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F Cesselin

Publications and source records attributed to F Cesselin.

At least 91 records · Page 5Linked to original sources
PubMed1987

Opposite effects of delta and mu opioid receptor agonists on the in vitro release of substance P-like material from the rat spinal cord.

Superfusion of slices from the dorsal half of the lumbar enlargement of rat spinal cord with Krebs-Henseleit medium supplemented with 30 microM bacitracin allowed the collection of substance P-like immunoreactive material (SPLI), which was released at a rate of approximately 10 pg/4 min. Tissue depolarization by an excess of K+ (30-60 mM) or veratridine (50 microM) induced a marked increase in SPLI outflow, provided that Ca2+ was present in the superfusing fluid. K+- or veratridine-induced SPLI overflow could be modulated in opposite directions by mu and delta opioid receptor agonists. Thus, the two preferential mu agonists Tyr-D-Ala-Gly-MePhe-Gly-ol (DAGO; 10 microM) and Tyr-D-Ala-Gly-MePhe-Met(O)5-OH (FK-33824; 0.1 microM) enhanced SPLI overflow from depolarized tissues, whereas the selective delta agonists Tyr-D-Thr-Gly-Phe-Leu-Thr (deltakephalin; 3 microM) and [2-D-penicillamine, 5-D-penicillamine]enkephalin (50 microM) reduced it. The effect of DAGO was antagonized by a low concentration (1 microM) of naloxone but not by the selective delta antagonist ICI-154129 (50 microM). In contrast, the latter drug prevented the inhibitory influence of delta agonists on K+-induced SPLI release. Complementary experiments with morphine (10 microM) and [2-D-alanine, 5-D-leucine]enkephalinamide (3 microM), in combination with 1 microM naloxone or 50 microM ICI-154129 for the selective blockade of mu or delta receptors, respectively, confirmed that the stimulation of mu receptors increased, whereas the stimulation of delta receptors reduced, SPLI overflow. The results suggest that, at the spinal level, and antinociceptive action of delta but not mu agonists might involve a presynaptic inhibition of substance P-containing primary afferent fibers.

Animals↗
PubMed1987

Enkephalinase is involved in the degradation of endogenous substance P released from slices of rat substantia nigra.

The effects of various peptidase inhibitors were examined upon the K+-evoked overflow of substance-like immunoreactive material (SPLI) from slices of rat substantia nigra in order to assess the possible involvement of "enkephalinase," angiotensin-converting enzyme (ACE) and calpain in the enzymatic inactivation of endogenous substance P in brain tissues. The calpain inhibitor leupeptin and the enkephalinase inhibitors thiorphan and phosphoramidon increased markedly SPLI overflow, whereas the two ACE inhibitors, captopril and enalaprilat (up to 10 microM in the superfusing medium), were inactive. Surprisingly kelatorphan, which inhibits not only enkephalinase but also aminopeptidase and dipeptidylaminopeptidase activities, was less potent than thiorphan or phosphoramidon to enhance SPLI overflow. However, in the presence of ICI-154129 or naloxone to block opiate receptors, kelatorphan was as potent as thiorphan, therefore suggesting some negative influence of endogenous opioids on SPLI release with kelatorphan but not thiorphan. In agreement with this interpretation, the direct stimulation of delta opiate receptors by deltakephalin was found to significantly reduce SPLI overflow. Furthermore, an increased outflow of [Met]enkephalin-like material was observed from substantia nigra slices superfused with kelatorphan but not thiorphan. These results indicate that endogenous substance P released within the substantia nigra is very probably inactivated by enkephalinase and calpain, but not ACE. They also demonstrate that endogenous opioids can exert a negative control upon substance P release in this brain region.

Animals↗
PubMed1986

Immunocytochemical study of enkephalin-like cell bodies in the thalamus of the cat.

Using an indirect immunoperoxidase technique, the localization of enkephalin-like cell bodies in the thalamus of the cat was carried out. Enkephalin-like cell bodies are widely distributed in the cat thalamus. However, immunoreactive cells may be regrouped in 4 clusters which do not exactly correlate with the anatomical subdivisions of the thalamus. One is located in the dorsocaudal aspect of the thalamus, another in the midline area, and the others are formed by the nuclei geniculatum mediale and laterale.

Animals↗
PubMed1986

Simultaneous determination of radio-immunoassayable methionine-enkephalin and radioreceptor-active opiate peptides in CSF of chronic pain suffering and non suffering patients.

Radio-immunoassayable methionine-enkephalin (ME) and radioreceptor-active opiate peptide levels (OP) were determined in CSF from patients, both with and without chronic pain, under investigation for vertebral disk disease. This study showed: that there was no direct correlation between ME and OP levels in CSF; OP levels were negatively correlated with the ME/OP ratio; migraine patients had higher levels of ME; ME concentrations were reduced in patients receiving anti-inflammatory drugs (nonsteroidal): patients with chronic pain (non migraine, no anti-inflammatory drug therapy) had lower ME levels than patients without pain. The data are discussed in relation to animal models of chronic pain.

Adolescent↗
PubMed1986

Lack of change in basal ganglia neuropeptide content following subacute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine treatment of the common marmoset.

Treatment of common marmosets with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP; 1-4 mg/kg for up to 4 days) caused a profound parkinsonian state. Ten days from the start of MPTP treatment, all animals showed marked motor impairment, consisting of bradykinesia and akinesia, limb rigidity, postural abnormalities, loss of vocalisation and blink reflex, and, on occasions, postural tremor. Measurement of caudate-putamen monoamine content at this time showed a profound loss in 3,4-dihydroxyphenylethylamine, homovanillic acid, and 3,4-dihydroxyphenylacetic acid concentrations. Measurement of neuropeptide concentrations in the caudate-putamen, internal and external segments of the globus pallidus, nucleus accumbens, substantia nigra, frontal cortex, and hippocampus showed met-enkephalin, leu-enkephalin, and cholecystokinin (CCK-8) concentrations to be unaffected by MPTP treatment. There was a small decrease in the substance P content of frontal cortex, but otherwise the content of this neuropeptide was unaltered. Parkinsonism in the marmoset, induced by MPTP treatment 10 days earlier, does not alter neuropeptide concentrations in the manner observed in Parkinson's disease.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1986

[Endomorphins and nociception].

Since the discovery of Met- and Leu-enkephalin (Hughes and Kosterlitz, in 1975) about 20 opioid peptides including beta-endorphin, enkephalins and dynorphins have been identified in the central nervous system. Multiple opiate receptors: mu, delta, kappa, etc, with distinct pharmacological characteristics and regional distributions are present in the CNS, which may correspond to the heterogeneity of opioid peptides. Although both endomorphins and opiate receptors have been found in all areas directly involved in nociception, pharmacological, electrophysiological and most biochemical investigations have not demonstrated so far that endomorphinergic neurones play a role in the control of pain. As emphasized in this review, only the measurement of endomorphin release directly in the CNS has allowed the demonstration that some endomorphinergic neurones, notably those containing Met-enkephalin in the spinal cord, can be activated by noxious stimuli. However, the characteristics of this activation depend on both the nature of the stimulus (chemical, mechanical or thermal) and the body area where it is applied. The functional significance of such "pain"--induced activation of spinal enkephalinergic neurones is still speculative.

Animals↗
PubMed1986

Effects of kelatorphan and other peptidase inhibitors on the in vitro and in vivo release of methionine-enkephalin-like material from the rat spinal cord.

The effects of the novel mixed peptidase inhibitor, kelatorphan [N-(R)-3-(N-hydroxyaminocarbonyl-2-benzyl-1-oxopropyl)-L-alanine], were compared to those of a combination of the potent "enkephalinase" inhibitor thiorphan and the nonselective aminopeptidase inhibitor bestatin, on the catabolism of [3H]Met-enkephalin and on the release of endogenous Met-enkephalin by the rat spinal cord in vitro and in vivo. At 20 microM, kelatorphan almost prevented completely the degradation of exogenous [3H] Met-enkephalin by slices of the dorsal zone of the lumbar enlargement. Similarly, the addition of 20 microM kelatorphan to a [3H] Met-enkephalin-containing artificial cerebrospinal fluid superfusing the whole spinal cord of halothane-anesthetized rats efficiently protected the exogenous peptide from enzymatic degradation. In contrast, in the same in vitro and in vivo models, thiorphan (1 microM) or bestatin (20 microM) alone was inactive, and only their combination induced a significant protection of the exogenous peptide. In vitro and in vivo, kelatorphan (20 microM) increased markedly the spontaneous outflow of endogenous Met-enkephalin-like material as well as the peptide overflow due to K+-induced depolarization (in vitro and in vivo) or noxious stimulation (in vivo). Under similar conditions, thiorphan (1 microM) plus bestatin (20 microM) also enhanced the efflux of Met-enkephalin-like material, but generally to a lower extent than kelatorphan. Compared to thiorphan plus bestatin, kelatorphan exerts additional inhibitory effects on dipeptidylaminopeptidase activity and the present results could indicate that this enzyme also may be involved in the inactivation of extracellular Met-enkephalin at the spinal level in rats.

Animals↗
PubMed1986

Partial characterization of angiotensin II-like material extracted from the rat brain.

Angiotensin II (ANG II)-like material was detected in acid extracts of rat brain using radio-immunoassay (RIA) and a radioreceptor assay (RRA). This material, expressed as ANG II equivalents, corresponded to 131 +/- 20 fmol/g and 33 +/- 4 pmol/g as assessed by RIA and RRA respectively. Such quantitative differences indicated that the brain material did not behave as authentic ANG II in both assays, and further chromatographic investigations confirmed this inference. In particular, gel filtration through Sephadex G-25 and TSK Spherogel 3000 SW revealed that the apparent molecular weight of ANG II-like material was much higher (approximately 5000-7000) than that of authentic ANG II. Furthermore, in contrast to the marked hypertension due to ANG II, a decrease in blood pressure (BP) was observed in rats following the systemic administration of chromatographic eluates enriched with brain ANG II-like material.

Angiotensin II↗
PubMed1985

Local and remote effects of intra-caudate administration of GABA-related drugs on Met-enkephalin release in the basal ganglia.

The possible influence of GABAergic systems on the activity of enkephalinergic neurones within the basal ganglia was examined by measuring the release of Met-enkephalin in the caudate nuclei and pallida of halothane-anesthesized cats treated by intra-caudate applications of GABA-related drugs. Depending on the concentration used, GABA exerted local stimulatory (at 10 microM of the amino acid) or inhibitory (at 0.5 mM) action on Met-enkephalin release in the cat caudate nucleus. Only the inhibition was reproduced by the GABA agonists muscimol (1 microM) and (-)-balcofen(10 microM) and by diazepam 10 microM). Conversely, the intra-caudate application of the GABA antagonist bicuculline enhanced markedly the local release of the pentapeptide. Complementary studies using slices of the rat striatum (caudate nucleus + putamen) revealed that a low concentration of GABA (10 microM) tended to increase the K+-evoked efflux of Met-enkephalin, whereas a high concentration of the amino acid exerted a strong inhibitory effect on the peptide release. Such in vivo and in vitro findings suggest that the GABA-induced inhibition of Met-enkephalin release took place via the stimulation of specific GABA A and GABA B receptors within the caudate nucleus, whereas the GABA-induced increase of the peptide release might involve some intracellular regulatory processes in striatal neurones containing both GABA and enkephalins. In addition to altering the local release of Met-enkephalin, intra-caudate applications of GABA-related drugs affected the peptide release in the ipsilateral globus pallidus and contralateral basal ganglia. The observed changes suggest that GABA A, but not GABA B, receptors participated in some tonic inhibitory influence of striatal GABAergic neurones on the striato-pallidal enkephalinergic system. Furthermore, the present results confirmed previous studies (Bourgoin et al.) showing that GABAergic neurones can contribute to some bilateral modulation of enkephalinergic neurones within the basal ganglia.

Animals↗
PubMed1985

In vitro and in vivo effects of kelatorphan on enkephalin metabolism in rodent brain.

Biologically relevant assays were used to compare the potency of kelatorphan (N-[3(R)-[(hydroxyamino)carbonyl]-2-benzyl-1-oxopropyl]-L-alanine) as inhibitor of the peptidase-induced metabolism of enkephalins to that of bestatin, a non-specific inhibitor of aminopeptidase and thiorphan, a highly potent blocker of the neutral endopeptidase (EC 3.4.24.11) designated as enkephalinase. Kelatorphan almost completely inhibited the formation of the three metabolites [3H]Tyr, [3H]Tyr-Gly and [3H]Tyr-Gly-Gly produced by incubation of [3H][Tyr1,Met5]enkephalin with rat striatal slices. Co-administered with [Met5]enkephalin in mouse brain, kelatorphan was able to prevent by 80% the degradation of the exogenous peptide. Moreover, a mixture of thiorphan (1 microM) and bestatin (20 microM) or kelatorphan alone (20 microM) induced a 2.2 to 2.5-fold increase in endogenous [Met5]enkephalin overflow after evoked depolarization of superfused rat striatal slices. In this assay, kelatorphan was the only compound to increase by 63% the basal level of released [Met5]enkephalin. Kelatorphan was about 100 times less potent than bestatin to inhibit the total rat striatal aminopeptidases, but as efficient (IC50 = 4 X 10(-7) M) as bestatin to inhibit a minor aminopeptidase activity resembling aminopeptidase M. Therefore the reported enhanced analgesic potency of kelatorphan with regard to the association of bestatin and thiorphan is very likely related to its ability to almost completely inhibit enkephalin-degrading enzymes (including the Tyr-Gly releasing peptidase) and to its better selectivity for the biologically relevant aminopeptidase M. Kelatorphan would be a valuable probe, preferable to the association of bestatin and thiorphan, to investigate the physiological functions regulated by a phasic enkephalinergic activity.

Aminopeptidases↗
PubMed1985

Dynorphin levels in parkinsonian patients: Leu5-enkephalin production from either proenkephalin A or prodynorphin in human brain.

When measured in postmortem parkinsonian brains, dynorphin levels were unchanged, as compared to control brains, in mesencephalic, striatal and corticolimbic areas. A significant reduction in Leu5-enkephalin and Met5-enkephalin levels had been previously observed in the pallidum and putamen whereas only Met5-enkephalin concentrations were decreased in the substantia nigra of parkinsonian brains. These data suggest that L-Enk could be generated either from proenkephalin A in the striatal areas or from prodynorphin in the nigral areas.

Aged↗
PubMed1985

Spontaneous and evoked release of methionine-enkephalin-like material from the rat spinal cord in vivo.

In vivo perfusion of the subarachnoid space with an artificial cerebrospinal fluid (CSF) in paralyzed halothane-anesthetized rats allowed the collection of methionine-enkephalin (Met-Enk)-like material (MELM) released from the spinal cord. Bio-Gel P2 chromatography and high-performance liquid chromatography showed that 65% of this material corresponded to authentic Met-Enk. Under resting conditions, about 1 pg of MELM per minute was regularly released for at least 3 h; for Met-Enk, this value corresponded to a fractional rate constant of 0.002% (i.e. tissue content of the pentapeptide which was released per minute from the whole spinal cord). Perfusion with K+-enriched (40-60 mM) CSF resulted in a marked enhancement (+ 150-200%) of spinal MELM release. Similarly, calibrated pinches of the muzzle and i.p. administration of acetic acid, two strong noxious stimuli in awake animals, induced a significant increase (+ 75-150%) in spinal MELM release. In contrast, pinches applied to the tail did not enhance but instead slightly reduced (-35%) MELM release from the rat spinal cord. These data suggest that mechanisms other than segmental controls could be involved in the activation of spinal enkephalinergic neurons by some nociceptive stimuli.

Animals↗
PubMed1985

[The spinal enkephalinergic and serotoninergic systems in the control of transmission of nociceptive messages].

Numerous anatomical, pharmacological and electrophysiological data described in the literature indicate that spinal enkephalinergic and serotoninergic systems are probably involved in the control of nociceptive inputs from the periphery to the cerebral cortex. However, reported evidence was generally indirect and did not provide a real demonstration of the physiological participation of these neurones in pain control. This led us to select appropriate experimental approaches for studying directly the activity of spinal enkephalinergic and serotoninergic systems in animals (rat, cat) submitted to noxious stimuli. Owing to two catheters introduced into the subarachnoidal space of anesthetized rats, it was possible to perfuse the whole spinal cord with an artificial cerebro-spinal fluid and thus collect the neuroactive compounds released by spinal neurones (at least those in superficial layers) under various experimental conditions. Using this technique, we observed that some (but not all) nociceptive stimuli such as intense pinching of the muzzle, intraperitoneal injection of acetic acid or noxious heat applied to the muzzle or the tail induced a significant increase in met-enkephalin release from the spinal cord (see fig. 2). Similar effects were observed following the blockade of enkephalin catabolism by thiorphan and bestatin (see fig. 1) indicating that they were not due to some alteration of peptidase activities but really involved the activation of spinal enkephalinergic systems. Since cervical cord transection suppressed the stimulatory action of noxious stimuli on spinal met-enkephalin release, it could be proposed that the mechanisms involved were not limited to the cord but depended on supraspinal structures. Bulbo-mesencephalic serotoninergic neurones projecting to the spinal cord might well correspond to such structures (or at least to some of them) since nociceptive stimuli (such as noxious heat applied to the tail) also evoked a marked increase of serotonin (5-HT) release at the spinal level (fig. 3). Such observations together with indirect evidence reported in the literature suggested therefore that the activation of spinal enkephalinergic systems triggered by noxious stimuli might result from excitatory influence due to descending serotoninergic projections. However, in vitro studies using slices of the dorsal zone of the rat lumbar cord did not reveal any stimulatory effect of 5-HT on the spontaneous or K+-evoked release of met-enkephalin (fig. 4).(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1984

Characterization of enkephalins and related peptides in rat hypophysial portal blood.

Rat hypophysial portal blood, collected from the pituitary stalk, was extracted and enkephalins were assayed by different RIA. Met-Enk-IR and Leu-Enk-IR levels were 1635 +/- 470 pg/ml and 125 +/- 50 pg/ml, respectively. Using HPLC characterization, the presence in portal blood of Met-Enk, Leu-Enk, proenkephalins fragments and dynorphin1-17 has been demonstrated. An unidentified Met-Enk-IR peptide has also been found.

Animals↗
PubMed1984

Evidence for an angiotensin II-like material and for a rapid metabolism of angiotensin II in the rat brain.

Radioimmunoassay and radioreceptor assay for angiotensin II (AII) have been developed to detect AII-like material in rat brain extracts using HCl extraction and boiling. The amount of AII-like material found was 270 +/- 39 fmol/brain with radioimmunoassay and 67 +/- 7.8 pmol/brain with radioreceptor assay. However, chromatographic separation by gel filtration on a Sephadex G25 column revealed that this material was not authentic AII, but of higher molecular weight. Column chromatography on Sephacryl S300 combined with radioimmunoassay permitted us to show that the major part of the AII-like material had a molecular weight of about 10,000. To test the hypothesis that very rapid degradation of AII could explain the difficulty in detecting endogenous AII in the rat brain, we studied the metabolism of AII using HPLC analysis of the in vitro degradation of [3H]AI and [3H]AII (20 nM) by brain homogenates HPLC analysis showed no detectable [3H]AII generation from [3H]AI. [3H]AI and [3H]AII yielded the same [3H]metabolites corresponding to two peaks alpha and beta. Nevertheless, by adding an excess of unlabeled Ileu5-AII, which competitively inhibits AII-angiotensinase activity, it was possible to detect the formation of [3H]AII from [3H]AI. We suggest that very low levels of AII could coexist with a higher molecular weight AII-like compound in the rat brain and that very rapid degradation of AII may account for the difficulty in detecting this peptide in the brain.

Angiotensin I↗
PubMed1984

Normal CSF levels of met-enkephalin-like material in a case of naloxone-reversible congenital insensitivity to pain.

In a case of naloxone-reversible congenital insensitivity to pain, met-enkephalin-like immunoreactivity in the CSF was in the normal range and not affected by the administration of naloxone. Chromatographic analysis of the met-enkephalin-like material revealed that it corresponded to at least two classes of molecules. A clear difference in the relative proportions of these two classes was detected in the CSF of the patient insensitive to pain when compared to controls. The possible functional significance of this alteration is discussed in relation to the well known antinociceptive action of enkephalins.

Adult↗