Guy Simonnet - Academia.edu (original) (raw)
Papers by Guy Simonnet
Douleurs : Evaluation - Diagnostic - Traitement, Oct 1, 2007
Les polyamines sont des constituants moleculaires universels et obligatoires de toute cellule viv... more Les polyamines sont des constituants moleculaires universels et obligatoires de toute cellule vivante. Considerees comme ubiquitaires tant au niveau cellulaire qu'a celui de l'organisme, elles participent a la perennite des processus vitaux et de croissance. Leur large spectre d'activite tient a la multiplicite de leurs cibles potentielles ainsi qu'a leur habilite a en modifier les proprietes physiques et/ou biologiques. Leurs roles dans les processus proliferatifs font que leur metabolisme est une cible privilegiee dans les therapies anti-cancereuses. Cependant, dans cette optique, il ne suffit pas de bloquer ou de perturber leur metabolisme, car les cellules en proliferation ont acces a une source exogene importante de polyamines provenant en grande partie de l'alimentation et dans une moindre mesure, de la production bacterienne intestinale. Des etudes pre-cliniques ont demontre in vivo l'interet d'une tri-therapie associant inhibiteurs de synthese des...
Neuropsychopharmacology, 2021
Opioids are a mainstay of pain management but can induce unwanted effects, including analgesic to... more Opioids are a mainstay of pain management but can induce unwanted effects, including analgesic tolerance and paradoxical hyperalgesia, either of which leads to increased pain. Clinically, however, the relationship between these two phenomena remains elusive. By evaluating changes in mechanical nociceptive threshold in male rats, we found that in contrast to a purely analgesic control response to a single subcutaneous administration of fentanyl (25 μg/kg), in rats subjected to inflammatory pain 2 weeks previously (Day0), the same test dose (D13) induced a bi-phasic response: initial decreased analgesia (tolerance) followed by hyperalgesia lasting several hours. Both the tolerance and hyperalgesia were further enhanced in rats that had additionally received fentanyl on D0. The dose-response profiles (5 fg to 50 μg/kg) of pain- and opioid-experienced rats were very different from pain/drug-naive rats. At ultra-low fentanyl doses (<5 ng/kg and <500 ng/kg for naïve control and pain/drug-experienced rats, respectively), solely hyperalgesia was observed in all cases. At higher doses, which now produced analgesia alone in naive rats, reduced analgesia (tolerance) coupled with hyperalgesia occurred in pain/fentanyl-experienced rats, with both phases increasing with dose. Transcriptomic and pharmacological data revealed that an overactivation of the spinal N-methyl-D-aspartate receptor-inducible NO synthase cascade plays a critical role in both acute tolerance and hyperalgesia, and together with the finding that the magnitudes of analgesia and associated hyperalgesia are negatively correlated, is indicative of closely related phenomena. Finally, a polyamine deficient diet prevented inducible NO synthase transcript upregulation, restored fentanyl’s analgesic efficacy and suppressed the emergence of hyperalgesia.
American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, 1979
The effects of intracerebral injection of angiotensin II (AII) on both water intake and arginine-... more The effects of intracerebral injection of angiotensin II (AII) on both water intake and arginine-vasopressin (AVP) release were tested on unanesthetized rhesus monkeys (Macaca mulatta). Injection of 10(-10) mol of peptide was administered with a cannula microinjection system stereotaxically implanted into different diencephalic structures. The preoptic area, anterior part of third ventricle, caudate nucleus, and septum appeared to be the injection sites most effective in eliciting both drinking behavior and AVP release when the animal did not have access to water. On the contrary, when water was presented, AVP release was blocked after AII microinjections in the preoptic area and the third ventricle. No drinking was observed after microinjection in the supraopticus nucleus although AVP release was stimulated. These data suggest that AII might be effective in the regulation of water balance by centrally controlling both the input (drinking) and the output (ADH secretion) of water.
Neuroendocrinological Aspects of Neurosurgery, 1990
Why are there tens of chemical messengers, when just two—one stimulatory the other inhibitory—wou... more Why are there tens of chemical messengers, when just two—one stimulatory the other inhibitory—would suffice for communication between the many different types of neuron, that act as mediators of the unique signal—the action potential? A naive question with a naive answer: there are several messengers because there are several types of message to be delivered. These latter aren’t limited simply to the opening of ionic channels gathered in a small area of the neuronal membrane to produce a localised depolarisation or hyperpolarization (excitatory or inhibitory post-synaptic potentials), but consist of complex modifications bearing on the whole cell thanks to the intervention of an intracellular second messenger.
Molecular pharmacology, 1978
Activation of Tryptophan Hydroxylase by Adenosine Triphosphate, Magnesium, and Calcium ... MICHEL... more Activation of Tryptophan Hydroxylase by Adenosine Triphosphate, Magnesium, and Calcium ... MICHEL HAMON, SYLVIE BOURGOIN, F. HERY, AND G. SIMONNET ... Groupe NB, Institut National de Ia Sante et de Ia Recherche M#{233}dicale U114, CollEge de France, 75231 ...
Journal de physiologie, 1981
The central renin-angiotensin system is implicated most importantly in the control of water balan... more The central renin-angiotensin system is implicated most importantly in the control of water balance, blood pressure and endocrine function (AVP and ACTH). Several central structures are sensitive to angiotensin II (A II), principally: the subfornical organ, the vascular organ of the lamina terminalis, the area postrema and the preoptic area. Furthermore, binding studies with radio-active ligands and also immunohistofluorescence have shown respectively the presence of A II receptors and immunoreactive material bound by A II antibodies in other central structures, and in particular parts of the motor system. In the present study, a double approach, both electrophysiological and biochemical, was used to investigate the possible role of the peptide A II in the neostriatum of the rat. 1 Microiontophoretic application of A II was shown to modify the spontaneous activity of some neurones (15/68) in the neostriatum. Generally, the action of A II was inhibitory and the inhibition was blocked...
AJNR. American journal of neuroradiology
The side effects in myelography are well known and frequently observed. The most common are heada... more The side effects in myelography are well known and frequently observed. The most common are headache, nausea, and vomiting. In this study, a rather new compound, Thiorphan, was examined, which displays an antinociceptive activity by inhibiting enkephalinase activity. Forty-two patients received intravenous infusions of Thiorphan before myelography. Another 42 patients were in a control group, and Thiorphan was not administered. In the treated group, postmyelographic headache was found in 24% (versus 52% in the control group). Nausea and vomiting were never seen. Low back pain or sciatica was diminished in 33% of cases. Enkephalin levels in cerebrospinal fluid were measured by a radioreceptor-assay method in both groups without any correlation.
Journal of hypertension. Supplement : official journal of the International Society of Hypertension, 1986
Angiotensin II (ANG II)-like material was detected in acid extracts of rat brain using radio-immu... more 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.
Immuno-analyse & Biologie Spécialisée, 2002
Les phéochromocytomes sont des tumeurs du tissu chromaffine capables de synthétiser des catéchola... more Les phéochromocytomes sont des tumeurs du tissu chromaffine capables de synthétiser des catécholamines et de les métaboliser en métanéphrines (met-adrénaline et met-noradrénaline). La détection de l'excrétion urinaire 3 jours consécutifs de ces dernières est plus performante que celle des catécholamines pour faire le diagnostic de phéochromocytome. Cela est lié à plusieurs raisons, notamment une sécrétion plus continue assurant un meilleur distinguo avec les pics sécrétoires de catécholamines liés aux circonstances de stress (génératrices de faux positifs). Par ailleurs les phéochromocytomes pouvant sécréter préférentiellement l'une ou l'autre des métanéphrines, leur dosage séparé après HPLC est plus performant que le dosage global par photométrie tout en souffrant de moins d'interférences analytiques. En pratique hospitalière, nous proposons en plus des résultats bruts, une représentation graphique des valeurs qui dans notre expérience permet de définir une zone de valeur prédictive négative de 100 % pour le diagnostic de phéochromocytome. Les valeurs situées en dehors de cette zone devant inciter à réaliser un bilan complémentaire de type imagerie. Des études en cours diront si le dosage des métanéphrines plasmatiques qui permettent une amélioration du confort de prélèvement peut apporter le même type de renseignement.
Regulatory Peptides, 1994
The neuropeptide FLFQPQRFamide (NPFF) is a FRMRamide like peptide able to modulate morphine-induc... more The neuropeptide FLFQPQRFamide (NPFF) is a FRMRamide like peptide able to modulate morphine-induced analgesia (1). Recently, we showed the presence of both NPFF immunoreactivity and NPFF receptors in the dorsal horn superficial layers of the rat spinal cord which is the area where fine diameter nociceptive afferent fibers terminate (2, 3). Moreover, we showed that NPFF receptors are different from opiate receptors suggesting that morphine modulating activity of NPFF was supported by the activation of specific receptors (4). In the present study we address the question of the relationship between NPFF receptors and primary afferent fibers carrying nociceptive cutaneous and muscular informations from the fore- or hindlimb
Neurochemical Research, 1978
The preincubation of tryptophan hydroxylase extracted from various areas of the central nervous s... more The preincubation of tryptophan hydroxylase extracted from various areas of the central nervous system of the rat with 30 mM dithiothreitol and 50 muM ferrous ammonium sulfate under nitrogen atmosphere resulted in a persistent increase of its activity. Studies on the enzyme characteristics indicated that this activation was associated with a doubling in its Vmax and a shift (from 7.6 to 7.2) of the optimal pH for its activity. In contrast, the molecular weight and the apparent affinities of tryptophan hydroxylase for its pterin cofactor and for tryptophan were not significantly altered by the preincubation with dithiothreitol and ferrous ammonium sulfate. Since this treatment did not prevent the stimulatory effects of various compounds (phosphatidylserine, ATP and MG(2+), Ca(2+)) on tryptophan hydroxylase activity, this might be a good procedure to activate this enzyme with only minor changes in its regulatory properties.
Endocrinology, 1993
The octapeptide FLFQPQRFamide (F8Fa) is a FMRFamide-like peptide with a certain number of antiopi... more The octapeptide FLFQPQRFamide (F8Fa) is a FMRFamide-like peptide with a certain number of antiopiate properties. Previous studies have shown that both F8Fa specific receptors and F8Fa-like material are present in the rat central nervous system. In this study, RIA revealed that the rat neurohypophysis also contains F8Fa immunoreactive (IR) material (230 +/- 49 pg/neural lobe). HPLC profiles revealed several forms of F8Fa IR. Neurohypophysis extracts can also inhibit the binding of F8Fa to rat spinal cord preparations, which suggests that this F8Fa-like material has a biological activity. Immunocytochemical observations, at the light and electron microscopic levels, confirmed the presence throughout the neural lobe of F8Fa IR, in axonal fibers and terminals similar to those containing the more classical neurohypophysial hormones. Immunogold staining showed that F8Fa IR was restricted to neurosecretory granules in certain axonal and terminal profiles. Double staining of the same ultrathin sections, using our anti-F8Fa antiserum and vasopressin or its neurophysin specific antibodies, revealed that F8Fa IR was colocalized with vasopressin. F8Fa IR was not visible in ocytocinergic fibers or terminals. A striking depletion of F8Fa IR (80%) was observed in rats which were given 2% saline to drink for 6 days. Similarly, an ip injection of an hypertonic saline solution was shortly followed by a 20% drop of F8Fa IR. In vitro F8Fa IR release from isolated neurohypophysis was evoked under a 56 mM KCl depolarization. These results suggest that F8Fa IR may act as a paracrine/endocrine mediator released from the rat neurohypophysis.
Brain Research, 1985
Characteristics of angiotensin II (AII) binding have been determined in cultured mouse spinal cor... more Characteristics of angiotensin II (AII) binding have been determined in cultured mouse spinal cord neurones using [125I]AII and [3H]AII. The Scatchard plot of equilibrium binding was curvilinear and could be described by postulating the existence of two different classes of independent binding sites (Kal = 0.43 nM, Bm,x~ = 12.5 fmol/1.5 x 106 cells; Kd2 = 25.6 riM, Bmax2 = 220 fmol/1.5 × l0 n cells). These values are in close agreement with the K d values obtained from kinetic studies. The high affinity binding sites appeared to be similar to the single class of sites described in other studies. The relative inhibition potency of AII-related peptides was studied. Sar ~ ,-LeuS-All was the most potent in inhibiting specific AII binding. The characteristics of the two AII binding sites suggest that they correspond to two receptors as described in a previous electrophysiological approach using this model in our laboratory. Taken together, these data confirm that this model of neurones in primary culture is a unique and very attractive model of receptor studies. The classical criteria necessary for positive identification of a ligand-receptor have been satisfied: saturability, reversibility, specificity and most importantly correlation of the binding parameters and biological effects of AII.
Annales d'Endocrinologie, 2013
Douleur et Analgésie, 2016
RésuméL’intensité de la sensation douloureuse n’est pas un simple reflet de l’importance de l’agr... more RésuméL’intensité de la sensation douloureuse n’est pas un simple reflet de l’importance de l’agression tissulaire nociceptive mais est également le reflet de processus de plasticité neuronale induits par des processus de sensibilisation périphériques et centraux, se traduisant par de l’hyperalgésie ou de l’allodynie, voire des douleurs spontanées.Bien que la morphine et ses dérivés soient reconnus comme les antalgiques de référence dans les douleurs modérées à sévères, des études expérimentales et cliniques montrent clairement que leur administration donne naissance à des hypersensibilités durables à la douleur pouvant conduire au développement de douleurs chroniques. Ces effets ne feraient que mimer ce que font les opioïdes endogènes eux-mêmes lorsqu’ils sont mis en jeu lors de stress environnementaux menaçant la survie de l’individu. Cette hypersensibilité induite par les substances opioïdes exogènes ou endogènes n’est pas limitée à la sensation douloureuse mais rend compte également de la vulnérabilité induite de la sphère émotionnelle comme il en est de l’anxiété par exemple.En raison de mécanismes différents de ceux de la nociception, l’hypersensibilité à la douleur ne peut être réduite par des antalgiques classiques (antinociceptifs) et requiert des thérapies spécifiques dites d’antisensibilisation, telles que les antagonistes NMDA, le protoxyde d’azote, le néfopam ou les régimes alimentaires pauvres en polyamines, capables de moduler négativement (sans les bloquer) les récepteurs NMDA.AbstractThe intensity of a pain does not simply reflect the severity of the injury that caused it, but also depends very much on the individual’s history. Therefore, clinical pain is also largely the expression of neural plasticity associated with peripheral and central sensitization leading to hyperalgesia, allodynia and persistent, spontaneous pain.Although opioids are recognized as unsurpassed analgesics for moderate to severe pain, for more than a century, experimental and clinical studies have reported that the administration of exogenous opioids not only produces analgesia but also induces long-term hypersensitivity to pain, in the form of prolonged hyperalgesia after an injury which is capable of facilitating the development of chronic pain. Like exogenous opioids, endogenous opioids released during situations of stress induce a latent hypersensitivity to pain that may emerge in the form of more severe pain on subsequent injuries. The hypersensitivity to pain induced by opioids is associated with a more general hypersensitivity affecting the emotional sphere, for example in terms of anxiety.The consequences of hypersensitivity to pain cannot be managed using analgesics alone but require specific antisensitisation strategies, such as NMDA receptor antagonists, nitrous oxide, nefopam and nutrition low in polyamines.
Douleurs : Evaluation - Diagnostic - Traitement, 2007
Introduction Apres une lesion tissulaire, il existe une sensibilisation du SNC de longue duree vi... more Introduction Apres une lesion tissulaire, il existe une sensibilisation du SNC de longue duree via des processus NMDA-dependants. Cette neuroplasticite conduisant a des hyperalgesies post-operatoires exacerbees est consideree comme une des causes principales de chronicisation de la douleur. Cependant, des traitements au long court avec des antagonistes des recepteurs NMDA sont limites par des effets indesirables. Puisque les polyamines modulent positivement le fonctionnement des recepteurs NMDA, et proviennent principalement de notre alimentation, nous avons developpe une therapie nutritionnelle basee sur un regime appauvri en polyamines (RAP) pour prevenir les douleurs exagerees. Materiel et methode Puisque l’augmentation de phosphorylation spinale de la sous-unite NR2B du recepteur NMDA est associee avec l’hyperalgesie d’origine inflammatoire, nous avons evalue la capacite du RAP a reduire cette hyper-activation de NR2B. Des modeles de douleur inflammatoire (carragenine) ou chirurgicale ont ete utilises chez des rats traites ou non par fentanyl (4 x 100 μg/kg, s.c.). La sensibilite a la douleur est evaluee quotidiennement par la determination du seuil nociceptif (SN) par le test de Randall-Selitto. Une fois le SN de retour aux valeurs de base, les rats ont ete exposes a des stress environnementaux non nociceptifs (SENN) repetes. Resultats Le RAP donne de facon preventive (7 jours) previent l’augmentation de phosphorylation de la sous-unite NR2B induite par l’inflammation. Le RAP reduit aussi fortement l’hyperalgesie induite par une inflammation ou une incision, en particulier chez les rats traites par le fentanyl. De plus, le RAP previent aussi l’exageration de l’hyperalgesie induite par une seconde carragenine administree 7 jours apres la premiere. Le RAP s’oppose aussi a l’hyperalgesie paradoxale induite par l’exposition des rats a un SENN. Discussion Puisque le RAP est depourvu d’effets indesirables, cette therapie nutritionnelle pourrait etre une strategie ideale pour reduire la transition de la douleur aigue (en particulier chirurgicale) en douleurs chroniques.
Pharmacology Biochemistry and Behavior, 1980
Angiotensin 11 (All) was microiontophoretically applied on neurones located in the septum and the... more Angiotensin 11 (All) was microiontophoretically applied on neurones located in the septum and the medial preoptic area (MPOA). All the septal neurones sensitive to All (15/37) responded by an inhibition to the peptide application. Of 44 units tested in the MPOA 21 cells (48%) were sensitive to All and responded either by an increase (11/21) or decrease (10/21) in their firing. The specificity of these responses were ascertained by simultaneous application of the antagonist SarMle"-Angiotensin II. These data suggest that Angiotensin II acts directly on neurones of the septum and medial preoptic area, structures implicated in the control of drinking behaviour.
Douleurs : Evaluation - Diagnostic - Traitement, Oct 1, 2007
Les polyamines sont des constituants moleculaires universels et obligatoires de toute cellule viv... more Les polyamines sont des constituants moleculaires universels et obligatoires de toute cellule vivante. Considerees comme ubiquitaires tant au niveau cellulaire qu'a celui de l'organisme, elles participent a la perennite des processus vitaux et de croissance. Leur large spectre d'activite tient a la multiplicite de leurs cibles potentielles ainsi qu'a leur habilite a en modifier les proprietes physiques et/ou biologiques. Leurs roles dans les processus proliferatifs font que leur metabolisme est une cible privilegiee dans les therapies anti-cancereuses. Cependant, dans cette optique, il ne suffit pas de bloquer ou de perturber leur metabolisme, car les cellules en proliferation ont acces a une source exogene importante de polyamines provenant en grande partie de l'alimentation et dans une moindre mesure, de la production bacterienne intestinale. Des etudes pre-cliniques ont demontre in vivo l'interet d'une tri-therapie associant inhibiteurs de synthese des...
Neuropsychopharmacology, 2021
Opioids are a mainstay of pain management but can induce unwanted effects, including analgesic to... more Opioids are a mainstay of pain management but can induce unwanted effects, including analgesic tolerance and paradoxical hyperalgesia, either of which leads to increased pain. Clinically, however, the relationship between these two phenomena remains elusive. By evaluating changes in mechanical nociceptive threshold in male rats, we found that in contrast to a purely analgesic control response to a single subcutaneous administration of fentanyl (25 μg/kg), in rats subjected to inflammatory pain 2 weeks previously (Day0), the same test dose (D13) induced a bi-phasic response: initial decreased analgesia (tolerance) followed by hyperalgesia lasting several hours. Both the tolerance and hyperalgesia were further enhanced in rats that had additionally received fentanyl on D0. The dose-response profiles (5 fg to 50 μg/kg) of pain- and opioid-experienced rats were very different from pain/drug-naive rats. At ultra-low fentanyl doses (<5 ng/kg and <500 ng/kg for naïve control and pain/drug-experienced rats, respectively), solely hyperalgesia was observed in all cases. At higher doses, which now produced analgesia alone in naive rats, reduced analgesia (tolerance) coupled with hyperalgesia occurred in pain/fentanyl-experienced rats, with both phases increasing with dose. Transcriptomic and pharmacological data revealed that an overactivation of the spinal N-methyl-D-aspartate receptor-inducible NO synthase cascade plays a critical role in both acute tolerance and hyperalgesia, and together with the finding that the magnitudes of analgesia and associated hyperalgesia are negatively correlated, is indicative of closely related phenomena. Finally, a polyamine deficient diet prevented inducible NO synthase transcript upregulation, restored fentanyl’s analgesic efficacy and suppressed the emergence of hyperalgesia.
American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, 1979
The effects of intracerebral injection of angiotensin II (AII) on both water intake and arginine-... more The effects of intracerebral injection of angiotensin II (AII) on both water intake and arginine-vasopressin (AVP) release were tested on unanesthetized rhesus monkeys (Macaca mulatta). Injection of 10(-10) mol of peptide was administered with a cannula microinjection system stereotaxically implanted into different diencephalic structures. The preoptic area, anterior part of third ventricle, caudate nucleus, and septum appeared to be the injection sites most effective in eliciting both drinking behavior and AVP release when the animal did not have access to water. On the contrary, when water was presented, AVP release was blocked after AII microinjections in the preoptic area and the third ventricle. No drinking was observed after microinjection in the supraopticus nucleus although AVP release was stimulated. These data suggest that AII might be effective in the regulation of water balance by centrally controlling both the input (drinking) and the output (ADH secretion) of water.
Neuroendocrinological Aspects of Neurosurgery, 1990
Why are there tens of chemical messengers, when just two—one stimulatory the other inhibitory—wou... more Why are there tens of chemical messengers, when just two—one stimulatory the other inhibitory—would suffice for communication between the many different types of neuron, that act as mediators of the unique signal—the action potential? A naive question with a naive answer: there are several messengers because there are several types of message to be delivered. These latter aren’t limited simply to the opening of ionic channels gathered in a small area of the neuronal membrane to produce a localised depolarisation or hyperpolarization (excitatory or inhibitory post-synaptic potentials), but consist of complex modifications bearing on the whole cell thanks to the intervention of an intracellular second messenger.
Molecular pharmacology, 1978
Activation of Tryptophan Hydroxylase by Adenosine Triphosphate, Magnesium, and Calcium ... MICHEL... more Activation of Tryptophan Hydroxylase by Adenosine Triphosphate, Magnesium, and Calcium ... MICHEL HAMON, SYLVIE BOURGOIN, F. HERY, AND G. SIMONNET ... Groupe NB, Institut National de Ia Sante et de Ia Recherche M#{233}dicale U114, CollEge de France, 75231 ...
Journal de physiologie, 1981
The central renin-angiotensin system is implicated most importantly in the control of water balan... more The central renin-angiotensin system is implicated most importantly in the control of water balance, blood pressure and endocrine function (AVP and ACTH). Several central structures are sensitive to angiotensin II (A II), principally: the subfornical organ, the vascular organ of the lamina terminalis, the area postrema and the preoptic area. Furthermore, binding studies with radio-active ligands and also immunohistofluorescence have shown respectively the presence of A II receptors and immunoreactive material bound by A II antibodies in other central structures, and in particular parts of the motor system. In the present study, a double approach, both electrophysiological and biochemical, was used to investigate the possible role of the peptide A II in the neostriatum of the rat. 1 Microiontophoretic application of A II was shown to modify the spontaneous activity of some neurones (15/68) in the neostriatum. Generally, the action of A II was inhibitory and the inhibition was blocked...
AJNR. American journal of neuroradiology
The side effects in myelography are well known and frequently observed. The most common are heada... more The side effects in myelography are well known and frequently observed. The most common are headache, nausea, and vomiting. In this study, a rather new compound, Thiorphan, was examined, which displays an antinociceptive activity by inhibiting enkephalinase activity. Forty-two patients received intravenous infusions of Thiorphan before myelography. Another 42 patients were in a control group, and Thiorphan was not administered. In the treated group, postmyelographic headache was found in 24% (versus 52% in the control group). Nausea and vomiting were never seen. Low back pain or sciatica was diminished in 33% of cases. Enkephalin levels in cerebrospinal fluid were measured by a radioreceptor-assay method in both groups without any correlation.
Journal of hypertension. Supplement : official journal of the International Society of Hypertension, 1986
Angiotensin II (ANG II)-like material was detected in acid extracts of rat brain using radio-immu... more 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.
Immuno-analyse & Biologie Spécialisée, 2002
Les phéochromocytomes sont des tumeurs du tissu chromaffine capables de synthétiser des catéchola... more Les phéochromocytomes sont des tumeurs du tissu chromaffine capables de synthétiser des catécholamines et de les métaboliser en métanéphrines (met-adrénaline et met-noradrénaline). La détection de l'excrétion urinaire 3 jours consécutifs de ces dernières est plus performante que celle des catécholamines pour faire le diagnostic de phéochromocytome. Cela est lié à plusieurs raisons, notamment une sécrétion plus continue assurant un meilleur distinguo avec les pics sécrétoires de catécholamines liés aux circonstances de stress (génératrices de faux positifs). Par ailleurs les phéochromocytomes pouvant sécréter préférentiellement l'une ou l'autre des métanéphrines, leur dosage séparé après HPLC est plus performant que le dosage global par photométrie tout en souffrant de moins d'interférences analytiques. En pratique hospitalière, nous proposons en plus des résultats bruts, une représentation graphique des valeurs qui dans notre expérience permet de définir une zone de valeur prédictive négative de 100 % pour le diagnostic de phéochromocytome. Les valeurs situées en dehors de cette zone devant inciter à réaliser un bilan complémentaire de type imagerie. Des études en cours diront si le dosage des métanéphrines plasmatiques qui permettent une amélioration du confort de prélèvement peut apporter le même type de renseignement.
Regulatory Peptides, 1994
The neuropeptide FLFQPQRFamide (NPFF) is a FRMRamide like peptide able to modulate morphine-induc... more The neuropeptide FLFQPQRFamide (NPFF) is a FRMRamide like peptide able to modulate morphine-induced analgesia (1). Recently, we showed the presence of both NPFF immunoreactivity and NPFF receptors in the dorsal horn superficial layers of the rat spinal cord which is the area where fine diameter nociceptive afferent fibers terminate (2, 3). Moreover, we showed that NPFF receptors are different from opiate receptors suggesting that morphine modulating activity of NPFF was supported by the activation of specific receptors (4). In the present study we address the question of the relationship between NPFF receptors and primary afferent fibers carrying nociceptive cutaneous and muscular informations from the fore- or hindlimb
Neurochemical Research, 1978
The preincubation of tryptophan hydroxylase extracted from various areas of the central nervous s... more The preincubation of tryptophan hydroxylase extracted from various areas of the central nervous system of the rat with 30 mM dithiothreitol and 50 muM ferrous ammonium sulfate under nitrogen atmosphere resulted in a persistent increase of its activity. Studies on the enzyme characteristics indicated that this activation was associated with a doubling in its Vmax and a shift (from 7.6 to 7.2) of the optimal pH for its activity. In contrast, the molecular weight and the apparent affinities of tryptophan hydroxylase for its pterin cofactor and for tryptophan were not significantly altered by the preincubation with dithiothreitol and ferrous ammonium sulfate. Since this treatment did not prevent the stimulatory effects of various compounds (phosphatidylserine, ATP and MG(2+), Ca(2+)) on tryptophan hydroxylase activity, this might be a good procedure to activate this enzyme with only minor changes in its regulatory properties.
Endocrinology, 1993
The octapeptide FLFQPQRFamide (F8Fa) is a FMRFamide-like peptide with a certain number of antiopi... more The octapeptide FLFQPQRFamide (F8Fa) is a FMRFamide-like peptide with a certain number of antiopiate properties. Previous studies have shown that both F8Fa specific receptors and F8Fa-like material are present in the rat central nervous system. In this study, RIA revealed that the rat neurohypophysis also contains F8Fa immunoreactive (IR) material (230 +/- 49 pg/neural lobe). HPLC profiles revealed several forms of F8Fa IR. Neurohypophysis extracts can also inhibit the binding of F8Fa to rat spinal cord preparations, which suggests that this F8Fa-like material has a biological activity. Immunocytochemical observations, at the light and electron microscopic levels, confirmed the presence throughout the neural lobe of F8Fa IR, in axonal fibers and terminals similar to those containing the more classical neurohypophysial hormones. Immunogold staining showed that F8Fa IR was restricted to neurosecretory granules in certain axonal and terminal profiles. Double staining of the same ultrathin sections, using our anti-F8Fa antiserum and vasopressin or its neurophysin specific antibodies, revealed that F8Fa IR was colocalized with vasopressin. F8Fa IR was not visible in ocytocinergic fibers or terminals. A striking depletion of F8Fa IR (80%) was observed in rats which were given 2% saline to drink for 6 days. Similarly, an ip injection of an hypertonic saline solution was shortly followed by a 20% drop of F8Fa IR. In vitro F8Fa IR release from isolated neurohypophysis was evoked under a 56 mM KCl depolarization. These results suggest that F8Fa IR may act as a paracrine/endocrine mediator released from the rat neurohypophysis.
Brain Research, 1985
Characteristics of angiotensin II (AII) binding have been determined in cultured mouse spinal cor... more Characteristics of angiotensin II (AII) binding have been determined in cultured mouse spinal cord neurones using [125I]AII and [3H]AII. The Scatchard plot of equilibrium binding was curvilinear and could be described by postulating the existence of two different classes of independent binding sites (Kal = 0.43 nM, Bm,x~ = 12.5 fmol/1.5 x 106 cells; Kd2 = 25.6 riM, Bmax2 = 220 fmol/1.5 × l0 n cells). These values are in close agreement with the K d values obtained from kinetic studies. The high affinity binding sites appeared to be similar to the single class of sites described in other studies. The relative inhibition potency of AII-related peptides was studied. Sar ~ ,-LeuS-All was the most potent in inhibiting specific AII binding. The characteristics of the two AII binding sites suggest that they correspond to two receptors as described in a previous electrophysiological approach using this model in our laboratory. Taken together, these data confirm that this model of neurones in primary culture is a unique and very attractive model of receptor studies. The classical criteria necessary for positive identification of a ligand-receptor have been satisfied: saturability, reversibility, specificity and most importantly correlation of the binding parameters and biological effects of AII.
Annales d'Endocrinologie, 2013
Douleur et Analgésie, 2016
RésuméL’intensité de la sensation douloureuse n’est pas un simple reflet de l’importance de l’agr... more RésuméL’intensité de la sensation douloureuse n’est pas un simple reflet de l’importance de l’agression tissulaire nociceptive mais est également le reflet de processus de plasticité neuronale induits par des processus de sensibilisation périphériques et centraux, se traduisant par de l’hyperalgésie ou de l’allodynie, voire des douleurs spontanées.Bien que la morphine et ses dérivés soient reconnus comme les antalgiques de référence dans les douleurs modérées à sévères, des études expérimentales et cliniques montrent clairement que leur administration donne naissance à des hypersensibilités durables à la douleur pouvant conduire au développement de douleurs chroniques. Ces effets ne feraient que mimer ce que font les opioïdes endogènes eux-mêmes lorsqu’ils sont mis en jeu lors de stress environnementaux menaçant la survie de l’individu. Cette hypersensibilité induite par les substances opioïdes exogènes ou endogènes n’est pas limitée à la sensation douloureuse mais rend compte également de la vulnérabilité induite de la sphère émotionnelle comme il en est de l’anxiété par exemple.En raison de mécanismes différents de ceux de la nociception, l’hypersensibilité à la douleur ne peut être réduite par des antalgiques classiques (antinociceptifs) et requiert des thérapies spécifiques dites d’antisensibilisation, telles que les antagonistes NMDA, le protoxyde d’azote, le néfopam ou les régimes alimentaires pauvres en polyamines, capables de moduler négativement (sans les bloquer) les récepteurs NMDA.AbstractThe intensity of a pain does not simply reflect the severity of the injury that caused it, but also depends very much on the individual’s history. Therefore, clinical pain is also largely the expression of neural plasticity associated with peripheral and central sensitization leading to hyperalgesia, allodynia and persistent, spontaneous pain.Although opioids are recognized as unsurpassed analgesics for moderate to severe pain, for more than a century, experimental and clinical studies have reported that the administration of exogenous opioids not only produces analgesia but also induces long-term hypersensitivity to pain, in the form of prolonged hyperalgesia after an injury which is capable of facilitating the development of chronic pain. Like exogenous opioids, endogenous opioids released during situations of stress induce a latent hypersensitivity to pain that may emerge in the form of more severe pain on subsequent injuries. The hypersensitivity to pain induced by opioids is associated with a more general hypersensitivity affecting the emotional sphere, for example in terms of anxiety.The consequences of hypersensitivity to pain cannot be managed using analgesics alone but require specific antisensitisation strategies, such as NMDA receptor antagonists, nitrous oxide, nefopam and nutrition low in polyamines.
Douleurs : Evaluation - Diagnostic - Traitement, 2007
Introduction Apres une lesion tissulaire, il existe une sensibilisation du SNC de longue duree vi... more Introduction Apres une lesion tissulaire, il existe une sensibilisation du SNC de longue duree via des processus NMDA-dependants. Cette neuroplasticite conduisant a des hyperalgesies post-operatoires exacerbees est consideree comme une des causes principales de chronicisation de la douleur. Cependant, des traitements au long court avec des antagonistes des recepteurs NMDA sont limites par des effets indesirables. Puisque les polyamines modulent positivement le fonctionnement des recepteurs NMDA, et proviennent principalement de notre alimentation, nous avons developpe une therapie nutritionnelle basee sur un regime appauvri en polyamines (RAP) pour prevenir les douleurs exagerees. Materiel et methode Puisque l’augmentation de phosphorylation spinale de la sous-unite NR2B du recepteur NMDA est associee avec l’hyperalgesie d’origine inflammatoire, nous avons evalue la capacite du RAP a reduire cette hyper-activation de NR2B. Des modeles de douleur inflammatoire (carragenine) ou chirurgicale ont ete utilises chez des rats traites ou non par fentanyl (4 x 100 μg/kg, s.c.). La sensibilite a la douleur est evaluee quotidiennement par la determination du seuil nociceptif (SN) par le test de Randall-Selitto. Une fois le SN de retour aux valeurs de base, les rats ont ete exposes a des stress environnementaux non nociceptifs (SENN) repetes. Resultats Le RAP donne de facon preventive (7 jours) previent l’augmentation de phosphorylation de la sous-unite NR2B induite par l’inflammation. Le RAP reduit aussi fortement l’hyperalgesie induite par une inflammation ou une incision, en particulier chez les rats traites par le fentanyl. De plus, le RAP previent aussi l’exageration de l’hyperalgesie induite par une seconde carragenine administree 7 jours apres la premiere. Le RAP s’oppose aussi a l’hyperalgesie paradoxale induite par l’exposition des rats a un SENN. Discussion Puisque le RAP est depourvu d’effets indesirables, cette therapie nutritionnelle pourrait etre une strategie ideale pour reduire la transition de la douleur aigue (en particulier chirurgicale) en douleurs chroniques.
Pharmacology Biochemistry and Behavior, 1980
Angiotensin 11 (All) was microiontophoretically applied on neurones located in the septum and the... more Angiotensin 11 (All) was microiontophoretically applied on neurones located in the septum and the medial preoptic area (MPOA). All the septal neurones sensitive to All (15/37) responded by an inhibition to the peptide application. Of 44 units tested in the MPOA 21 cells (48%) were sensitive to All and responded either by an increase (11/21) or decrease (10/21) in their firing. The specificity of these responses were ascertained by simultaneous application of the antagonist SarMle"-Angiotensin II. These data suggest that Angiotensin II acts directly on neurones of the septum and medial preoptic area, structures implicated in the control of drinking behaviour.