Elsevier

Current Opinion in Pharmacology

Volume 2, Issue 6, 1 December 2002, Pages 630-641
Current Opinion in Pharmacology

Review
Pharmacology of transmission to gastrointestinal muscle

https://doi.org/10.1016/S1471-4892(02)00225-4Get rights and content

Abstract

The identity of excitatory and inhibitory neurotransmitters is well established. Excitatory motor neurons synthesize and release acetylcholine and tachykinins, which act through postjunctional muscarinic M2 and M3 or tachykinin NK1 and NK2 receptors, respectively, to induce smooth muscle contraction. A residual excitatory component is mediated by ATP acting on P2X1 receptors. Conversely, inhibitory motor neurons express nitric oxide synthase and vasoactive intestinal peptide (VIP), which together with ATP, induce a coordinated muscle relaxation. The receptors involved in the inhibitory effects of ATP and VIP are unknown. Likewise, the relationships between inhibitory signals triggered by NO and those mediated by VIP need to be clarified. Recent evidence obtained using receptor knockout mice have confirmed the involvement of the above-mentioned excitatory transmitters but have revealed an unexpected complexity in the nitrergic transmission, where the effects of NO are manifested only in the presence of carbon monoxide. Interstitial cells of Cajal (ICC) are being recognized as targets of intestinal motor neurons; therefore, the signaling mechanisms are probably integrated by these cells before being transmitted to smooth muscle. Challenges in future years will be to identify the physiological role of the various excitatory and inhibitory components, and to understand the relative importance of neurotransmitter receptors expressed on ICC and smooth muscle cells.

Introduction

Intestinal smooth muscle is organized into two layers separated by a neuronal network (myenteric plexus). In the outer layer, smooth muscle cells are oriented along the length of intestinal segments (longitudinal muscle, LM) whereas in the inner layer, smooth muscle cells are oriented transversally to the length of the intestine (circular muscle, CM). These are the basic elements involved in intestinal motility, of which the propulsion of digesta in the oro-caudad direction is a major function. Propulsive motility is termed peristalsis and is subserved by a complex pattern of neural reflexes that aim to relax intestinal muscle downstream (descending inhibitory reflex) and contract the muscle upstream (ascending excitatory reflex) of the intestinal bolus. In addition, there are two non-propulsive motor patterns that involve intestinal smooth muscle: myogenic rhythmic contractions and regulation of basal tone.

In the absence of specialized structures at the intestinal neuro-muscular junction, such as the motor end-plate in skeletal muscle, the efficiency of intestinal neuromuscular transmission is guaranteed by a third type of cells termed interstitial cells of Cajal (ICC). These cells form a network, which connects myenteric neurons to smooth muscle cells. The observation that ICC receive dense excitatory and inhibitory innervation suggests that these cells play an important role in neuromuscular transmission [1•]. However, the debate about the relative importance of ICC and smooth muscle cells in intestinal motility continues 2., 3..Several functions have been attributed to ICC:

  • 1.

    Pacemakers that generate slow wave electrical activity, which propagates to and regulates the excitability of smooth muscle cells.

  • 2.

    An integrative bridge between motor neurons and smooth muscle cells.

  • 3.

    An electrical cable that efficiently conducts the stimulus from single neuronal endings to several smooth muscle cells.

  • 4.

    An amplifier of neural inputs to the smooth muscle.

  • 5.

    A connection between LM and CM.

  • 6.

    Participation in sensory mechanisms.

A question that arises concerns the possible modulation of slow waves by transmitters released by excitatory or inhibitory motor neurons. Slow wave rhythms can be modulated either by prostaglandins [4], second messengers such as cGMP [5], muscarinic agonists or by stimulation of the extrinsic (vagus) nerve [6]. However, as recently pointed out [6], there is little evidence for a physiological modulation of ICC pacemakers by intramural neurons. An independent pacemaking activity has also been identified in smooth muscle. Experiments using isolated guinea-pig colon have shown that atropine or tetrodotoxin (TTX) reduces slow wave rhythm in longitudinal smooth muscle cells, suggesting the existence of cholinergic control of spontaneous muscular contractility [7•].

There is evidence that ICC are important elements in neuromuscular transmission. A recent study has investigated morphological and functional characteristics of excitatory neurotransmission in the gastric fundus of control or W/Wv mice (which lack intramuscular ICC in the stomach) [8••]. Electrical field stimulation (EFS) produced an atropine-sensitive excitatory junction potential (EJP) followed by an inhibitory junction potential (IJP) in the smooth muscle of control mice. However, no response was seen in W/Wv mice, which was associated with a parallel impairment of the mechanical response. In control mice, filling the stomach induced an atropine-sensitive increase in intraluminal pressure that was directly related to the infusion rate. In contrast, W/Wv mice displayed an increased gastric compliance that did not vary by increasing the infusion rate, or following the addition of atropine. However, the response to exogenous acetylcholine (ACh), ACh release and the morphological characteristics of excitatory or inhibitory motor neurons were similar in both groups, indicating that a specific defect of neuromuscular coupling occurs in W/Wv mice. Interestingly, in the presence of both cholinesterase and nitric oxide synthase (NOS) inhibitors, the EJP in control animals was enhanced and a secondary (slow) depolarization was also evident. In W/Wv mice, however, this treatment unmasked only the secondary depolarization, suggesting that following inhibition of its metabolism, ACh can diffuse to postjunctional receptors located on smooth muscle [8••]. The impairment of excitatory transmission is not the only neuromuscular dysfunction in W/Wv mice, as it has been previously shown that these animals have impaired NO-dependent inhibitory transmission in the stomach [1•]. These results in vitro may correlate with the impairment of propulsive activity observed in W/Wv mice [9]. Interestingly, it was found that ICC and smooth muscle cells express almost the same repertoire of neurotransmitter receptors (Fig. 1, Fig. 2), which implies a role for ICC in neuromuscular transmission [10•]. However, it should be noted that W/Wv mice are not only defective in neuroeffector function but also selectively lack a class of intramuscular mechanoceptors, supporting the concept that ICC participate in sensory mechanisms [11]. The participation of smooth muscle cells in intestinal sensory mechanisms has been also hypothesized. Co-cultures of sensory neurons and colonic smooth muscle cells develop gap junctions, and Ca2+ transients triggered in the smooth muscle by stretch can invade nerve terminals and possibly generate an action potential. A similar response can be elicited by substance P (SP), although the molecular entities that mediate Ca2+ mobilization in response to stretch or SP are different [12]. Again, the physiological relevance of these sensory mechanisms is unknown.

Section snippets

Excitatory neuroeffectors

Although excitatory motor neurons might not be a homogeneous class of cells (e.g. projecting to the CM or LM, short or long projections, ascending or descending), they are indeed homogeneous in the repertoire of neurotransmitters expressed, since all excitatory motor neurons express choline acetyl transferase and a high percentage of them also co-express the tachykinins (TKs) SP and neurokinin A (NKA) [13]. The relative roles of ACh and TKs in the excitatory junction potential induced by EFS in

Acetylcholine

As mentioned previously, ACh is the most efficient intestinal excitatory neurotransmitter in terms of stimulus intensity for evoking contraction, latency to contraction and contraction amplitude. For example, in the guinea-pig colon (pretreated with guanethidine, apamin, nitroarginine and nifedipine) single pulse EFS produced an atropine-sensitive fast EJP (and an associated contraction) with a short latency (110 ms), time to peak (250 ms) and duration (about 2 s) [14]. ACh contracts visceral

Tachykinins

Three TK receptors have been cloned and identified: NK1, NK2 and NK3 receptors, which are preferentially activated by SP, NKA and neurokinin B (NKB), respectively. There are two neuronal sources of TKs that could be involved in motor effects in intestinal muscle layers: firstly, excitatory cholinergic motor neurons; and secondly, extrinsic capsaicin-sensitive sensory neurons. However, the contractile effect induced by capsaicin, the pungent component of hot chilli, in various intestinal

ATP

There is evidence that ATP mediates a non-cholinergic, non-tachykininergic component of the EJP and mechanical response in intestinal smooth muscle. In the presence of cholinergic transmission blockers (e.g. atropine), inhibitory transmission blockers (e.g. guanethidine, apamin, NOS inhibitor) and nifedipine, EFS induced an EJP in the guinea-pig duodenum with fast and slow components. The slow component was almost abolished by NK1 and NK2 receptor antagonists, whereas the fast component was

Inhibitory transmitters

Inhibitory neurotransmitters participate in peristalsis by promoting the inhibitory descending reflex, which is aimed to facilitate propulsion of digesta towards the anus. Therefore, it could be expected that the inhibition of this inhibitory reflex would slow intestinal propulsion. In contrast, when either ATP-mediated inhibitory mechanisms were blocked by apamin or NO production was suppressed by NOS inhibitors, persitalsis was enhanced and only the combined administration of apamin and NOS

ATP

ATP is considered the main mediator of the EFS-evoked apamin-sensitive IJP on the basis of the following evidence: firstly, the α-β-methylene-ATP-induced IJP is apamin-sensitive; secondly, α-β-methylene-ATP desensitization abolishes the apamin-sensitive IJP; and thirdly, suramin and PPADS antagonize both the α-β-methylene-ATP-induced IJP and the EFS-induced apamin-sensitive IJP 49., 57., 60., 61.. Suramin, which blocks PACAP-induced guinea-pig colon relaxation [62] and PPADS, which blocks IP3

Nitric oxide and VIP

Three different NOS isoforms can be responsible for NO production. nNOS and endothelial NOS (eNOS) are constitutive and Ca2+-dependent but can be subject to up- or down-regulation. nNOS can be either cytosolic or membrane-bound whereas eNOS is membrane-bound. Inducible NOS (iNOS) can also be constitutive but is Ca2+-independent and cytosolic 56., 77.. As mentioned above, it has been difficult to divide the inhibitory effects mediated by NO and VIP, which are both contained in inhibitory motor

Conclusions

Excitatory neurotransmission in the intestinal smooth muscle can be induced by either electrical or physiologic-like stimulation (distension and/or mucosal stroking) of gastrointestinal strips or segments. The availability of selective receptor antagonists and knockout animals have greatly facilitated the characterization of the mediators and receptors involved in this process. The application of novel techniques, from receptor immunohistochemistry, which is associated with the monitoring of

Update

Recently, a capsaicin-induced, NO-dependent relaxation of precontracted human sigmoid colon CM has been described [96•]. Capsaicin-induced relaxation was reduced by 50% by inhibitors of NOS or guanylate cyclase, whereas TTX and PPADS were inactive. The capsaicin-induced relaxation was subject to tachyphylaxis upon repeated challenges, suggesting that capsaicin directly stimulates NO production from extrinsic sensory nerves (a subset of which express NOS).

Recent work [97] has shown that the

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

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