Antagonism of non-cholinergic excitatory junction potentials in the guinea-pig ileum by a substance P analogue antagonist

doi:10.1016/0304-3940(86)90006-6

Neuroscience Letters

Volume 63, Issue 1, 2 January 1986, Pages 23-26

https://doi.org/10.1016/0304-3940(86)90006-6 Get rights and content

Abstract

In the presence of atropine electrical transmural stimulation (using repetitive volleys, e.g. 3 pulses at 50 Hz applied every 4 s) of full thickness longitudinal strips of guinea-pig ileum produced non-cholinergic excitatory junction potentials (EJPs) and inhibitory junction potentials (IJPs) in the circular muscle layer. After abolition of the IJPs with apamin, the non-cholinergic EJPs clearly showed facilitation. In the presence of apamin and the substance P analogue antagonist, [d-Arg¹,d-Pro²,d-Trp^7,9,Leu¹¹]-substance P (SPA), the non-cholinergic EJPs were reduced by 60–90%; transmural stimulation now revealed an apamin-resistant IJP followed by a slow depolarization. The atropine-resistant EJPs are probably caused by the release of substance P (or a similar compound) and are likely to underlie the non-cholinergic contractions reported to occur in this tissue.

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It is known that there is an age-related increase in gastrointestinal diseases. However, there is a lack of studies dealing with the correlation between age-related changes in function and intrinsic innervation in the gastrointestinal tract. The purpose of this work was to study this subject in the guinea pig ileum, whose functional and structural features are well known in the young age. Ileal longitudinal muscle — myenteric plexus (LMMP) preparations were obtained from 3-to 24-month-old guinea pigs. Both functional and immunohistochemical techniques were applied. The force of the contraction elicited by excitatory stimuli (electrical stimulation, acetylcholine, substance P, and opioid withdrawal) increased in parallel with an age-dependent reduction in the density of excitatory motor neurones to the longitudinal muscle, whereas other subpopulations of neurones, including inhibitory motor neurones, decreased much more slowly. Although the increase in responsiveness could be related to the age/weight-related increment in muscle bulk, some compensatory modifications to the lowered density of excitatory neurones could also be involved. On the other hand, the acute inhibitory response to morphine remained unaltered in old animals, whilst in vitro tolerance was lower. These results suggest that although age-dependent neuronal loss does not cause dramatic changes in intestinal motility, it is a factor that could contribute to disturbing normal responsiveness and, perhaps, underlie the higher frequency of gastrointestinal diseases encountered in the elderly.
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The nature of the electrically- or stretch-evoked nonadrenergic, noncholinergic (NANC) inhibitory junction potentials (UPs) in circular smooth muscle cells of the guinea-pig proximal and distal colon were investigated using standard intracellular microelectrode recording techniques. We have confirmed that the NANC UP, recorded in the presence of hyoscine (1 μM) and nifedipine (1 μM), can be divided into two components with apamin (250 nM), a blocker of the small conductance Ca²⁺-activated K⁺ channels. Both the apamin-sensitive and the apamin-resistant components of the UP were blocked by tetrodotoxin (1.6 μM) or by lowering the external Ca²⁺ concentration (to 0.25 mM). The apamin-sensitive UP was also blocked by ω-conotoxin GVIA (100 nM), a blocker of ‘N-type’ Ca²⁺ channels. The apamin-resistant UP and rebound post-stimulus depolarization (PSD) were reduced upon exposure to either N^G-l-arginine (NOLA), an inhibitor of nitric oxide synthase (NOS), or the nitric oxide (NO) scavenger, haemoglobin. The effects of NOLA were partially reversed in the presence of excess l-arginine, a substrate for NOS, suggesting that NO, or a related NO-donor compound, is likely to be the apamin-resistant inhibitory transmitter. Blockade of either the apamin-sensitive or apamin-resistant UP was associated with membrane depolarization and a decrease in the membrane conductance in the absence of nerve stimulation. In the proximal colon, the apamin-resistant UP and PSD could both be demonstrated to arise from an increase in the membrane conductance after subtraction of a non-linear background conductance. The hyperpolarization upon repetitive NANC nerve stimulation was mimicked by the NO donor, S-nitroso-l-cysteine (2.5–25 RM), which evoked a transient apamin-sensitive, but w-conotoxin GVIA resistant, component followed by a slower apamin-resistant component. These results suggest that neurally-released NO has a number of actions in the guinea-pig colon, causing apamin-resistant hyperpolarization and depolarization, as well as directly opening apamin-sensitive K⁺ channels.
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The enteric nervous system contains neurons with well-defined functions. However, when neurons of the same function are examined in different regions or species, they are found to show subtle differences in their pharmacologies of transmission and different chemical coding. Individual enteric neurons use more than one transmitter, i.e., transmission is plurichemical. For example, enteric inhibitory neurons have three or more primary transmitters, including nitric oxide, vasoactive intestinal peptide, and possibly adenosine triphosphate and pituitary adenylyl cyclase activating peptide. Primary transmitters are highly conserved, although their relative roles vary considerably between gut regions. Multiple substances, including transmitters and their synthesizing enzymes and nontransmitters (such as neurofilament proteins), provide neurons with a chemical coding through which their functions and projections can be identified. Although equivalent neurons in different regions have the same primary transmitters, other chemical markers differ substantially. Caution must be taken in extrapolating pharmacological and neurochemical observations between species or even between regions in the one species. On the other hand, careful interregion and interspecies comparisons lead to an understanding of the features of enteric neurons that are highly conserved and can be used in valid extrapolation.

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Antagonism of non-cholinergic excitatory junction potentials in the guinea-pig ileum by a substance P analogue antagonist

Abstract

Neurosci. Lett.

Neurosci. Lett.

J. Auton. Nerv. Syst.

J. Auton. Nerv. Syst.

Eur. J. Pharmacol.

Life Sci.

Cable properties of smooth muscle

J. Physiol. (London)

Atropine-resistant longitudinal muscle spasms due to excitation of non-cholinergic neurones in Auerbach's plexus

J. Physiol. (London)

Effects of substance P, cholecystokinin octapeptide, bombesin and neurotensin on the peristaltic reflex of the guinea-pig ileum in the absence and in the presence of atropine

Naunyn-Schmiedeberg's Arch. Pharmacol.

Evidence for non-cholinergic, non-adrenergic transmission in the guineapig ileum

J. Physiol. (London)

The nature of non-cholinergic, non-adrenergic transmission in longitudinal and circular muscles of the guinea-pig ileum

J. Physiol. (London)

Inhibition of smooth muscle contractions induced by capsaicin and electrical transmural stimulation by a substance P antagonist

Acta. Physiol. Scand. Suppl.