Session 23 : Neuro-pharmacologie

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Session 23 : Neuro-pharmacologie

219

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, Chemin du Chêne Vert 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 pain. Although morphine is nowadays most commonly administered by injection or by oral route, other routes of administrations may be of interest. The nasal route presents the advantage to avoid first-pass hepatic metabolism. Morphine alone (100-500 µg), administered via the nasal route in a volume of 10 µl, in male Swiss mice, induced a dose-dependent antinociceptive activity in the tail-flick test. 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 administration, the antinociceptive activity of morphine was nearly maximal (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 effective dose. At this time, two hypothesis could explain the increased delivery of the drug to the brain induced by SMBV: the activation of a direct passage from the nose mucosa to the cerebrospinal fluid or an indirect way involving the blood brain barrier. Results of experiments involving nasal instillations of morphine and SMBV with or without NaDOC, a surfactant, strongly support the first hypothesis. This study opens new perspectives of morphine administration in man.

220

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 administration, NPFF induces a long

lasting analgesia. In mice, central NPFF receptors control body temperature1 independently from opioid functions since third ventricle administration of NPFF, or of stable 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 part by action on calcium channels since in spinal ganglion neurons, NPFF and its analogs reduced the intracellular [Ca2+] rise induced by short depolarizations2.

Third ventricle administration 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 dose 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.

221

ARE TACHYKININS INVOLVED IN ALLODYNIA DEVELOPPED IN CHRONIC PAIN DUE TO DIABETES ?

M.A. COUDORE-CIVIALE, C. COURTEIX, A. ESCHALIER*, J .FIALIP

Equipe NPPUA, Laboratoire de Pharmacologie, Faculté de Pharmacie, * Laboratoire de Pharmacologie Médicale, Faculté de Médecine, 63001 Clermont-Ferrand Cedexl, France.

The streptozocin-induced diabetic (STZ-D) rat has been proposed as a model of chronic pain with mechanical hyperalgesia involving tachykinin receptors (NK1 and NK2, personal results). Since allodynia is frequently reported in neuropathic pain, it was of interest (i) to evaluate mechanical allodynia in STZ-D rats and (ii) to examine the spinal effect of tachykinin receptor (NK1 and NK2) antagonists on this trouble.

Male Sprague Dawley rats (200-250g, Charles River, France) were rendered diabetic by an injection of STZ (75 mg/kg i.p., Upjohn), (diabetic (D) rats had a blood glucose

2.87 g) 30 min after drug injection.

The present data (i) show that D rats as humans developed alterations in tactile perception 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).

222

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 Pitié-Salpêtrière, 91 Boulevard de l’Hôpital, 75634 Paris Cedex 13, France

In the central nervous system, 5-HT1B receptors located on terminals of serotoninergic neurons are involved in a local 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-/- knock-out 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. Administration of the selective 5-HT reuptake blocker citalopram induced a dose-dependent inhibition 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