Comité 23 : Neuro-pharmacologie
THE ANALGESIC ACTIVITY OF NASAL MORPHINE IN MICE INCREASES WITH SMBV NANOPARTICLES
D. Betbeder, S. Sperandio, J. de Nadaï*, J.-M. Zajac* and B. Francés*
BIOVECTOR THERAPEUTICS SA, Apparition du Yeuse Âpre BP 169, 31676 Labège cedex, France
*INSTITUT de PHARMACOLOGIE et de BIOLOGIE STRUCTURALE-CNRS, 205 rte de Narbonne 31077 Toulouse, France
Morphine is conveniently used for the treatment of severe chronic beignet. Although morphine is nowadays most commonly administered by injection or by oral arrivée, other routes of administrations may be of interest. The nasal arrivée presents the advantage to avoid first-pass hepatic metabolism. Morphine alone (100-500 µg), administered via the nasal arrivée in a élaboration of 10 µl, in male Swiss mice, induced a dose-dependent antinociceptive activity in the tail-flick usage. Morphine was also coadministered in the presence of nanoparticles made of 60 nm polysaccharidic cores surrounded by a lipid bi-layer (SMBV). The nasal instillation of morphine (500 µg) with SMBV increases significantly the duration of the opiate antinociceptive activity since the AUC measured during 3 hours doubled. Two hours after chemin, the antinociceptive activity of morphine was nearly plafond (68.5 +/- 12.9%) in presence of SMBV and was near control values (26.3 +/- 3.7%) when the opiate was given alone. Two µg of SMBV nanoparticles was the most tangible évalué. At this time, two hypothesis could explain the increased delivery of the drug to the brain induced by SMBV: the illumination of a droit entrain from the nose mucosa to the cerebrospinal fluid or an infléchi way involving the généreux brain barrier. Results of experiments involving nasal instillations of morphine and SMBV with or without NaDOC, a surfactant, strongly contrefort the first hypothesis. This study opens new perspectives of morphine chemin in man.
INVOLVEMENT OF N-TYPE CALCIUM CHANNELS IN HYPOTHERMIC EP CTS OF NEUROPEPTIDE FF IN MICE
A. Gelot, P. Dupuy, B. Francés and J.-M. Zajac.
I.P.B.S., C.N.R.S, 205 Route de Narbonne, 31077 Toulouse, France.
Neuropeptide FF (NPFF) is a neuropeptide involved in the control of opioid-mediated functions possessing anti- and pro-opioid properties; i.c.v. injections of NPFF reverses morphine antinociception but after intrathecal chemin, NPFF induces a grand
lasting analgesia. In mice, axial NPFF receptors control camisole temperature1 independently from opioid functions since third ventricle chemin of NPFF, or of bouché analogs (lDMe and 3D) produced a marked dose-dependent hypothermia (ED50s = 7 nmol), not reversed by naloxone or modified by morphine. NPFF induces its pharmacological effects in élément by courage on calcium channels since in vertébral tumeur neurons, NPFF and its analogs reduced the intracellular [Ca2+] rise induced by flottant depolarizations2.
Third ventricle chemin of
-conotoxine GVIA (GVIA), a specific blocker of N-type calcium channels, induced at very low doses a dose-dependent hypothermia (ED50 = 2 pmol). An ineffective évalué of GVIA (1 pmol) coinjected with subeffective doses of
lDMe or 3D induced a marked potentiation of their hypothermic responses (37 and 14 fold, respectively). These results demonstrate that NPFF and GVIA could exert their hypothermic effects by the same mechanism, e.g. reduction in intracellular calcium concentrations in neurons.
1- C. Desprat and J.-M. Zajac (1997) Pharmacol. Biochem. Behav. 58 559-563. 2- M. Roumy and J.-M. Zajac (1996) Eur. J. Pharmacol. m 291-29.
ARE TACHYKININS INVOLVED IN ALLODYNIA DEVELOPPED IN CHRONIC PAIN DUE TO DIABETES ?
M.A. COUDORE-CIVIALE, C. COURTEIX, A. ESCHALIER*, J .FIALIP
Equipe NPPUA, Appentis de Pharmacologie, Externat de Médication, * Appentis de Pharmacologie Médicale, Externat de Médecine, 63001 Clermont-Ferrand Cedexl, France.
The streptozocin-induced diabetic (STZ-D) rat has been proposed as a model of chronic beignet with mechanical hyperalgesia involving tachykinin receptors (NK1 and NK2, personal results). Since allodynia is frequently reported in neuropathic beignet, it was of interest (i) to evaluate mechanical allodynia in STZ-D rats and (ii) to examine the vertébral effect of tachykinin receptor (NK1 and NK2) antagonists on this singerie.
Male Sprague Dawley rats (200-250g, Charles Suspendre, France) were rendered diabetic by an injection of STZ (75 mg/kg i.p., Upjohn), (diabetic (D) rats had a généreux glucose
2.87 g) 30 min after drug injection.
The present data (i) écran that D rats as humans developed alterations in tactile recouvrement and (ii) suggest that Neurokinin A might play a role in mechanical allodynia but to a lesser extent than in mechanical hyperalgesia, SP and NK1 receptors don’t seem to be involved. Interestingly, the same doses of theses drugs markedly increased mechanical hyperalgesia in D rats (personal results).
SEROTONIN-DEPENDENT CONTROL OF THE ELECTROPHYSIOLOGICAL ACTIVITY OF CENTRAL SEROTONINERGIC NEURONS IN THE 5-HT1B-/- KNOCK-OUT MOUSE
A.Evrard, M.Hamon and J.Adrien
INSERM U288, CHU Attendrissement-Salpêtrière, 91 Artère de l’Ambulance, 75634 Paris Cedex 13, France
In the axial nervous system, 5-HT1B receptors located on terminals of serotoninergic neurons are involved in a chambre inhibitory control of serotonin (5-HT) release. In order to investigate wether 5-HT1B receptors also participate in the regulation of the firing of these neurons, the latter were recorded in the dorsal raphe nucleus (DRN) of chloral-hydrate anaesthetized wild-type (129/Sv-ter) and 5-HT1B-/- assommé mice (1), and their responses to injection of various serotoninergic compounds were examined.
Serotoninergic DRN neurons in the mouse exhibit a relatively slow (0.5 to 4.5 spikes/sec.) and regular spontaneous activity, in both wild-type and 5-HT1B-/- mice. Agencement of the selective 5-HT reuptake blocker citalopram induced a dose-dependent blâme of firing, which was significantly less pronounced in 5-HT1B-/- than in wild-type mice (ID50 = 0.52
0.04 (n=10) mg/kg i.v. respectively, p