons (IPANS) - sensory, recieve input from the muscosal lining (Ach)
Ascending (towards mouth) interneurons - Ach
Descending (towards ;) ) interneurons - Ach, 5-HT, ATP
Enteric glial cells - possible inhibitory function (NO)
Intestinal cells of Cajal - have gap junctions to smooth muscles
Which neurons are found in the submucosal plexus?
- Secretormotor neurons
- Vasodilator neurons
- Intrinsic primary afferents (sensory)
ACh and VIP for all
Which cells are found within the mucosa?
Enterochromaffin Cells (ECs) - release 5HT and induce motility patterns Immune cells
What is accomodation?
Reflex of the stomach which allows it to stretch according to the volume of food, involves an inhibitory reflex which relaxes the circular muscle
What is peristalsis?
Occurs in eosophagus and intestines, involves contraction of muscles above food and relaxation below (oral excitation and anal inhibition)
What is the migrating motor complex (MMC)?
High amplitude, rhythmic propagating waves for slow transit in stomach and intestine. Induced by spontaneous bursts of activity in the myenteric plexus believed to be induced by mucosal stimulation or stretch
- Colonic migratory motor complex (CMMC) involves gut induced seretogenic activation and is self organised
- Involves synchronous activity of the circular and longitudinal muscle layers (former usually shows spontanous activity and later tonic activity)
What evidence indicates the role of serotonin in the colonic migratory motor complex?
- 5-HT3 antagonist removes events
- Removing mucosa also removes events
- Addition of 5-HT reintroduces events
What is the circuitry of the colonic migratory motor complex?
- EC’s (Enterochromaffin Cells) in the mucosal epithelium release 5-HT following mucosal stimulation
- 5-HT then activates IPANS located in the submucosal plexus and myenteric plexus via multiple 5-HT receptors to invoke large scale contraction event
What are the 5-HT receptors of the myenteric plexus?
- 5-HT3 located at mucosal terminals
- 5-HT7 found in the soma
- 5-HT1A found at soma and processes
Augment response to serotonin
What are the 5-HT receptors of the submucosal plexus?
- 5-HT1p found at mucosal terminals
- 5-HT4, pre-synaptic terminal receptors
How is 5-HT3R different from other 5-HT receptors?
Ionotropic - are ligand gated and not g-protein coupled like most, therefore have much faster effect upon stimulation of IPANS
What drugs are commonly used in motility studies regarding serotonin receptors?
Used in organ bath studies
5-HT3R antagonist odanseton (also known as Zofran given to alleviate nausea in chemo patients)
5-HT4R partial agonist tegaserod, also commonly prescribed to patients with IBS-C (but withdrawn as increases heart attack risk)
What did the Bulbing lab discover with regards to the role of 5-HT in CMMC?
- 5-HT released in response to intraluminal pressure
- Able to initiate peristaltic reflex and propulsive motility
What is the dispute between the Smith and Spencer labs?
Smith
- Removal of mucosa does not alter frequency or amplitude of CMCCs
- CMCCs could be evoked following depletion of 5-HT
Spencer
- Argued that technique was poor: dissection not done in ice-cold saline resulting in an accumulation of 5-HT in the neurons
- Argues removal of mucosa abolished CMCC in preparations
- Mucosal stimulation failed to produce CMCCs in TPH knockout mice (no 5-HT synthesis)
What is the circuitry responsible for smooth muscle contraction in the CMMC?
- MP IPANS release Ach causing excitation in ascending and descending interneurons via postsynaptic nicotinic receptors (nAChRs)
- SP IPANS also release ACh to activate secretory neurons and descending interneurons via nAChRs
- Ascending interneurons synapse with ascending motorneurons to activate smooth muscle (both circular and longitudinal) via muscarinic and nicotinic receptors via Ach causing the smooth muscles layers to contract
What is the circuitry responsible for smooth muscle relaxation in the CMMC?
- Descending interneurons release 5-HT and Ach which activate descending inhibitory motorneurons via 5-HT3Rs and nAChRs respectively
- Descending motorneurons then release NO, ATP, Neuropeptide Y (NPY) and vasoactive intestinal peptide (VIP) to cause smooth muscle relaxation
What is IBS and what are the two types?
Chronic and debilitating condition affecting 9-21% of the population
IBS-C (with constipation: gas, bloating)
IBS-D (diarrhoea: sudden urgent movements and loose stools)
How has altered gastrointestinal signalling been implicated in IBS?
- Neurotransmission is altered in IBS
- Shown to have polymorphisms of 5-HT receptors and transporters
What treatments have been trialed for IBS-C?
- Selective serotonin reuptake inhibitor (fluoxetine) used to combat lower plasma 5-HT levels
- Improvements in abdominal discomfort however resulted in a number of harmful psychological and physiological side effects
What treatment has been trialed for IBS-D?
Cilansetron
- 5-HT3R antagonist still under trial
- Shows improvement for abdominal pain and bowel movements
What is the experimental evidence for the role of Ach and Tachykinins in CMMC?
- Organ bath setup to record tension from circular and longitudinal muscle cells
- Application of atropine (competitive antagonist of mAChRs) decreased CMMC amplitude for rapid component (typical neurotransmitter)
- MEN 10 376 competitive antagonist of TKs virtually abolished CMMCs for sustained slow component (large neuropeptides which are also not broken down at the synaptic cleft)
What is the experimental evidence of the role of NO CMMC relaxation?
- Organ bath setup
- Methalocholine to induce contraction
- NO addition rapidly relaxed the muscle
- L-NNA (nNOS inhibitor) inhibited relaxation
What is the experimental evidence of the role of VIP in CMMC relaxation?
- Addition of antagonist reduces area of relaxation
- VIP is a neuropeptide (like TK) and produces slow sustained effect
Why are treatments hard to find for IBS?
- 5-HT receptors are incredibly sensitive, upregulation leads to diarrhea and downregulation to constipation
- Diet changes currently the only treatmets available
