Actions of serotonin and substance P on myenteric neurons of guinea-pig distal colon

doi:10.1016/0014-2999(88)90447-5

European Journal of Pharmacology

Volume 148, Issue 1, 22 March 1988, Pages 1-8

https://doi.org/10.1016/0014-2999(88)90447-5 Get rights and content

Abstract

Intracellular methods were used to study the effects of serotonin and substance P (SP) on the electrical behavior of myenteric neurons in guinea-pig distal colon in vitro. Serotonin evoked either a short-duration transient depolarization, a long-lasting depolarization or a multiphasic response consisting of a rapid depolarization followed by a short duration hyperpolarizing potential and then a long-lasting depolarization. Application of SP evoked a long-lasting depolarization. Depolarizing potentials to both substances were accompanied by enhaced excitability that was reflected by repetitive spike discharge. Long-lasting depolarizations were associated with increased input resistance. The responses to serotonin or SP were unaltered by the presence of tetrodotoxin, hexamethonium or elevated extracellular Mg²⁺ and reduced Ca²⁺. Some neurons responded to both serotonin and SP indicating that both receptors coexisted on the same neuron. The putative SP antagonist, [D-Arg¹, D-Phe⁵,D-Trp^7,9,Leu[¹¹]SP did not affect the responses to SP. It did suppress the slow-depolarizing response to serotonin, while the fast response was unaffected. The responses to serotonin and SP in myenteric neurons of guinea-pig colon resembled the responses reported by others for small intestinal myenteric neurons.

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The focus of neurogastroenterology in Rome II was the enteric nervous system (ENS). To avoid duplication with Rome II, only advances in ENS neurobiology after Rome II are reviewed together with stronger emphasis on interactions of the brain, spinal cord, and the gut in terms of relevance for abdominal pain and disordered gastrointestinal function. A committee with expertise in selective aspects of neurogastroenterology was invited to evaluate the literature and provide a consensus overview of the Fundamentals of Neurogastroenterology textbook as they relate to functional gastrointestinal disorders (FGIDs). This review is an abbreviated version of a fuller account that appears in the forthcoming book, Rome III. This report reviews current basic science understanding of visceral sensation and its modulation by inflammation and stress and advances in the neurophysiology of the ENS. Many of the concepts are derived from animal studies in which the physiologic mechanisms underlying visceral sensitivity and neural control of motility, secretion, and blood flow are examined. Impact of inflammation and stress in experimental models relative to FGIDs is reviewed as is human brain imaging, which provides a means for translating basic science to understanding FGID symptoms. Investigative evidence and emerging concepts implicate dysfunction in the nervous system as a significant factor underlying patient symptoms in FGIDs. Continued focus on neurogastroenterologic factors that underlie the development of symptoms will lead to mechanistic understanding that is expected to directly benefit the large contingent of patients and care-givers who deal with FGIDs.
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Background & Aims: Serotonin (5-hydroxytryptamine [5-HT]) is a key signaling molecule in the gut. Recently, the neural 5-HT₃ receptor received a lot of attention as a possible target in functional bowel diseases. Yet, the 5-HT₃ receptor–mediated changes in properties of human enteric neurons is unknown. Methods: We used a fast imaging technique in combination with the potentiometric dye 1-(3-sulfonatopropyl)-4-[β[2-(di-n-octylamino)-6-naphthyl]vinyl]pyridinium betaine to monitor directly the membrane potential changes in neurons of human submucous plexus from surgical specimens of 21 patients. An Ussing chamber technique was used to study 5-HT₃ receptor involvement in chloride secretion. Results: Local microejection of 5-HT directly onto ganglion cells resulted in a transient excitation of enteric neurons characterized by increased spike discharge. This response was mimicked by the 5-HT₃ receptor agonist, 2-methyl-5-HT, and blocked by the 5-HT₃ receptor antagonist, tropisetron. The proportions of 5-HT–responsive nerve cells per ganglion ranged from 25.5% ± 18.4% in the duodenum to 54.2% ± 46.9% in the colon. Interestingly, 2-methyl-5-HT did not evoke chloride secretion in the human intestine but it did in the guinea-pig intestine. Specific 5-HT_3A and 5-HT_3B receptor subunit immunoreactivity as well as 5-HT_3A and 5-HT_3B receptor–specific messenger RNA were detected in the tissue samples. Based on co-labeling with the pan-neuronal marker HuC/D we conclude that submucous nerve cells potentially express heteromeric 5-HT_3A/B receptors. Conclusions: We show that 5-HT excited human enteric neurons via 5-HT₃ receptors, which may comprise both 5-HT_3A and 5-HT_3B receptor subunits.
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2004, Gastroenterology
Citation Excerpt :
Two receptors mediate the excitatory actions of 5-HT at the cell bodies of guinea-pig enteric neurons. One of the receptors, identified as a 5-HT1p receptor, is a metabotropic receptor linked to intraneuronal transduction pathways by a G protein.58–61 The response to stimulation of 5-HT1P receptors, similar to stimulation of histamine H2 receptors, mimics slow EPSPs (Figure 3C).
Minute-to-minute behavior of the bowel, whether it is normal or disordered, is determined by integrative functions of the enteric nervous system (ENS). Information input processed by the ENS is derived from local sensory receptors, the central nervous system, and immune/inflammatory cells including mast cells. Enteric mast cells use the power of the immune system for detection of antigenic threats and for long-term memory of the identity of the specific antigens. Specific antibodies attach to the mast cells and enable the mast cell to detect sensitizing antigens when they reappear in the gut lumen. Should the sensitizing antigen reappear, mast cells detect it and signal its presence to the ENS. The ENS interprets the mast cell signal as a threat and calls up from its program library secretory and propulsive motor behavior that is organized to eliminate the threat rapidly and effectively. Operation of the alarm program protects the individual, but at the expense of symptoms that include cramping abdominal pain, fecal urgency, and diarrhea. Enteric mast cells use immunologic memory functions to detect foreign antigens as they appear and reappear throughout the life of the individual. Mast cells use paracrine signaling for the transfer of chemical information to the neural networks of the ENS. Integrative circuits in the ENS receive and interpret the chemical signals from the mast cells. Signals from the mast cells are interpreted by the ENS as a labeled code for the presence of a threat in the intestinal lumen.
Correlation of morphology, electrophysiology and chemistry of neurons in the myenteric plexus of the guinea-pig distal colon
1999, Journal of the Autonomic Nervous System
Intracellular recordings were made from myenteric neurons of the guinea-pig distal colon to determine their electrical behaviour in response to intracellular current injection and stimulation of synaptic inputs. The recording microelectrode contained the intracellular marker biocytin, which was injected into impaled neurons so that electrophysiology, shape and immunohistochemistry could be correlated. Myenteric neurons in the distal colon were divided into four morphological groups based on their shapes and projections. One group (29 of the 78 that were characterized electrophysiologically, morphologically and immunohistochemically) was the multiaxonal Dogiel type II neurons, the majority (25/29) of which were calbindin immunoreactive. Each of these neurons had an inflection on the falling phase of the action potential that, in 24/29 neurons, was followed by a late afterhyperpolarizing potential (AHP). Slow excitatory postsynaptic potentials were recorded in 20 of 29 Dogiel type II neurons in response to high frequency internodal strand stimulation and two neurons responded with slow inhibitory postsynaptic potentials. Low amplitude fast excitatory postsynaptic potentials occurred in 3 of 29 Dogiel type II neurons. Neurons of the other three groups were all uniaxonal: neurons with Dogiel type I morphology, filamentous ascending interneurons and small filamentous neurons with local projections to the longitudinal or circular muscle or to the tertiary plexus. Dogiel type I neurons were often immunoreactive for nitric oxide synthase or calretinin, as were some small filamentous neurons, while all filamentous ascending interneurons tested were calretinin immunoreactive. All uniaxonal neurons exhibited prominent fast excitatory postsynaptic potentials and did not have a late AHP following a single action potential, that is, all uniaxonal neurons displayed S type electrophysiological characteristics. However, in 6/19 Dogiel type I neurons and 2/8 filamentous ascending interneurons, a prolonged hyperpolarizing potential ensued when more than one action potential was evoked. Slow depolarizing postsynaptic potentials were observed in 20/29 Dogiel type I neurons, 6/8 filamentous ascending interneurons and 8/12 small filamentous neurons. Six of 29 Dogiel type I neurons displayed slow inhibitory postsynaptic potentials, as did 2/8 filamentous ascending interneurons and 4/12 small filamentous neurons. These results indicate that myenteric neurons in the distal colon of the guinea-pig are electrophysiologically similar to myenteric neurons in the ileum, duodenum and proximal colon. Also, the correlation of AH electrophysiological characteristics with Dogiel type II morphology and S electrophysiological characteristics with uniaxonal morphology is preserved in this region. However, filamentous ascending interneurons have not been encountered in other regions of the gastrointestinal tract and there are differences between the synaptic properties of neurons in this region compared to other regions studied, including the presence of slow depolarizing postsynaptic potentials that appear to involve conductance increases and frequent slow inhibitory postsynaptic potentials.
Tachykinins in the gut. Part II. Roles in neural excitation, secretion and inflammation
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The preprotachykinin-A gene-derived peptides substance (substance P; SP) and neurokinin (NK) A are expressed in intrinsic enteric neurons, which supply all layers of the gut, and extrinsic primary afferent nerve fibers, which innervate primarily the arterial vascular system. The actions of tachykinins on the digestive effector systems are mediated by three different types of tachykinin receptor, termed NK₁, NK₂ and NK₃ receptors. Within the enteric nervous system, SP and NKA are likely to mediate, or comediate, slow synaptic transmission and to modulate neuronal excitability via stimulation of NK₃ and NK₁ receptors. In the intestinal mucosa, tachykinins cause net secretion of fluid and electrolytes, and it appears as if SP and NKA play a messenger role in intramural secretory reflex pathways. Secretory processes in the salivary glands and pancreas are likewise influenced by tachykinins. The gastrointestinal arterial system may be dilated or constricted by tachykinins, whereas constriction and an increase in the vascular permeability are the only effects seen in the venous system. Various gastrointestinal disorders are associated with distinct changes in the tachykinin system, and there is increasing evidence that tachykinins participate in the hypersecretory, vascular and immunological disturbances associated with infection and inflammatory bowel disease. In a therapeutic perspective, it would seem conceivable that tachykinin antagonists could be exploited as antidiarrheal, anti-inflammatory and antinociceptive drugs.

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^∗: Present address: Department of Physiology, Giltner Hall, Michigan State University, East Lansing, MI 48823, U.S.A.

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Actions of serotonin and substance P on myenteric neurons of guinea-pig distal colon

Abstract

Neuroscience

Gastroenterology

J. Auton. Nerv. Syst.

European J. Pharmacol.

Neuroscience

Neuroscience

Neuroscience

Human enteric neurones: intracellular recordings

Gastroenterology

Antiperistalsis and other muscular activities of the colon

J. Physiol. (London)

An intracellular study of myenteric neurons in the mouse colon

J. Neurophysiol.

Synaptic modulation of calcium-dependent potassoum conductance in myenteric neurons in the guinea-pig

J. Physiol. (London)

Calcium action potentials in mammalian peripheral neurons

Nature (London)

Multiple actions of 5-hydroxytryptamine on myenteric neurons of the guinea-pig ileum

J. Physiol. (London)

Does substance P mediate slow synaptic excitation within the myenteric plexus

Nature (London)