ReviewPharmacology of transmission to gastrointestinal muscle
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
References (97)
- et al.
ICC in neurotransmission: hard to swallow a lack of involvement
Gastroenterology
(2002) - et al.
Reply to the above letter
Gastroenterology
(2002) - et al.
Interstitial cells of Cajal direct normal propulsive contractile activity in the mouse small intestine
Gastroenterology
(1998) - et al.
Sequential activation of the triple excitatory transmission to the circular muscle of guinea-pig colon
Neuroscience
(1997) - et al.
Tachykinin-dependent and independent components of peristalsis in the guinea-pig distal colon
Gastroenterology
(2001) - et al.
Intrinsic primary afferent neurons of the intestine
Prog Neurobiol
(1998) Muscarinic receptors and gastrointestinal tract function
Life Sci
(2001)- et al.
Selective modulation of PKC isozymes by inflammation in canine colon circular muscle cells
Gastroenterology
(2002) - et al.
Tachykinin receptors are involved in the ‘local efferent’ motor response to capsaicin in the guinea-pig small intestine and oesophagus
Neuroscience
(1999) Principles of tachykininergic co-transmission in the peripheral and enteric nervous system
Regul Pept
(2000)
Gq-linked NK2 receptors mediate neurally induced contraction of human sigmoid circular smooth muscle
Gastroenterology
Differential alterations in tachykinin NK2 receptors in isolated circular smooth muscle in inflammatory bowel disease and idiopathic chronic constipation
Regul Pept
Immunohistochemical demonstration of the NK1 tachykinin receptors on muscle and epithelia in guinea-pig intestine
Gastroenterology
Neurokinin B- and substance P-like immunoreactivity are co-localized in enteric nerves of the rat ileum
Regul Pept
Interstitial cells of Cajal and purinergic signalling
Auton Neurosci
Coexpression of ligand-gated P2X and G protein-coupled P2Y receptors in smooth muscle. Preferential activation of P2Y receptors coupled to phospholipase C (PLC)-β1 via Gαq/11 and PLC-β3 via Gβγi3
J Biol Chem
The novel heteromeric bivalent ligand SB9 potently antagonizes P2Y(1) receptor mediated responses
J Auton Nerv Syst
Smooth muscle does not have a common P2X receptor phenotype: expression, ontogeny and function of P2X1 receptors in the mouse ileum, bladder and reproductive systems
Auton Neurosci
Regulation of guinea-pig intestinal peristalsis by endogenous endothelin acting at ETB receptors
Gastroenterology
Electrophysiology of autonomic neuromuscular transmission involving ATP
J Auton Nerv Syst
Histochemical, pharmacological, biochemical and chromatographic evidence that pituitary adenylate cyclase activating peptide is involved in inhibitory neurotransmission in the taenia of the guinea-pig caecum
J Auton Nerv Syst
Cloning, functional expression and tissue distribution of the human P2Y6 receptor
Biochem Biophys Res Commun
Molecular cloning and characterization of the mouse P2Y4 nucleotide receptor
Eur J Pharmacol
Effects of VIP and NO on the motor activity of vascularly perfused rat proximal colon
Peptides
Peptidergic and nitrergic inhibitory neurotransmission in the hamster jejunum: regulation of vasoactive intestinal peptide release by nitric oxide
Neuroscience
Selective expression of vasoactive intestinal peptide (VIP)2/pituitary adenylate cyclase-activating polypeptide (PACAP)3 receptors in rabbit and guinea-pig gastric and taenia coli smooth muscle cells
Regul Pept
PACAP-(6-38) inhibits the effects of vasoactive intestinal polypeptide, but not PACAP, on the small intestinal circular muscle
Eur J Pharmacol
Inhibition of the NANC relaxation of the guinea-pig proximal colon longitidinal muscle by the purinoceptor antagonist PPADS, inhibition of nitric oxide synthase, but not by a PACAP/VIP receptor antagonist
Pharmacol Res
Coupling of M2 muscarinic receptor to L-type Ca channel via c-src kinase in rabbit colonic circular muscle
Gastroenterology
Interstitial cells of Cajal: primary targets of enteric motor innervation
Anat Rec
Regulation of pacemaker frequency in the murine gastric antrum
J Physiol
Regulation of pacemaker currents in interstitial cells of Cajal from murine small intestine by cyclic nucleotides
J Physiol
Physiology and pathophysiology of the interstitial cells of Cajal: from bench to the bedside III. Interaction of interstitial cells of Cajal with neuromediators: an interim assessment
Am J Physiol Gastrointest Liver Physiol
Electrical rhythmicity and spread of action potentials in longitudinal muscle of guinea-pig distal colon
Am J Physiol Gastrointestinal Liver Physiol
Interstitial cells of Cajal mediate cholinergic neurotransmission from enteric motor neurons
J Neurosci
Molecular markers expressed in cultured and freshly isolated interstitial cells of Cajal
Am J Physiol Cell Physiol
C-kit mutant mice have a selective loss of vagal intramuscular mechanoceptors in the forestomach
Anat Embryol
Calcium waves in colonic myocytes produced by mechanical and receptor-mediated stimulation
Am J Physiol Gastrointest Liver Physiol
Anatomy and physiology of the enteric nervous system
Gut
Dose-response study of the analgesic effect of lanepitant in patients with painful diabetic neuropathy
Clin Neuropharmacol
Prevention of cisplatin-induced emesis by the oral neurokinin-1 antagonist MK-869 in combination with granisetron and dexamethasone or with dexamethasone alone
J Clin Oncol
A novel tachykinin NK2 receptor antagonist prevents motility-stimulating effects of neurokinin A in small intestine
Br J Pharmacol
Analysis of whole cell currents by patch clamp of guinea-pig myenteric neurons in intact ganglia
J Physiol (Lond)
Membrane currents in cultured human intestinal smooth muscle cells
J Physiol
Nicotinic acetylcholine receptors at sites of neurotransmitter release to the guinea-pig intestinal circular muscle
J Pharmacol Exp Ther
Muscarinic M3 receptor inactivation reveals a pertussis toxin-sensitive contractile response in the guinea-pig colon: evidence for M2/M3 receptor interactions
J Pharmacol Exp Ther
Coupling of M2 muscarinic receptors to Src activation in cultured canine colonic smooth muscle cells
Am J Physiol Gastrointest Liver Physiol
Multiple functional defects in peripheral autonomic organs in mice lacking muscarinic acetylcholine receptor gene for the M3 subtype
Proc Natl Acad Sci USA
Cited by (88)
Regional cytoarchitecture of the adult and developing mouse enteric nervous system
2022, Current BiologyResveratrol alleviates oxidative damage in enteric neurons and associated gastrointestinal dysfunction caused by chemotherapeutic agent oxaliplatin
2017, MaturitasCitation Excerpt :NO has various location-dependent functions, and, in the GI tract acts as a mediator of vasodilation and GI relaxation [13,14]. In the enteric neurons embedded in the GI tract wall, neuronal NOS (nNOS) is expressed by descending interneurons and inhibitory motor neurons supplying the intestinal smooth muscle [15]. Release of NO from neurons and smooth muscle is essential for the complex muscle co-ordinations that produce GI peristaltic motility [16,17].
ATP as a cotransmitter in the autonomic nervous system
2015, Autonomic Neuroscience: Basic and ClinicalCitation Excerpt :Although ATP initially emerged as the best candidate for the NANC inhibitory neurotransmitter, it is now clear that other substances, particularly NO and vasoactive intestinal peptide (VIP) also serve this function (Burnstock, 2001, 2008; Lecci et al., 2002). Whereas ATP elicits fast, transient ijps and relaxations, the responses evoked by NO and VIP have a slower time-course and are more maintained (see Jiménez et al., 2014; Lecci et al., 2002). The relative contribution of each neurotransmitter to NANC relaxation varies depending upon both the region of gastrointestinal tract and also the species under study (Lecci et al., 2002).
Benzodiazepine Delorazepam Induces Locomotory Hyperactivity and Alterations in Pedal Mucus Texture in the Freshwater Gastropod Planorbarius corneus
2023, International Journal of Molecular Sciences