Search PubMed⌕ Search

Biomedical subjects

J Fialip

Publications and source records attributed to J Fialip.

At least 37 records · Page 2Linked to original sources
PubMed1996

Daily insulin treatment relieves long-term hyperalgesia in streptozocin diabetic rats.

Painful neuropathy is common in human diabetes. In rats, experimental diabetes results in altered pain sensitivity. We examined the effect of chronic insulin treatment on diabetes-induced hyperalgesia in streptozocin diabetic rats. A 20-week period of diabetes resulted in a 62% decrease in paw withdrawal thresholds compared with age-matched normal rats. Daily injections of insulin progressively reversed mechanical hyperalgesia to normal values parallel to the correction of hyperglycaemia. When the treatment was stopped, mechanical hyperalgesia reappeared, but never reached the degree of hyperalgesia observed before insulin treatment, suggesting that indirect mechanisms underlie the effect of normoglycaemia on nociception. The present data suggest that appropriate blood glucose control can help relieve pain in long-term diabetes through indirect mechanisms.

Animals↗
PubMed1996

Effects of morphine, naloxone and their interaction in the learned-helplessness paradigm in rats.

The aim of this study was to investigate the possible involvement of the mu-opioid system on the learned-helplessness paradigm, an experimental model of depression, in rats. In this test, rats were first exposed to inescapable foot-shocks (IS); 48 h later, they were submitted to a daily shuttle-box session (30 trials) for 3 consecutive days. Avoidance responses, escape failures and animal activity during each intertrial interval were recorded. Twice daily injections of morphine (0.25-8 mg/kg per day, SC), a mu-opioid agonist, reduced the increased escape failures induced by IS, as did tricyclic antidepressants. Significantly higher intertrial activity was observed in rats treated with morphine (2-8 mg/kg per day) compared with their associated control groups. Naloxone (1 and 2 mg/kg, IP), a mu-opioid antagonist, injected 10 min before each shuttle-box session impaired escape behavior in non-stressed rats and worsened the escape deficit induced by IS. Morphine-induced improvement of escape behavior and increase in intertrial activity were clearly reversed by a low inactive dose of naloxone (0.5 mg/kg). These results suggest that mu-opioid receptor mediation is involved in the deleterious effects of uncontrollable stress.

Animals↗
PubMed1996

Study of the antinociceptive effect of tetrahydro-papaveroline derivatives. Interaction with opioids.

The antinociceptive effect of racemic tetrahydropapaveroline (THP), of its two R(+)- and S(-) enantiomers, of 1-2-dehydro-THP and of 1-carboxy-THP was assessed using different pain tests in mice. None of these drugs possessed a significant activity in the hot-plate and tail-flick tests. However, after i.p. injection, they reduced the number of abdominal writhes induced by phenylbenzoquinone, with ED50 values of 51 +/- 7, 73 +/- 9 and 79 +/- 7 mg/kg for the most potent compounds: 1,2-dehydro-THP, +/- THP and -THP, respectively. This activity was not antagonized by naloxone (1 mg/kg, s.c.). However combination of inactive doses of these three compounds (32 mg/kg, i.p.) and of morphine (0.5 mg/kg, s.c.) led to a significant antinociceptive effect (83 to 85% of reduction of the number of writhes). This synergistic potentiation confirmed with the combination of +/- THP (16 mg/kg, i.p.) and morphine (0.5 mg/kg, s.c.) was totally inhibited by naloxone (1 mg/kg, s.c.). These results, although excluding a direct agonistic effect of THP derivatives on opiate receptors, suggest an indirect interaction of these drugs with the endogenous opioid system.

Analgesia↗
PubMed1996

Plasma and brain pharmacokinetics of amitriptyline and its demethylated and hydroxylated metabolites after one and six half-life repeated administrations to rats.

The purposes of the present study were as follows: 1. After an acute intraperitoneal (IP) administration of amitriptyline (AMI) to male Sprague-Dawley rats we found that: (i) its absorption rate is rapid; (ii) its elimination half-life is much shorter than in humans; and (iii) its levels largely exceeded those of its metabolites. The most important metabolites being 10-hydroxynortriptyline and nortriptyline in plasma and brain, respectively. 2. After six (every half-life) repeated IP administrations: (i) AMI kinetic parameters were unchanged; and (ii) amounts of metabolites were significantly increased and the levels of AMI were lowered both in plasma and brain.

Amitriptyline↗
PubMed1996

Pharmacokinetics of amitriptyline and its demethylated and hydroxylated metabolites in streptozocin-induced diabetic rats.

Plasma and brain levels of amitriptyline (AMI), its demethylated and hydroxylated metabolites were determined after acute IP administration of AMI (20 mg/kg) in streptozocin-induced diabetic Sprague-Dawley rats. Results showed 1. in plasma: rapid AMI absorption, but slow elimination; the proportion of AMI similar to those of the rest of compounds; the proportion of its demethylated metabolite, nortriptyline, 1.8-fold higher than that of 10-hydroxy-nortriptyline. 2. in brain: the proportions of AMI and nortriptyline were 9.5- and 2.6-fold higher respectively, than those of whole hydroxylated metabolites, which represented 7.4% of the total amount.

Amitriptyline↗
PubMed1994

A method to perform direct transcutaneous intrathecal injection in rats.

This work describes a method for performing direct intrathecal (i.t.) injections in rats without introducing a spinal catheter. Its ease of use in awake animals yields rapid and reproducible results with no sign of motor impairment. The quality of each injection was ensured by the observation of an injection-induced tail-flick. A 10-microL injection of methylene blue was well localized yielding a very limited diffusion along the spinal cord. The method was validated by demonstrating that morphine (i.t.) had a marked antinociceptive effect and that naloxone (i.t.) blocked the effect of systemic (s.c.) morphine in mononeuropathic rat.

Administration, Cutaneous↗
PubMed1994

Mice plasma and brain pharmacokinetics of amitriptyline and its demethylated and hydroxylated metabolites after half-life repeated administration. Comparison with acute administration.

Kinetics of amitriptyline (AMI), its demethylated metabolites nortriptyline (NOR) and demethylnortriptyline (DM-NOR), and its hydroxylated metabolites, the E and Z isomers or 10-hydroxy-amitriptyline (E- and Z-10-OH-AMI) and of 10-hydroxynortriptyline (E- and Z-10-OH-NOR) were studied in plasma and brain from Swiss CD1 mice after six successive intraperitoneal injections of amitriptyline (10 mg/kg) administered every elimination half-life time (t1/2 = 3.1 h) to obtain the steady state. In these conditions, AMI was metabolised rapidly. Compared with acute administration, hydroxylation reactions were saturated by the repeated AMI injections and demethylation became preponderant both in plasma and brain. Thus, plasma levels of demethylated metabolites, NOR and DM-NOR, increased (49% and 13% of total AUC against 22% and 7% in acute conditions, respectively), while levels of AMI and its hydroxylated metabolites, 10-OH-AMI and 10-OH-NOR, decreased (8%, 2.5% and 27.5% against 17%, 8% and 46% in acute conditions, respectively). Likewise in brain tissue, when AMI was repeatedly administered, NOR and DM-NOR increased (62% and 22% against 29% and 11%, respectively) while AMI and 10-OH-AMI decreased (11.5% and 1% against 47% and 9%, respectively). These differences may account for modified pharmacological effects seen after half-life repeated administration of AMI since demethylated metabolites exert a more marked inhibiting effect than AMI on noradrenaline reuptake.

Amitriptyline↗
PubMed1992

High-performance liquid chromatographic determination of amitriptyline and its main metabolites using a silica column with reversed-phase eluent. Application in mice.

A method was developed for the assay of amitriptyline, amitriptyline N-oxide, nortriptyline, desmethylnortriptyline and E (trans) and Z (cis) isomers of 10-hydroxyamitriptyline and of 10-hydroxynortriptyline in plasma and brain of animals, using high-performance liquid chromatography with ultraviolet detection (254 nm). Single extraction was performed at pH 10.5 from 0.25 ml of plasma or 1 ml of brain mixture. Chromatographic separations were achieved with a silica column and an aqueous methanol mobile phase containing ammonia. This procedure offers high sensitivity (8-10 ng/ml), high linearity (r > 0.99) and acceptable precision (coefficient of variation < or = 13.3%). The method was used to determine levels of amitriptyline and its major metabolites in mice 30 min after a single intraperitoneal administration of amitriptyline (20 mg/kg).

Amitriptyline↗
PubMed1992

Antinociceptive activity of metapramine in mice. Relationship with its pharmacokinetic properties.

The antinociceptive effect of acutely and chronically (every brain elimination half-life time) administered metapramine, a tricyclic antidepressant without anticholinergic or cardiotoxic effects, was studied in three different pain tests. In the hot plate test, its action was more potent when jumping was used as a pain parameter (acute ED50 = 19 +/- 3 mg/kg, i.p.) than when pain was assessed by licking of forepaws (only 20 mg/kg, i.p. was weakly active). Five chronic doses of 15 mg/kg were as active in the tail-flick test as an acute dose of 20 mg/kg (only active dose). Metapramine was more effective in the PBQ-induced writhing test after acute (ED50 = 9.9 +/- 0.1 mg/kg, i.p.) and chronic administration. A significant linear correlation was found between the effect in this test and plasma and overall brain levels of metapramine. No correlation was observed with levels of its three desmethylated metabolites. The usefullness of using a well-defined pattern of administration based on pharmacokinetic parameters and the involvement of monoaminergic mechanisms and of some metabolites of metapramine are discussed.

Animals↗
PubMed1992

Compared plasma and brain pharmacokinetics of clomipramine and its metabolite demethylclomipramine in two strains of mice (NMRI and CD1).

The fate of clomipramine (CMI) and its main demethylated metabolite demethylclomipramine (DCMI) was studied in two strains of Swiss mice (NMRI and CD1) after intraperitoneal injection. A study of its distribution among various tissues showed that fixation was most marked in lungs, perirenal fat and kidneys, and only moderate in the brain. The pharmacokinetic parameters of both molecules were determined in brain tissue and plasma. Absorption was rapid (tmax CMI = 14 min), metabolism prompt (tmax DCMI = 17 or 18 min according to the breed) and elimination rapid from both plasma and brain tissue. The first two stages were similar in the two strains, but elimination of CMI from both plasma and brain was faster in the NMRI mice (plasma t1/2 = 53 min against 165 min in the CD1 mice). Both values were well below that reported for man (mean plasma t1/2 = 24 h). The data presented can serve as a basis for designing true chronic administration protocol in animals.

Animals↗
PubMed1992

Comparative effects of different uptake inhibitor antidepressants in two pain tests in mice.

The purpose of this study was to compare the analgesic effect of acute injections (1.25 and 20 mg/kg, ip) of several antidepressants with different effects on monoamine reuptake, on two pain tests in mice (hot-plate and phenylbenzoquinone-induced abdominal writhes). Serotonergic inhibitors (citalopram, fluvoxamine and clomipramine) were more effective in the hot-plate test whereas noradrenaline reuptake inhibitors (desipramine and maprotilline) were more effective in the writhing test. The mixed antidepressants (amitriptyline and to a lesser degree trimipramine) were more effective in the two tests than the other antidepressant drugs. Changes in motor activity of clomipramine and amitriptyline could not account for the modifications of pain threshold. Amineptine (a dopamine reuptake inhibitor) failed to induce any antinociceptive effect in the hot-plate test and was hyperalgesic in the writhing test, which could be explained by an increased motor activity. These findings indicate that the antinociceptive potency of reuptake inhibitors varies according to their monoamine specificity and the nature of stimuli. They would suggest that the preferential choice of serotonergic antidepressants in the management of chronic pain is arguable.

Animals↗
PubMed1991

Long-lasting antinociceptive effect of RC-160, a somatostatin analog, in mice and rats.

The effect of RC-160 (D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Trp-NH2) was studied in mice by means of the hot plate test and in rats with the tail flick test. In mice, 512 micrograms/kg (s.c.) induced an antinociceptive effect maximal (+88 +/- 17%) at the 6th hour after injection but still significant at the 24th hour; 16 micrograms/kg (s.c.) was active for 3 h; 64, 256 and 1024 micrograms/kg were active 30 min, 3 and 24 h after injection. The effects of these last three doses were not different. The antinociceptive action was as high at 24 h as at 3 h (e.g. for 512 micrograms/kg, 44 +/- 9% and 51 +/- 12%, respectively); 48 h after injection the scores of the treated groups were not different from the score for saline treatment in the tail flick test, 512 micrograms/kg induced a significant antinociceptive effect for 12 h (maximal at the 3rd hour: +60%). No behavioral changes, and particularly no motor activity modifications were observed.

Amino Acid Sequence↗
PubMed1989

Antinociceptive activity of salsolinol (racemate, R(+)-, S(-)-enantiomers): evidence of a peripheral mechanism.

The existence and the characteristics of the antinociceptive action of salsolinol (racemate) and its two R(+)- and S(-)-enantiomers were studied using different pain tests in mice. None of these drugs possessed a significant activity on the tests sensitive to central acting analgesics (hot-plate and tail-flick tests), either after systemic (i.p.) or central (i.c.v.) injections. However, injected i.p., they reduced the number of writhes induced by phenylbenzoquinone; the ED50 was 79 +/- 2, 73 +/- 2 and 61 +/- 2 mg/kg for racemate, R(+)- and S(-)-enantiomer respectively. This activity was not antagonized by naloxone. Moreover, racemate and S(-) reduced, only for the highest used active dose on the PBQ test (128 mg/kg, i.p.), the edema induced by an intraplantar injection of carrageenin. These results provide evidence of an analgesic activity independent of the endogenous opiate systems and involving a peripheral mechanism.

Analgesia↗
PubMed1989

Pharmacokinetics of metapramine and its demethylated metabolites in plasma and brain of mice.

Previous studies on pharmacokinetic parameters of tricyclic antidepressants (TCAs) in rodents have shown different results from those obtained for the same drugs in man. The kinetics of metapramine (META) and its major demethylated metabolites (METs) were studied in the SWISS CD 1 mouse after acute administration in order to establish the pharmacokinetic parameters in plasma and brain. The plasma half-life (T1/2) was very short (87 min) compared with the half-life (7 h) in man. The metabolism of META was intensive as was the transfer of META and its metabolites into the brain. The kinetic profiles of the substances were quite similar both in plasma and in brain, namely a bicompartment open model. META was rapidly absorbed (Tmax = 10 min) into and quickly eliminated (T 1/2 = 40 min) from the brain. These parameters were used to schedule sampling (blood and brain) at the appropriate time after acute administration of increased doses. The administered doses were significantly correlated to firstly the plasma or brain levels of META, secondly the plasma levels of the main monodemethylated metabolite (MET I), and thirdly the plasma or brain levels of META + METs. Finally, the evolution of plasma and brain levels of the substances was studied after repeated injections (i.e. every 40 min) and confirmed the high affinity of META and its metabolites for the brain regions.

Animals↗
PubMed1989

Pharmacokinetic patterns of repeated administration of antidepressants in animals. II. Their relevance in a study of the influence of clomipramine on morphine analgesia in mice.

Many studies have shown tricyclic antidepressants (TCAs) to potentiate morphine analgesia, but more recent work, using different modes of administration, has revealed inhibition of morphine analgesia by TCAs. The influence of different modes of administration of clomipramine (CMI) on morphine analgesia assessed by the hot-plate test was studied in mice. The administration procedure was based on the pharmacokinetic parameters of CMI determined in the strain used. Acute and chronic (i.e., every half-life of 130 min for five half-lives) administration of CMI (10 or 20 mg/kg i.p.) had opposite effects; the former potentiated morphine analgesia and the latter inhibited it. Five closely repeated administrations (i.e., every 40 min) suppressed the potentiation without producing inhibition. The time course of the influence of CMI showed that the inhibition of morphine analgesia observed after repeated administration of a given dose of CMI occurred if the latter was present for sufficient time; this time decreased when the dose of CMI was increased. Moreover, comparison with literature data shows the importance of standardized patterns of repeated administration: the variability in the frequency of repeated administration and in the time-lag between the last injection of TCA and the test may account for the varying results observed. The discrepancies in the literature regarding TCA/morphine interaction are thus only apparent, and arise merely from varying conditions. Possible mechanisms for the CMI-morphine interaction are discussed: involvement of opiate receptors and/or the serotonergic system.

Analgesia↗