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M Marcoli

Publications and source records attributed to M Marcoli.

At least 19 recordsLinked to original sources

In vitro cortical neuronal networks as a new high-sensitive system for biosensing applications.

By taking advantages of the main features of the microelectrode array (MEA) technology (i.e. multisite recordings, stable and long-term coupling with the biological preparation), we analyzed the changes in activity patterns induced by applying specific substances to dissociated cortical neurons from rat-embryos (E18). Data were recorded simultaneously from 60 electrodes, and the electrophysiological behavior was investigated during the third week in vitro, both at the spike and burst level. The analysis of the electrophysiological activity modulation, by applying agonists of the ionotropic glutamate receptors at low (i.e. 0.2-1-5 microM) and high (i.e. 50-100 microM) concentrations, is presented. Preliminary results show that the dynamics of the in vitro cortical neurons is very sensitive to pharmacological manipulation of the glutamatergic transmission and the effects on the network behavior are strictly dependent from the drug concentration. In particular, the addition of a high-dose of agonist determined a global and irreversible depression of the network activity, while, in the low-concentration case, the electrophysiological behavior showed different results, depending on the type of receptor involved. From these observations, we are encouraged to think of a more engineered system, based on in vitro cortical neurons, as a novel sensitive system for drug (pre)-screening and neuropharmacological evaluations.

Action Potentials↗

Networks of neurons coupled to microelectrode arrays: a neuronal sensory system for pharmacological applications.

Two main features make microelectrode arrays (MEAs) a valuable tool for electrophysiological measurements under the perspective of pharmacological applications, namely: (i) they are non-invasive and permit, under appropriate conditions, to monitor the electrophysiological activity of neurons for a long period of time (i.e. from several hours up to months); (ii) they allow a multi-site recording (up to tens of channels). Thus, they should allow a high-throughput screening while reducing the need for animal experiments. In this paper, by taking advantages of these features, we analyze the changes in activity pattern induced by the treatment with specific substances, applied on dissociated neurons coming from the chick-embryo spinal cord. Following pioneering works by Gross and co-workers (see e.g. Gross and Kowalski, 1991. Neural Networks, Concepts, Application and Implementation, vol. 4. Prentice Hall, NJ, pp. 47-110; Gross et al., 1992. Sensors Actuators, 6, 1-8.), in this paper analysis of the drugs' effects (e.g. NBQX, CTZ, MK801) to the collective electrophysiological behavior of the neuronal network in terms of burst activity, will be presented. Data are simultaneously recorded from eight electrodes and besides variations induced by the drugs also the correlation between different channels (i.e. different area in the neural network) with respect to the chemical stimuli will be introduced (Bove et al., 1997. IEEE Trans. Biomed. Eng., 44, 964-977.). Cultured spinal neurons from the chick embryo were chosen as a neurobiological system for their relative simplicity and for their reproducible spontaneous electrophysiological behavior. It is well known that neuronal networks in the developing spinal cord are spontaneously active and that the presence of a significant and reproducible bursting activity is essential for the proper formation of muscles and joints (Chub and O'Donovan, 1998. J. Neurosci., 1, 294-306.). This fact, beside a natural variability among different biological preparations, allows a comparison also among different experimental session giving reliable results and envisaging a definition of a bioelectronic 'neuronal sensory system'.

Algorithms↗

Inhibitory presynaptic 5-hydroxytryptamine(2A) receptors regulate evoked glutamate release from rat cerebellar mossy fibers.

We studied the pharmacological characterization of the 5-hydroxytryptamine(2) (5-HT(2)) heteroreceptor located on glutamatergic cerebellar mossy fiber nerve terminals. Depolarization-evoked overflow of endogenous glutamate from rat cerebellar "giant" mossy fiber synaptosomes was inhibited by 5-HT or (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane [(+/-)-DOI], exhibiting pD(2) (= -log EC(50)) values of 7.37 and 7.29, respectively. Trazodone inhibited the depolarization-evoked glutamate overflow, exhibiting lower potency (pD(2) = 6.42) and lower efficacy with respect to 5-HT or (+/-)-DOI (maximal inhibition, 54%, compared with 70% for either 5-HT or (+/-)-DOI). Ketanserin, a 5-HT(2A)/5-HT(2C) receptor antagonist, counteracted the inhibitory effect of (+/-)-DOI or trazodone. Inhibition of glutamate overflow by 5-HT, (+/-)-DOI, or trazodone was prevented by the selective 5-HT(2A) receptor antagonist R-(+)-alpha-(2,3-dimethyoxyphenyl)-1-(2-(4-fluorophenyl)ethyl)-4-piperidine-methanol (MDL 100907), while the potent and selective 5-HT(2C) receptor antagonist 6-chloro-5-methyl-1-[6-(methylpyridin-3-yloxy)pyridin-3yl-carbamoyl] indoline (SB 242084) was ineffective. In cerebellar slices, MDL 100907 increased on its own the K(+)-evoked release of glutamate. It is concluded that the evoked release of glutamate from cerebellar mossy fibers can be controlled by inhibitory presynaptic 5-HT(2A) heteroreceptors, the receptors can be activated by endogenously released 5-HT, and trazodone behaves as a partial agonist at these receptors.

Animals↗

Serotonin inhibition of the NMDA receptor/nitric oxide/cyclic GMP pathway in human neocortex slices: involvement of 5-HT(2C) and 5-HT(1A) receptors.

The NMDA receptor/nitric oxide (NO)/cyclic GMP pathway and its modulation by 5-hydroxytryptamine (5-HT) was studied in slices of neocortical samples obtained from patients undergoing neurosurgery. The cyclic GMP elevation produced by 100 microM NMDA was blocked by 100 microM of the NO synthase inhibitor N(G)-nitro-L-arginine (L-NOARG) or by 10 microM of the soluble guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3,-alpha] quinoxaline-1-one (ODQ). The NMDA effect was prevented by 5-HT or by the 5-HT(2) agonist (+/-)-1-(2, 5-dimethoxy-4-iodophenyl)-2-aminopropane ((+/-)-DOI; EC(50)=22 nM). The (+/-)-DOI inhibition was insensitive to the 5-HT(2A) receptor antagonist MDL 100907 or the 5-HT(2B) antagonist rauwolscine; it was largely prevented by 1 microM of the non-selective 5-HT(2C) antagonists mesulergine (5-HT(2A,B,C)), ketanserin (5-HT(2A,C)) or SB 200646A (5-HT(2B,C)); it was completely abolished by 0.1 microM of the selective 5-HT(2C) receptor antagonist SB 242084. The NMDA-induced cyclic GMP elevation also was potently inhibited by the selective 5-HT(2C) agonist RO 60-0175 and by the antidepressant trazodone, both added at 1 microM, in an SB 242084-sensitive manner. Finally, the 5-HT(1A) agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT; 1 microM) inhibited the NMDA-evoked cyclic GMP response, an effect blocked by the selective 5-HT(1A) receptor antagonist WAY 100635. In conclusion, the NMDA receptor/NO/cyclic GMP pathway in human neocortex slices can be potently inhibited by activation of 5-HT(2C) or 5-HT(1A) receptors.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

A subtype of the gamma-aminobutyric acid(B) receptor regulates cholinergic twitch response in the guinea pig ileum.

The pharmacological profile of the gamma-aminobutyric acid (GABA)(B) receptor regulating cholinergic twitch contraction in the guinea pig ileum myenteric plexus-longitudinal muscle preparation was investigated. GABA and (-)-baclofen inhibited the contraction, exhibiting quite close potencies (pD(2) for GABA = 5.70; pD(2) for (-)-baclofen = 5.33). The compound CGP 47656 also reduced the cholinergic twitch concentration (pD(2) = 5.42), but its efficacy was significantly lower than that of (-)-baclofen or GABA. Added at varying concentrations, CGP 47656 modified the concentration-response curve of (-)-baclofen as expected for a partial agonist. Phaclofen, CGP 36742, CGP 35348, and CGP 52432 behaved as competitive antagonists of (-)-baclofen, exhibiting the following pA(2) values: 3.90, 4.88, 5.02, and 7.82, respectively. The compound CGP 56999 behaved as a potent noncompetitive GABA(B) receptor antagonist. In comparing the pharmacological profile of the ileal receptor with those of the previously characterized pharmacological subtypes of the GABA(B) receptor present in the central nervous system, it can be seen that the GABA(B) receptor inhibiting cholinergic twitch contraction in guinea pig ileum myenteric plexus-longitudinal muscle mostly resembles the receptor located on somatostatin human neocortex nerve terminals.

Animals↗

Pharmacological diversity between native human 5-HT1B and 5-HT1D receptors sited on different neurons and involved in different functions.

The releases of [3H]5-hydroxytryptamine ([3H]5-HT) and of endogenous glutamic acid and their modulation through presynaptic h5-HT1B autoreceptors and h5-HT1D heteroreceptors have been investigated in synaptosomal preparations from fresh neocortical samples obtained from patients undergoing neurosurgery. The inhibition by 5-HT of the K+ (15 mM)-evoked overflow of [3H]5-HT was antagonized by the 5-HT1B/5-HT1D receptor ligand GR 127935, which was ineffective on its own; this drug was previously found to behave as a full agonist at the h5-HT1D heteroreceptor regulating glutamate release. The recently proposed selective h5-HT1B receptor ligand SB-224289 also prevented the effect of 5-HT at the autoreceptor, being inactive on its own; in contrast, SB-224289, at 1 microM, was unable to interact with the h5-HT1D heteroreceptor. The inhibitory effect of 5-HT on the K+-evoked overflow of glutamate was antagonized by the h5-HT1D receptor ligand BRL-15572; added in the absence of 5-HT the compound was without effect. BRL-15572 (1 microM) was unable to modify the effect of 5-HT at the autoreceptor regulating [3H]5-HT release. The selective 5-HT1A receptor antagonist (+)-WAY 100135, previously found to be an agonist at the h5-HT1D heteroreceptor regulating glutamate release, could not interact with the h5-HT1B autoreceptor when added at 1 microM. It is concluded that native h5-HT1B and h5-HT1D receptors exhibit a hitherto unexpected pharmacological diversity.

Adult↗

Glutamate release in human cerebral cortex and its modulation by 5-hydroxytryptamine acting at h 5-HT1D receptors.

1. The release of glutamic acid and its modulation by 5-hydroxytryptamine (5-HT) in the human brain has been investigated in synaptosomal preparations from fresh neocortical samples obtained from patients undergoing neurosurgery to reach deeply sited tumours. 2. The Ca2+-dependent K+ (15 mM)-evoked overflow of glutamate was inhibited by 5-HT in a concentration-dependent manner (EC50 = 2.9 nM; maximal effect approximately 50%). The inhibition caused by 5-HT was antagonized by the 5-HT1/5-HT2 receptor antagonist methiothepin. The 5-HT1B/5-HT1D receptor agonist sumatriptan mimicked 5-HT (EC50 = 6.4 nM; maximal effect approximately 50%); the effect of sumatriptan was also methiothepin-sensitive. Selective 5-HT1A receptor antagonists could not prevent the inhibition of glutamate release by 5-HT. 3. The 5-HT1B/5-HT1D receptor ligand GR 127935 and the 5-HT2C/5-HT1B/5-HT1D receptor ligand metergoline were unable to prevent the 5-HT effect; instead they inhibited glutamate release, their effects being abolished by methiothepin. Some 5-HT1A receptor antagonists also displayed intrinsic agonist activity. 4. The effect of sumatriptan was prevented by ketanserin, a drug known to display much higher affinity for recombinant h 5-HT1D than for h 5-HT1B receptors. 5. We propose that neocortical glutamatergic nerve terminals in human brain cortex possess release-inhibiting presynaptic heteroreceptors that appear to belong to the h 5-HT1D subtype.

Adult↗

Trazodone is a potent agonist at 5-HT2C receptors mediating inhibition of the N-methyl-D-aspartate/nitric oxide/cyclic GMP pathway in rat cerebellum.

The effects of trazodone on the cyclic GMP elevation elicited by N-methyl-D-aspartate in rat cerebellar slices were analyzed. Trazodone inhibited in a concentration-dependent manner (EC50 = 0.82 nM) the cyclic GMP response evoked by 0.1 microM N-methyl-D-aspartate. The inhibition was near complete at 10 nM trazodone. The effect of 10 nM trazodone was unaffected by 0.3 microM spiperone or rauwolscine, antagonists with selectivity for the 5-HT(serotonin)2A or the 5-HT2B subtype, respectively, but it was totally prevented by 0.01 microM mesulergine, a 5-HT2A/5-HT2B/5-HT2C receptor antagonist. Trazodone was potently counteracted (IC50 = 2.7 nM) by the selective 5-HT2B/5-HT2C receptor antagonist N-(1-methyl-5-indolyl)-N-(3-pyridil) urea HCl and, less potently (IC50 = 95 nM), by ketanserin, a 5-HT2A/5-HT2C receptor blocker. It is concluded that trazodone behaves as a potent full agonist at the 5-HT2C receptor mediating inhibition of the cerebellar N-methyl-D-aspartate/nitric oxide/cyclic GMP system.

Animals↗

Serotonin inhibition of the NMDA receptor/nitric oxide/cyclic GMP pathway in rat cerebellum: involvement of 5-hydroxytryptamine2C receptors.

Previous studies have shown that 5-hydroxytryptamine (5-HT) can potently inhibit glutamatergic transmission in rat cerebellum through the activation of multiple 5-HT receptors. The aim of this study was to subclassify the 5-HT2 receptor mediating inhibition of the cyclic GMP response elicited by N-methyl-D-aspartate in adult rat cerebellar slices. Seven receptor antagonists, endowed with relative selectivities for the 5-HT2A, 5-HT2B, and 5-HT2C subtypes, differentially affected the inhibition by (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane of the cyclic GMP response, suggesting that the receptor involved belongs to the 5-HT2C subtype.

Adrenergic alpha-Antagonists↗

Effect of desipramine-induced blockade of neuronal uptake mechanisms on adrenoceptor-mediated responses in the guinea-pig colon.

In order to clarify whether adrenoceptors in the guinea-pig distal colon are under sympathetic control, we assessed possible variations in the sensitivity to adrenoceptor agonists after blockade of neuronal catecholamine uptake mechanisms by desipramine (DMI). First, experiments were carried out to investigate the effects of DMI added in the organ bath on propulsion velocity, endogenous and [3H] prelabelled acetylcholine overflow, electrically evoked noradrenaline overflow and longitudinal smooth muscle tone. Secondly, we studied the effects of adrenoceptor agonists on the above parameters in untreated animals and in animals chronically treated with DMI. DMI added in the organ bath at concentrations equal to or higher than 30 nM inhibited all the parameters under study. Thus, when evaluating the effect of DMI on concentration-response curves to adrenoceptor agonists, concentrations which were per se inactive were used. DMI added in the organ bath at concentrations up to 30 nM potentiated the inhibitory effects of exogenous noradrenaline on propulsion velocity and acetylcholine overflow, but it did not affect the concentration-response curve to exogenous noradrenaline on longitudinal smooth muscle tone. Furthermore, 30 nM DMI inhibited propulsion velocity during sympathetic nerve stimulation. In preparations obtained from animals chronically treated with DMI, no significant change of propulsion velocity, endogenous and [3H] prelabelled acetylcholine overflow was found with respect to untreated animals. Nevertheless, in such preparations subsensitivity to isoprenaline (acting mainly on muscular beta-adrenoceptors) and clonidine (acting on neuronal alpha 2-adrenoceptors) and super-sensitivity to phenylephrine were observed. Electrically evoked noradrenaline overflow was enhanced, in a frequency-dependent way, by yohimbine and inhibited by clonidine.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗

Inhibition of endogenous acetylcholine release by blockade of voltage-dependent calcium channels in enteric neurons of the guinea-pig colon.

The effects on acetylcholine release from the guinea-pig colon of the N-type calcium channel blocker omega-conotoxin GVIA (omega-conotoxin), the L-type calcium channel blocker nifedipine and the putative blocker of T-type channels, flunarizine, have been investigated. Endogenous basal acetylcholine release and electrically (1 Hz, 1 ms, 450 mA)-evoked overflow in the presence of cholinesterase inhibitor were studied. omega-Conotoxin (1-10 nM) and nifedipine (0.03-3 microM) dose-dependently inhibited basal and electrically-evoked acetylcholine release. Maximal inhibition of basal or electrically-evoked acetylcholine release was about 40% for nifedipine and about 75% for omega-conotoxin. The potency of nifedipine was inversely related to the external calcium concentration: its EC50 value in low-calcium medium (0.5 mM) was as low as 12 nM. Flunarizine inhibited acetylcholine release only at concentrations higher than 0.2 microM. Our results are consistent with an involvement of N- and L-type calcium channels in the control of the endogenous acetylcholine release from the guinea-pig colon.

Acetylcholine↗

Supersensitivity to morphine after chronic sympathetic denervation in guinea-pig colon.

The possible role of opioid systems in the adaptive changes which follow chronic sympathetic denervation in the guinea-pig colon has been studied by comparing the effects of the opioid agonist morphine in control animals and after chronic sympathetic denervation. Supersensitivity to the inhibitory effects of morphine on the peristaltic reflex was observed after chronic sympathetic denervation, while the potency against acetylcholine release was unmodified. Our results suggest that a modification of the opioid system occurs after sympathetic denervation in the guinea-pig colon. Supersensitivity to endogenous opioids at a site different from that regulating acetylcholine release could account for the counter-regulation of intestinal motility after chronic sympathetic denervation.

Acetylcholine↗

Interaction between (-)naloxone and morphine in modifying superoxide generation from human granulocytes.

The effect of the opioid agonist morphine and of the (-) and (+) stereoisomers of the antagonist naloxone were studied on superoxide generation from human granulocytes. Morphine or naloxone had no effect on basal or phorbol 12-myristate 13-acetate (PMA)-stimulated superoxide generation. Combined equimolar (-)naloxone and morphine concentrations (0.1 pM-0.1 microM) inhibited PMA-stimulated superoxide generation, while combined (+)naloxone and morphine had no effect. The stereospecific effect of naloxone suggests the involvement of opioid receptors. Thus, inhibition of superoxide generation by combined (-)naloxone and morphine could result from the unmasking of non opioid effects of morphine. It is suggested that the opioid control of oxidative metabolism in human granulocytes could involve multiple receptors mediating opposite effects.

Adult↗

Selectivity of Ca2+ channel blockers in inhibiting muscular and nerve activities in isolated colon.

1. Potency and efficacy of nifedipine, verapamil and diltiazem and of Bay K 8644 in modifying propulsion and nerve or smooth muscle activities have been compared in the guinea-pig isolated distal colon. Both the neuronal and muscular effects of Ca2+ channel blockers seem to develop at concentrations that are devoid of any significant effect apart from that on Ca2+ channels. 2. Nifedipine, verapamil and diltiazem were all able to impair propulsion, resting and stimulated acetylcholine (ACh) release and smooth muscle contractility in a concentration-dependent way. However, some degree of selectivity for neuronal and muscular effects could be observed. Nifedipine was more than 500 fold more potent than verapamil in relaxing musculature but less than twice as potent in reducing ACh release. On the other hand, verapamil was the most efficacious Ca2+ channel blocker tested in inhibiting ACh release, its effects being inversely correlated to the external Ca2+ concentration, and completely abolished by Bay K 8644. 3. By comparing the potencies exhibited by each drug against peristaltic reflex, smooth muscle contractility and ACh release, verapamil proved to be almost as potent in slowing the peristaltic reflex as in reducing ACh release, while nifedipine was about 100 fold more potent against the peristaltic reflex than against ACh release, but nearly equal against the peristaltic reflex and smooth muscle tone. Therefore, interference with cholinergic neurotransmission is likely to play a major role in the antipropulsive effect of verapamil, while peristaltic reflex impairment by nifedipine is likely to be dependent on inhibition of smooth muscle. 4. A facilitatory effect of Bay K 8644 on both the efficiency of the peristaltic reflex and the nonadrenergic, non-cholinergic (NANC) nerve-mediated relaxation could be observed at concentrations at least 10 fold lower than those required to affect ACh release or smooth muscle. 5. It is concluded that the effects of Ca2+ channel blockers on neurotransmitter release may be relevant to their effects on the gastrointestinal motor function.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗

Peptide opioids and morphine effects on inflammatory process.

Morphine was found to inhibit human granulocyte aggregation and ATP, thromboxane B2 (TxB2), and leukotriene B4 (LTB4) secretion during cell aggregation. None of the opioid peptides tested [(D-Ala2, D-Leu5)-enkephalin (DADL), (D-Ala2, N-Me-Phe4, Gly-ol5)-enkephalin (DAGO) or dynorphin 1-9 (Dyn 1-9)] was capable of mimicking morphine effects, while Dyn 1-9 per se induced TxB2 and LTB4 secretion from granulocytes. Morphine inhibition of both cell aggregation and ATP, but not of arachidonic acid metabolism product secretion, was prevented by naloxone. The naloxone-sensitive impairment by morphine of CD11b-CD18 complex surface expression observed could play a role in opioid inhibition of granulocyte activation.

Adenosine Triphosphate↗

A stereoselective blockade by naloxone of opioid and non-opioid-induced granulocyte activation.

Naloxone was found to prevent both opioid and non-opioid-induced migration of human granulocytes in a stereoselective way. Indeed, besides being able to inhibit morphine-induced migration, (-) but not (+), naloxone isomer proved to abolish either casein, serum of fMLP-induced chemotaxis. It is concluded that opioid-induced modulation of granulocyte migration is likely to be mediated through specific receptors, possibly of the mu type. Moreover, the antichemotactic effect of naloxone suggests an involvement of opioid receptors and/or endogenously released opioids in the mechanism of granulocyte activation by different chemoattractants.

Chemotaxis, Leukocyte↗

[3H]acetylcholine release from the guinea-pig distal colon: comparison with ileal [3H]acetylcholine release and effect of adrenoceptor stimulation.

To study cholinergic function in the guinea-pig colon, resting and electrically evoked 3H release after preincubation with [3H] choline has been compared in colonic and ileal myenteric plexus preparations. Fractional spontaneous colonic 3H release was significantly higher than ileal 3H release, while the reverse was true for electrically evoked 3H outflow. Electrically evoked 3H outflow in the colon was linearly related to stimulation frequency (0.2-3 Hz range) and current intensity (300-600 mA range), while 3H outflow per pulse was inversely related to stimulation frequency. Electrically evoked 3H outflow was prevented in Ca2(+)-free solution, indicating that it probably mirrored neuronal exocytotic [3H]acetylcholine release. Both noradrenaline and clonidine concentration-dependently inhibited electrically evoked 3H outflow, clonidine being more potent but less efficacious than noradrenaline. For both noradrenaline and clonidine, the potency and efficacy for inhibition of 3H outflow were close to the values previously reported for the inhibition of electrically evoked endogenous acetylcholine output from colonic preparations. In conclusion, these data indicate that 3H release after incubation with [3H]choline is a valid alternative to measurement of endogenous acetylcholine output to study colonic cholinergic neuronal function in the guinea-pig.

Acetylcholine↗

Effect of beta-casomorphins on intestinal propulsion in the guinea-pig colon.

beta-Casomorphins are a family of opioid peptides originally isolated from beta-casein. In view of a possible physiological significance of these milk-derived compounds, the effects of bovine beta-casomorphin-5 (beta-CM-5), beta-casomorphin-4 (beta-CM-4) and D-Ala2-beta-casomorphin-4-NH2 (D-Ala2-beta-CM-4-NH2) have been investigated on the peristaltic reflex in the guinea-pig isolated colon and compared with morphine. beta-CM-5 and D-Ala2-beta-CM-4-NH2 each dose-dependently inhibited the velocity of propulsion of an intraluminal bolus; beta-CM-4 was ineffective. IC50 values were 0.30, 5.21 and 0.29 microM for morphine, beta-CM-5 and D-Ala2-beta-CM-4-NH2, respectively. The potency ratios vs morphine were 0.06 and 0.96 for beta-CM-5 and D-Ala2-beta-CM-4-NH2, respectively. Blockade of the peristaltic reflex by beta-CM-5 or D-Ala2-beta-CM-4-NH2 was reversed by the opioid antagonist naloxone. D-Ala2-beta-CM-4-NH2 also dose-dependently inhibited resting acetylcholine output (IC50 = 5.69 microM; potency ratio vs morphine: 0.63). In conclusion, certain beta-casomorphins inhibit intestinal propulsion and cholinergic neurotransmission in the guinea-pig colon, probably by acting at opioid receptors.

Acetylcholine↗