Receptors of the Enteric Nervous System: Potential Gut: First Published As 10.1136/Gut.47.Suppl 4.Iv20 on 1 December 2000

iv20 Gut 2000;(Suppl IV)47:iv20–iv22

Receptors of the enteric nervous system: potential Gut: first published as 10.1136/gut.47.suppl_4.iv20 on 1 December 2000. Downloaded from targets for drug therapy

J Tack

It is recognised that the enteric nervous system activation of a motilin receptor.9 However, (ENS) has a unique ability to mediate reflex direct muscular eVects are also involved in activity independently of input from the brain some of the eVects of motilides.13 Inhibitors of or spinal cord.1–4 This ability implies that the gastrointestinal motility, such as clonidine, ENS contains sensory receptors, primary botulinum toxin, or sumatriptan, may inhibit aVerent neurones, interneurones, and motor release of acetylcholine or stimulate the release neurones. The events that are controlled, at of nitric oxide from intrinsic neurones.14–17 least in part, by the ENS are multiple and The observation that drugs which are used include motor activity, secretion, absorption, clinically to alter gastrointestinal motility act blood flow, and interaction with other organs via the ENS confirms the view that the ENS is such as the gall bladder or pancreas.1–4 a valid target for the pharmacotherapy of The extensive regulatory activities of the gastrointestinal motor disorders. ENS are made possible by the presence and abundance of diVerent types of neurones The ENS as a target for achieving within the wall of the gastrointestinal tract. The improved specificity of pharmacological ENS contains about 108 neurones, approxi- actions mately the number of neurones found in the Pharmacological treatment of gastrointestinal spinal cord. Morphological, electrophysiologi- motility disorders is intended to stimulate or cal, and pharmacological studies have revealed inhibit motility. Established sites of action of a substantial diversity of neurones within the motility drugs are gastrointestinal smooth ENS. Moreover, a surprisingly large number of muscle, the ENS, autonomic ganglia, and the established or candidate neurotransmitters can central nervous system. Drugs acting at diVer- be found in enteric neurones. Most neurones ent sites may cause a similar net eVect on contain several of these substances, and gastrointestinal motility. Enhancement of distinctive patterns of colocalisation of media- gastrointestinal motility can be achieved by tors allow identification of diVerent functional direct stimulation of gastrointestinal smooth classes of neurones.23 The presence of recep- muscle, by activation of excitatory neural path- tors on enteric neurones is another expression ways, or by inhibition of inhibitory pathways. of their heterogeneity. Myenteric neurones can Similarly, inhibition of gastrointestinal motility http://gut.bmj.com/ express receptors for both peptide and non- can be achieved by a direct relaxant eVect on peptide (amines, amino acids, purines) gastrointestinal smooth muscle, by inhibition neurotransmitters.1–5 Generally, expression of a of excitatory neural pathways, or by activation receptor is limited to a subset of myenteric of inhibitory pathways. neurones, with probably the only exception When stimulation or inhibition of contractile being expression of nicotinic cholinergic recep- activity is achieved through agents that act

tors on all myenteric neurones in the guinea pig directly on gastrointestinal smooth muscle (for on September 26, 2021 by guest. Protected copyright. stomach.67 Unfortunately, we know very little example, cholinergics, cholinesterase inhibi- about the relationship between the functional tors, nitrates, L-type calcium channel block- role of enteric neurones and their expression of ers), the eVect is often non-specifically present receptors. throughout the gastrointestinal tract. Motilides may be an exception to this, as smooth muscu- The ENS is a target for pharmacotherapy lar motilin receptors are mainly expressed in of gastrointestinal disorders the stomach and proximal small intestine in A number of drugs, which are used clinically to humans.18 alter gastrointestinal motility, act via the ENS. Most drugs aVecting gastrointestinal motil- Prokinetic drugs, such as cisapride, motilin and ity do so by acting as an agonist or antagonist at erythromycin, stimulate gastrointestinal motil- specific cellular receptors. Stimulation or inhi- ity at least in part through release of acetylcho- bition of contractile activity through receptors line from intrinsic cholinergic neurones.89Cis- on enteric neuronal circuitry oVers the poten- apride enhances cholinergic neurotransmission tial of achieving higher specificity. Serotonin 3

via activation of a presynaptic 5-hydroxy- (5-HT3) receptor antagonists, for example, Center for 810 tryptamine (5-HT)4 receptor. In addition, inhibit colonic motor activity in humans via a Gastroenterological cisapride has a direct postsynaptic excitatory neural pathway but they have no clearly Research, University Hospitals Leuven, eVect on a subpopulation of antral neurones, demonstrable eVect on gastric emptying 11 19 20 Herestraat 49, B-3000 which is not mediated by a 5-HT4 receptor. rate. Leuven, Belgium Indeed, non-serotonergic eVects have also been The selection of a drug therapy with optimal J Tack implicated in the prokinetic actions of cis- speciﬁcity requires both a precise knowledge of apride.12 Motilin and erythromycin can induce Correspondence to: Professor J Tack. prolonged depolarisation in a subset of neu- Abbreviations used in this paper: ENS, enteric [email protected] rones in the guinea pig stomach, possibly by nervous system; 5-HT, 5-hydroxytryptamine.

www.gutjnl.com Receptors of the enteric nervous system: potential targets for drug therapy iv21 Gut: first published as 10.1136/gut.47.suppl_4.iv20 on 1 December 2000. Downloaded from

Vagal afferent GI tract

CNS ACh NO 5-HT?

Vagal Interneurone Inhibitory efferent motor neurone

Nicotinic receptor 5-HT receptor Figure 1 Neural pathways mediating gastric accommodation (animal studies). 5-HT,5-hydroxytryptamine; ACh, acetylcholine; NO, nitric oxide.

the type of change in motor behaviour that is Excitatory Inhibitory required, as well as of the circuitry and the motor motor receptors that are involved in its control. This neurone neurone statement is best illustrated by an example. A subgroup of patients with functional dyspepsia has impaired accommodation of the proximal stomach to ingestion of a meal, and this is asso- ciated with symptoms of early satiety and ACh NO Sub P VIP weight loss.21 Several attempts have been made to improve defective gastric accommodation in these patients. Nitrates can enhance relaxation of the stomach after ingestion of a meal but produce several side eVects related to their action on extraintestinal smooth muscle.22 In 5-HT1P 5-HT3 the mouse and guinea pig, involvement of 5-HT Figure 2 5-Hydroxytryptamine (5-HT) receptors on receptors on intrinsic neurones in the vagally gastric myenteric neurones. ACh, acetylcholine; NO, nitric oxide; Sub P,substance P; VIP,vasoactive intestinal mediated gastric relaxation has been demon- peptide. http://gut.bmj.com/ strated (ﬁg 1).23 Selective 5-HT re-uptake inhibitors act both centrally and peripherally to enhance the availability of physiologically re- circuitry and receptors that are involved in any 24 leased 5-HT. We demonstrated that a selective given motor phenomenon in humans. Unfortu- 5-HT reuptake inhibitor can enhance gastric nately, our knowledge of the ENS in humans is 25 accommodation to a meal in humans. How- extremely limited, and most of the information ever, probably because such drugs enhance the available is extrapolated from animal studies, as on September 26, 2021 by guest. Protected copyright. availability of 5-HT at vagal aVerents that are has been illustrated above. The availability of activated by 5-HT receptors, they are associ- 3 human tissue for physiological and pharmaco- ated with nausea. Hence they are less well logical studies is extremely limited. Hence suited for therapeutic use in dyspeptic patients. More recently, it was demonstrated that 5-HT labourious and slow techniques, such as intra- induced relaxations of the guinea pig stomach cellular electrophysiological studies of receptor are mediated via release of nitric oxide through responses, are not suitable for studying the 26 human ENS. Immunohistochemical demon- activation of a 5-HT1-like receptor. Combin- ing 5-HT responsiveness with immunohisto- stration of receptor expression on human chemical studies in myenteric neurones of the myenteric neurones may be one more fruitful approach. Recently, we investigated the use of guinea pig stomach revealed that a 5-HT1P receptor is present on intrinsic nitrergic neu- optical imaging of neuronal calcium concentra- rones (ﬁg 2).27 We recently demonstrated that tion as a technique to study the responsiveness

sumatriptan is an agonist at the 5-HT1P receptor of enteric neurones to neuroligands. This tech- on gastric antral myenteric neurones.28 We con- nique, which was validated on cultured my- ﬁrmed that administration of sumatriptan can enteric neurones, is also applicable to ex vivo improve impaired gastric accommodation in preparations and on neurones that are retro- dyspeptic patients with early satiety, with a gradely labelled with DiI.29–31 In preliminary resultant improvement in early satiety.21 studies, we demonstrated that circular muscle motor neurones of the guinea pig small The ENS in humans as a target for intestine showed characteristic responsiveness pharmacotherapy to groups of neuroligands. We are currently Selection of a drug therapy with optimal adapting this technique for use on human speciﬁcity requires a precise knowledge of the specimens.

www.gutjnl.com iv22 Ta c k

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