Biomedical subjects

B Francés

Publications and source records attributed to B Francés.

14 recordsLinked to original sources

PubMed2001

Cholera and pertussis toxins inhibit differently hypothermic and anti-opioid effects of neuropeptide FF.

In mice pretreated intracerebroventricularly (i.c.v.) with pertussis or cholera toxins, effects of neuropeptide FF (NPFF), on hypothermia and morphine-induced analgesia, were assessed. NPFF and a potent NPFF agonist, 1DMe (0.005-22 nmol) injected into the lateral ventricle decreased morphine analgesia and produced naloxone (2.5 mg x kg(-1), s.c.)-resistant hypothermia after administration into the third ventricle. Cholera toxin (CTX 1 microg, i.c.v.) pretreatment (24 or 96 h before) inhibited the effect of 1DMe on body temperature, but failed to reverse its anti-opioid activity in the tail-flick test. CTX reduced hypothermia induced by a high dose of morphine (8 nmol, i.c.v.) but not the analgesic effect due to 3 nmol morphine. Pertussis toxin (PTX) pretreatment inhibited both morphine-hypothermia and -analgesia but did not modify hypothermia induced by 1DMe. The present results suggest that NPFF-induced hypothermia depends on the stimulation of Gs (but not Gi) proteins. In contrast, anti-opioid effects resulting from NPFF-receptor stimulation do not involve a cholera toxin-sensitive transducer protein.

Animals↗

PubMed2001

Identification of neuropeptide FF-related peptides in rodent spinal cord.

Peptides which should be generated from the neuropeptide FF (NPFF) precursor were identified in mouse and rat spinal cord, by using reverse phase high pressure liquid chromatography with radioimmunoassay and electrospray mass spectrometry detection. In both species, two octapeptides, NPFF (Phe-Leu-Phe-Gln-Pro-Gln-Arg-Phe-amide) and NPSF (Ser-Leu-Ala-Ala-Pro-Gln-Arg-Phe-amide) were identified but a longer peptide NPA-NPFF (Asn-Pro-Ala-Phe-Leu-Phe-Gln-Pro-Gln-Arg-Phe-amide) was present at the highest concentration in rat spinal cord. In mouse, the homologous peptide, SPA-NPFF (Ser-Pro-Ala-Phe-Leu-Phe-Gln-Pro-Gln-Arg-Phe-amide) was not detected. Both peptides NPFF and NPSF reverse morphine-induced analgesia in the tail flick test. Our data reveal species differences in the maturation of NPFF precursor.

Amino Acid Sequence↗

PubMed2000

Opposing interplay between Neuropeptide FF and nitric oxide in antinociception and hypothermia.

This study examined the ability of the anti-opioid Neuropeptide FF (NPFF) to modify the endogenous activity of nitric oxide (NO). Antinociceptive and hypothermic effects of 1DMe (D.Tyr-Leu-(n.Me)Phe-Gln-Pro-Gln-Arg-Phe-NH(2)), an NPFF agonist, and of L-NAME (N(omega)nitro-L-arginine methyl ester), an inhibitor of nitric oxide synthase, were investigated in mice. Intraperitoneal (i.p.) injection of L-NAME induced, in the hot plate test, a dose-dependent antinociception not reversed by naloxone, an opioid antagonist, but inhibited by L-Arg, the NO synthesis precursor. Intracerebroventricular (i.c.v.) injections of 1DMe inhibit the antinociceptive activity of L-NAME in a dose-dependent manner. On the contrary, L-NAME markedly potentiated hypothermia induced by 1DMe injected in the third ventricle. These data show that Neuropeptide FF receptors exert a dual effect on endogenous NO functions and could modulate pain transmission independently of opioids.

Analgesics, Opioid↗

PubMed2000

Biovector nanoparticles improve antinociceptive efficacy of nasal morphine.

PURPOSE: We have studied the antinociceptive activity and blood and brain delivery of nasal morphine with or without Biovector nanoparticles in mice. METHODS: A tail flick assay was used to evaluate the antinociceptive activity. The kinetics of morphine were evaluated in blood and brain, using tritiated morphine as tracer. RESULTS: These nanoparticles were shown to increase the duration of the antinociceptive activity of morphine after nasal administration. This effect was not due to an increase of morphine in the blood; and the analgesic activity of morphine in association with nanoparticles was reversed by naloxone. The ED50 value was 33.6+/-15.6 mg/kg for morphine alone and 14.4+/-7.6 mg/kg in presence of nanoparticles. They were only effective at low doses (1.5 to 2.5 microg), a higher or a lower dose had no effect. No interaction was found between nanoparticles and morphine. NaDOC, a permeation enhancer, was unable to improve nasal morphine activity. CONCLUSIONS: These results show the presence of nanoparticles only at a very specific dose increases the antinociceptive activity of nasal morphine in mice. The occurrence of a direct transport of morphine from the nasal mucosa to the brain is discussed.

Administration, Intranasal↗

PubMed1998

Anti-opioid efficacy of neuropeptide FF in morphine-tolerant mice.

The modulatory effects of 1DMe (d-Tyr-Leu-(NMe)Phe-Gln-Pro-Gln-Arg-Phe-NH2), an agonist of Neuropeptide FF (NPFF) receptors, on opioid antinociceptive activity have been compared in naive and tolerant mice in the tail-flick and the hot-plate tests. In naive mice, 1DMe alone had no effect on pain threshold but decreased dose-dependently (3-22 nmol) the analgesic activity of morphine in both tests. In tolerant mice, injections of 60-fold lower doses of 1DMe (0.05-0.5 nmol) reverse morphine-induced analgesia in the tail-flick test but this anti-opioid effect was no longer observed with the highest doses of 1DMe tested (3-22 nmol). In the hot-plate test, the anti-opioid action of 1DMe was not detected, whatever doses tested. Neither the NPFF-like immunoreactivity content of spinal cord and of olfactory bulbs, nor the density of NPFF receptors in olfactory bulbs, were altered. These results indicate that a chronic morphine treatment modifies the pharmacological properties of NPFF but the type of pain test is crucial in determining NPFF effects.

Animals↗

PubMed1998

Antisense oligonucleotides to human SQA-neuropeptide FF decrease morphine tolerance and dependence in mice.

Neuropeptide FF (Phe-Leu-Phe-Gln-Pro-Gln-Arg-Phe-NH2) is able to modulate opioid analgesia. Intracerebroventricular treatment for 5 days with antisense-oligodeoxynucleotides complementary to the sequence of human SQA-neuropeptide FF (Ser-Gln-Ala-Phe-Leu-Phe-Gln-Pro-Gln-Arg-Phe-NH2) precursor gene or by mismatch-oligodeoxynucleotides did not change the antinociceptive activity of morphine in the mouse tail flick test. In contrast, antisense- but not mismatch-oligodeoxynucleotides attenuated significantly the tolerance to the analgesic activity of morphine and the withdrawal syndrome precipitated by naloxone in morphine-treated mice. These treatments with oligodeoxynucleotides did not modify neuropeptide FF-immunoreactivity content in whole brain but repeated injections of an agonist of neuropeptide FF receptors increased the intensity of morphine tolerance. These results demonstrate the important role of neuropeptide FF in opioid pharmacodependence.

Amino Acid Sequence↗

PubMed1998

Biochemical, cellular and pharmacological activities of a human neuropeptide FF-related peptide.

We report on the biochemical, cellular and pharmacological activities of SQA-neuropeptide FF (Ser-Gln-Ala-Phe-Leu-Phe-Gln-Pro-Gln-Arg-Phe-NH2), a peptide sequence contained in the human neuropeptide FF (neuropeptide FF, Phe-Leu-Phe-Gln-Pro-Gln-Arg-Phe-NH2) precursor. Quantitative autoradiography revealed that, in the superficial layers of the rat spinal cord, SQA-neuropeptide FF displayed the same high affinity for [125I]1DMe ([125I]D-Tyr-Leu-(NMe)Phe-Gln-Pro-Gln-Arg-Phe-NH2) binding sites (Ki = 0.33 nM) as did neuropeptide FF (Ki = 0.38 nM). In acutely dissociated mouse dorsal root ganglion neurones, SQA-neuropeptide FF reduced by 40% the depolarisation-induced rise in intracellular Ca2+ as measured with the Ca2+ indicator, Fluo-3. In mice, 1DMe and SQA-neuropeptide FF dose-dependently inhibited the antinociceptive effect of intracerebroventricular (i.c.v.) injections of morphine, but SQA-neuropeptide FF was less potent than 1DMe. Furthermore, SQA-neuropeptide FF, as well as 1DMe, produced marked hypothermia following third ventricle injections in mice. These data demonstrate that the human peptide, SQA-neuropeptide FF, exhibits biochemical and pharmacological properties similar to those of neuropeptide FF or neuropeptide FF analogues, and belongs to the neuropeptide FF family.

Analgesics, Opioid↗

PubMed1998

Does intrathecal morphine in the treatment of cancer pain induce the development of tolerance?

OBJECTIVE: This retrospective study was designed to investigate whether chronic lumbar intrathecal administration of morphine leads to the development of opioid tolerance in patients suffering from intractable cancer pain. METHODS: Between 1978 and 1995, 159 patients with refractory cancer pain were treated with intrathecal morphine in our Multidisciplinary Pain Center. The treatment consisted of preservative-free morphine administered through an access port as a single bolus. In this series of patients (n = 159), the daily doses of intrathecal morphine were determined as a function of duration of follow-up. RESULTS: The mean follow-up period was 95 days (range, 5-909 d), the mean starting daily dose of intrathecal morphine was 2.69 mg (range, 1-7.5 mg), and the mean terminal dose was 7.82 mg (range, 1-80 mg). The results demonstrated that only a moderate increase in daily dose of intrathecal morphine was required during the course of treatment (a two- to threefold increase for a 3-mo period). Furthermore, the dose increment was similar for patients followed up for more or less than 60 days. This increase did not result in any central opioid-related side effects, and the pain was managed satisfactorily. CONCLUSION: The requirement for a moderate increase in intrathecal opioid doses reflects the development of tolerance but did not limit the patients' ability to obtain adequate analgesia during the course of their painful disease.

Adult↗

PubMed1997

Evaluation of [125I]7 alpha-O-iodoallyl diprenophine as a new potential SPECT opioid receptor imaging agent.

A new iodinated diprenorphine analog, [125I]7 alpha-O-iodoallyl diprenorphine ([125I]7 alpha-O-IA-DPN), was prepared by iododestannylation and characterized. As an opioid antagonist, this agent showed very high affinity (Ki = 0.4 +/- 0.2 nM) and 63% of specific binding by in vitro and in vivo binding studies. Inhibition curves indicated that this tracer labeled with the same affinities to three opioid receptors (mu = delta = kappa). The findings demonstrate that this proposed compound appears to be potential radioprobe for future study of opioid receptors by in vivo SPECT.

Animals↗

PubMed1994

In vivo binding of [125I]NH2-carfentanil to mu opioid receptors in mouse brain.

A functionalized derivative of the mu opioid agonist carfentanil was synthesized (NH2-carfentanil) and showed high specific activity when radiolabeled with iodine. [127I]NH2-carfentanil displayed high affinity and pronounced mu-binding selectivity with a delta/mu selectivity ratio of over 1200. The ability of [125I]NH2-carfentanil to interact in vivo with opioid receptors was determined in mouse brain using ex vivo binding techniques. Twenty minutes after intraperitoneal injection, 0.1% of the [125I]NH2-carfentanil injected into the mouse was present in the brain. [125I]NH2-carfentanil specific binding was inhibited by co-injection of naloxone or morphine while naltrindole, a delta-selective antagonist, was unable to displace the bound radioligand. Autoradiographic experiments revealed a heterogeneous distribution of [125I]NH2-carfentanil specific binding sites, maximal binding occurred in areas with high densities of mu receptors. Peripherally administered iodo-NH2-carfentanil selectively labelled central mu opioid receptors in mouse indicating great potential for single photon emission computed tomography studies.

Animals↗

PubMed1992

Effects of ibogaine on naloxone-precipitated withdrawal in morphine-dependent mice.

In naive mice, ibogaine at a tremorigenic dose (30 mg/kg, ip), did not produce antinociception but did potentiate the antinociceptive potency of morphine in the tail-flick test. In morphine-dependent mice, ibogaine did not eliminate withdrawal symptoms but significantly increased the number of repetitive vertical jumps induced by naloxone, whatever the duration of the chronic morphine treatment. By comparison, repetitive jumping induced by alpha-napthoxyacetic acid (alpha-NOAA), a non-convulsant drug which induced jumping without affecting other morphine-withdrawal signs, was not significantly modified by ibogaine. These results indicate that while acute antinociceptive effects of morphine are modulated by ibogaine, this drug, shown to alleviate opiate dependence in man, does not attenuate in mice opioid withdrawal manifestations.

Animals↗

PubMed1990

Morphine-6-glucuronide is more mu-selective and potent in analgesic tests than morphine.

6-glucuronidation of morphine confers to this widely used analgesic increased potencies both in terms of receptor binding (selectivity) and of antinociceptive properties. In binding studies, 6-glucuronidation of morphine results in increased mu/kappa selectivity (comparable to DAGO). Na+ ions and Gpp(NH)p inhibit similarly the binding of morphine and M6G at the mu sites, suggesting that M6G is a mu agonist. The agonist nature of M6G was further confirmed by its antinociceptive properties: M6G (i.c.v.) was considerably more potent than morphine in the writhing (45 fold) and in the tail-flick (61 fold) tests. Furthermore, M6G induced a longer lasting analgesic effect than morphine. These data strongly suggest that M6G may significantly contribute to the pharmacological activity of morphine.

Analgesics↗

PubMed1988

Solubilization and characterization of the kappa-opioid receptor type from guinea-pig cerebellum.

The kappa-opioid receptor (kappa Op) from guinea-pig cerebellum membranes has been solubilized in an active form and in good yield (30-40%) with digitonin in 10 mM Tes-KOH buffer, pH 7.4. [3H]Bremazocine (KD = 1.1 nM in the soluble extract) was used to monitor the binding and hydrodynamic characteristics of the digitonin-solubilized receptor, s-kappa Op. Opioid agonists and antagonists bind s-kappa Op with a generally lower (yet still high) apparent affinity than they do its membrane-bound counterpart, m-kappa Op, but with the same rank order of potency. In particular, U50488, a kappa selective agonist, binds s-kappa Op with a considerably higher apparent affinity than do [D-Ala2, MePhe4, Glyol5]enkephalin, a mu selective agonist, and [D-Thr2,Leu5]enkephalyl-Thr, a delta selective agonist. s-kappa Op has also retained substantial stereospecificity since levorphanol was nearly 200-fold as potent as dextrorphan in competing with binding of [3H]bremazocine in the soluble extract. However, s-kappa Op appeared to be desensitized to regulation by Na+ ions: the selective inhibition by the allosteric effector of binding of agonists at the m-kappa Op was no longer observed in digitonin extracts from guinea-pig cerebellum membranes. The s-kappa Op behaved as a unique macromolecular entity both in molecular exclusion chromatography (appr. rs = 6.7 nm) and in sedimentation on linear density gradients (app. S20,w = 11.8 S).

Analgesics↗

PubMed1988

The kappa-opioid receptor from human placenta: hydrodynamic characteristics and evidence for its association with a G protein.

The kappa nature of opioid binding sites in a brush border membrane (BBM) fraction from human placenta has been confirmed: these sites display considerably higher apparent affinity (KI = 1.2 nM) for the kappa selective ligand U-50488 than they do for the mu and delta selective ligands [D-Ala2, MePhe4, Glyol5] enkephalin (KI = 1.5-2 microM) and [D-Thr2, Leu5] enkephalyl-Thr (KI = 10-15 microM), respectively. The BBM fraction from human placenta was incubated either with the agonist 3H-etorphine or with the antagonist 3H-diprenorphine and subsequently solubilized with digitonin. The solubilized macromolecular radioactivity was found to behave as a homogeneous entity both in molecular exclusion chromatography (app. rs = 6.1 nm) and in linear sucrose gradients (app. S20.w = 12 S). Two lines of evidence indicated that the placental kappa opioid receptor is capable of interacting with a guanine nucleotide regulatory (G) protein: (i) equilibrium binding of the agonist 3H-etorphine in the BBM fraction was clearly inhibited by 5'-guanylylimidodiphosphate (Gpp(NH)p), especially in the presence of Na+ ions while binding of the antagonist 3H-diprenorphine was significantly less so and (ii) the sedimentation velocity of the kappa opioid receptor was decreased down to about 10 S when the BBM fraction was prelabeled with radioligand in the presence of Gpp(NH)p prior to its solubilization with digitonin. The G protein that mediates the effect of Gpp(NH)p might be neither Gs nor Gi since no adenylate cyclase activity could be demonstrated in the BBM fraction from human placenta.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗