Biomedical subjects

G Pinardi

Publications and source records attributed to G Pinardi.

At least 19 recordsLinked to original sources

PubMed2004

Isobolographic analysis of the antinociceptive interactions of clonidine with nonsteroidal anti-inflammatory drugs.

The present study was undertaken to characterize the interactions between nonsteroidal anti-inflammatory drugs and the alpha(2)-adrenoceptor agonist clonidine in an acute nociceptive test. The writhing test was selected as a model of acute visceral pain. Isobolograms were constructed to assess the interactions of clonidine and each nonsteroidal anti-inflammatory drugs, when coadministered intraperitoneally and intrathecally (i.t.). The simultaneous intraperitoneal administration of fixed ratios of ED(50) fractions of all nonsteroidal anti-inflammatory drugs (naproxen, piroxicam, paracetamol, dipyrone or metamizol and nimesulide) combined with clonidine resulted in synergistic interactions. The same combinations administered intrathecally were additive. The synergistic interactions between systemic nonsteroidal anti-inflammatory drugs and clonidine may involve supraspinal mechanisms.

Analgesics↗

PubMed2004

Synergy between the antinociceptive effects of morphine and NSAIDs.

The intraperitoneal administration of morphine, diclofenac, ketoprofen, meloxicam, metamizol, paracetamol and piroxicam induced dose-dependent antinociception in mice tested with the acetic acid writhing test. The isobolographic analysis of the simultaneous intraperitoneal administration of fractions of the ED50's of morphine with each nonsteroidal anti-inflammatory drug (NSAID) demonstrated the existence of a supra-additive interaction (synergy). The selective antagonist of micro -opioid receptors naltrexone partially reversed the supra-additive interactions to additive interactions; however, the combinations of morphine/metamizol and morphine/paracetamol were completely antagonized, resulting in subadditive interactions. The selective antagonist of delta-opioid receptors naltrindole failed to significantly attenuate the combinations of morphine with ketoprofen, meloxicam and piroxicam, but decreased the activity of the combinations of morphine with diclofenac, metamizol and paracetamol, transforming the interactions from supra-additive to additive. Nor-binaltorphimine was used to evaluate the involvement of kappa-opioid receptors. Nor-binaltorphimine did not modify the supra-additive interaction of morphine and NSAIDs and the additive interaction of the co-administration of morphine and metamizol. The synergy between morphine and NSAIDs could be related to different pathways of pain transmission, probably related to the different intracellular signal transduction mechanisms of action of opioid and non-opioid agents.

Analgesics↗

PubMed2003

Effect of the inhibition of serotonin biosynthesis on the antinociception induced by nonsteroidal anti-inflammatory drugs.

The antinociceptive activity of nonsteroidal anti-inflammatory drugs (NSAIDs) has been explained mainly on the basis of their inhibition of the enzyme cyclooxygenase (COX); however, this inhibition is not enough to completely explain the analgesic efficacy of these drugs. The modulation exerted by serotonergic systems on antinociception is well known. The purpose of the present work was to further explore the role of serotonin in the antinociceptive activity of NSAIDs using the writhing test and the tail-flick test of the mice after the inhibition of serotonin biosynthesis with intraperitoneal p-chlorophenylalanine (p-CPA). Pretreatment with p-CPA produced a significant decrease in the antinociceptive activity of NSAIDs administered either by the intraperitoneal or intrathecal routes, in both algesiometric tests. These results suggest a complementary mechanism of antinociception for NSAIDs, independent of their ability to inhibit the activity of COX, involving the activation of descending serotonergic pathways. By the pharmacological nature of the study, one limitation was the absence of biochemical measurement of the synthesis of 5-HT, since the reduction of the brain 5-HT synthesis by pretreatment with p-CPA will be expressed as a diminished antinociceptive activity of NSAIDs, which would be a new argument to consider NSAIDs acting as central analgesic agents.

Animals↗

PubMed2003

Atropine reverses the antinociception of nonsteroidal anti-inflammatory drugs in the tail-flick test of mice.

The nonsteroidal anti-inflammatory drugs (NSAIDs) clonixin, diclofenac, piroxicam, ketoprofen, meloxicam, and paracetamol induced antinociception after intraperitoneal or intrathecal administration in mice submitted to an acute thermal algesiometric test without inflammation (tail-flick). Antinociception was evaluated by the increase in reaction time difference (Delta latency), between readings obtained before and after the administration of drugs. The antinociception induced by doses of NSAIDs producing between 20% and 30% of the maximum possible effect (MPE) 30 min after intraperitoneal and 15 min after intrathecal injections was compared with the antinociception obtained after pretreatment with 1 mg/kg atropine ip, 30 min before. Systemic atropine (1 mg/kg) significantly antagonized NSAID-induced antinociception in all cases, both after intraperitoneal and intrathecal administration. Cholinergic depletion by intracerebroventricular hemicholinium-3 (HC-3, 5 microg) 5 h before prevented the antinociceptive effect of all NSAIDs. These observations suggest that intrinsic muscarinic cholinergic facilitatory pathways represent an important modulating system in pain perception in this animal model of acute thermal pain. The results of the present work support the increasingly accepted notion that NSAIDs are effective analgesics even when inflammation is not present, acting by mechanisms that involve actions on spinal and supraspinal nociceptive transmission. It is suggested that, similar to morphine and clonidine, the active mechanism of NSAIDs may involve the release of acetylcholine (ACh) in the spinal cord.

Analgesics↗

PubMed2002

Adrenergic mechanisms in antinociceptive effects of non steroidal anti-inflammatory drugs in acute thermal nociception in mice.

OBJECTIVE: The interactions of alpha-adrenoceptors with the antinociceptive effects of non-steroidal antiinflammatory drugs (NSAIDs) were assessed in acute thermal nociception in mice. MATERIALS AND METHODS: The analgesic effect was analyzed by the tail-flick test. RESULTS: The pretreatment with yohimbine (1 mg/kg i.p.), 30 min prior to the intraperitoneal injection of ketoprofen (50 mg/kg), diclofenac (30 mg/kg) and piroxicam (50 mg/kg) antagonized the antinociception induced by these NSAIDs, significantly reducing the tail-flick latency. Yohimbine did not affect paracetamol (125 mg/kg) induced antinociception. Prazosin (1 mg/kg i.p.) antagonized only the effect of paracetamol, without affecting the latency of the other drugs. When NSAIDs were administered i.t. (ketoprofen 2 m/kg; diclofenac 0.9 mg/kg; piroxicam 1.5 mg/kg; paracetamol 3.75 mg/kg), the same results were obtained after i.p. pretreatment with yohimbine and prazosin. The pretreatment of phenoxybenzamine (1 mg/kg i.p.) antagonized all antinociceptive effects. CONCLUSIONS: NSAIDs induced antinociception in an acute thermal pain model without inflammation. The mechanism of antinociception induced by ketoprofen, diclofenac and piroxicam involves an activation of alpha2-adrenoceptors at spinal and supraspinal levels, while paracetamol-induced antinociception is probably due mainly to central activation of the descending noradrenergic inhibitory system by alpha1-adrenoceptors.

Adrenergic alpha-Antagonists↗

PubMed2002

Comparing two programs of cognitive training in Alzheimer's disease: a pilot study.

OBJECTIVES: To evaluate the efficacy of two different procedures of individual cognitive training in mild to moderate Alzheimer's Disease (AD). MATERIAL AND METHODS: Twenty-two AD patients entered the study. We compared stimulation of procedural memory (group 1) with training of partially spared cognitive functions (group 2). Assessment included: neuropsychological tests, scales, and the Functional Living Skills Assessment (FLSA), a standardized battery built to directly evaluate patients' performance in everyday life. RESULTS: We observed a significant improvement for both groups after training in FLSA total score (P=0.005) and subscales. For group 1, we also found a slightly improved performance in two tests: Attentional Matrices (P=0.041), and Verbal Fluency for Letters (P=0.059). After 3 months, patients' results showed a tendency to regress to the pre-training level. CONCLUSION: Both AD groups showed a substantial improvement after training in a direct performance measure of everyday functioning. However, results at neuropsychological tests suggest that training activities of daily living (supported by procedural memory) may be more effective than stimulating "residual" cognitive functions.

Aged↗

PubMed2002

Carbachol interactions with nonsteroidal anti-inflammatory drugs.

The inhibition of cyclooxygenase enzymes by nonsteroidal anti-inflammatory drugs (NSAIDs) does not completely explain the antinociceptive efficacy of these agents. It is known that cholinergic agonists are antinociceptive, and this study evaluates the interactions between carbachol and some NSAIDs. Antinociceptive activity was evaluated in mice by the acetic acid writhing test. Dose-response curves were constructed for NSAIDs and carbachol, administered either intraperitoneally (i.p.) or intrathecally (i.t.). The interactions of carbachol with NSAIDs were evaluated by isobolographic analysis after the simultaneous administration of fixed proportions of carbachol with each NSAID. All of the drugs were more potent after spinal than after systemic administration. The combinations of NSAIDs and carbachol administered i.p. were supra-additive; however, the i.t. combinations were only additive. Isobolographic analysis of the coadministration of NSAIDs and carbachol and the fact that atropine antagonized the synergistic effect suggest that carbachol may strongly modulate the antinociceptive activity of NSAIDs; thus, central cholinergic modulation would be an additional mechanism for the antinociceptive action of NSAIDs, unrelated to prostaglandin biosynthesis inhibition.

Animals↗

PubMed2001

Interaction between the antinociceptive effect of ketoprofen and adrenergic modulatory systems.

The interaction between the antinociceptive activity of ketoprofen and adrenergic agents was evaluated in the writhing test of mice. Dose-response curves were obtained for systemic and intrathecal antinociceptive effects of ketoprofen, phenylephrine, clonidine, desipramine, and prazosin; and ED50 were calculated. The interactions were evaluated by isobolographic analysis of the systemic or intrathecal co-administration of fixed-ratio combinations of ketoprofen with each adrenergic agent. The intraperitoneal combinations of ketoprofen with phenylephrine, clonidine, and prazosin showed supra-additivity, indicating that activation of alpha1 and alpha2 adrenoceptors play a role in nociceptive transmission at supraspinal levels. The same combinations given intrathecal were only additive. Desipramine intraperitoneal was also supra-additive: however, when ketoprofen was administered intrathecally with desipramine, only an additive interaction was obtained. The supra-additive interactions suggest that complementary mechanisms of antinociception have been activated, related with interference with the multiplicity of receptors and systems involved in the transmission of the nociceptive information. Racemic ketoprofen has an antinociceptive activity which is probably not only due to COX inhibition but also involves noradrenergic systems at spinal and supraspinal levels.

Adrenergic alpha-Agonists↗

PubMed2001

Effects of ketoconazole on oestrus cycle and convulsant action of pentylenetetrazol in mice.

The frequency of oestrus cycles in female mice was significantly reduced by the implantation of a pellet of subcutaneous ketoconazole (50 mg every 6 days). The effect was more pronounced after 22 days than after 13 days and it was probably related with the progressive reduction in steroid synthesis induced by the inhibition of key steroidogenic P450 cytochromes by the drug. In addition, the influence of ketoconazole on the incidence of seizures after the administration of intraperitoneal pentylenetetrazol was evaluated in female mice. Pentylenetetrazol produced a higher percentage of seizures during dioestrus than during oestrus. Pretreatment with ketoconazole significantly increased the percentage of animals with induced seizures in oestrus but not in dioestrus as compared to controls, probably through reduced progesterone levels. The reduced seizure threshold confirm the modulatory role exerted by progesterone on central nervous system excitability, and may be relevant in epileptic patients undergoing antifungal therapy.

Animals↗

PubMed2001

An isobolographic analysis of the adrenergic modulation of diclofenac antinociception.

UNLABELLED: We evaluated the noradrenergic modulation of the antinociceptive activity of diclofenac in mice using the acetic acid writhing test. Dose-response curves were obtained for the antinociceptive effect of diclofenac, phenylephrine, clonidine, desipramine, prazosin, and yohimbine administered both systemically and intrathecally, and ED(50)s were calculated. Noradrenergic modulation was evaluated by performing an isobolographic analysis of the systemic or intrathecal coadministration of fixed-ratio combinations of diclofenac with each adrenergic drug. The systemic, but not the intrathecal, combinations of diclofenac with phenylephrine or clonidine showed supraadditivity, suggesting that the activation of alpha(1) and alpha(2) adrenoceptors interfered with the nociceptive transmission at spinal and supraspinal levels. Supraadditive effects were not demonstrated for the intrathecal injection of diclofenac combined with phenylephrine, clonidine and a selective norepinephrine uptake inhibitor (desipramine) or adrenergic antagonists. We conclude that interaction between adrenoceptors and diclofenac can modulate antinociception by activating common or different mechanisms. Diclofenac has an antinociceptive activity that, in addition to cyclooxygenase inhibition, can be modulated by additive and supraadditive interactions with adrenergic drugs. IMPLICATIONS: Diclofenac analgesia in mice can be modulated by interaction with adrenergic drugs. The systemic but not the intrathecal administration of phenylephrine and clonidine produced supraadditive interactions. For desipramine, prazosin, and yohimbine, supraadditive interactions were not statistically demonstrated. The coadministration of drugs inducing supraadditive effects could be clinically relevant for the treatment of chronic pain because of reduction of doses and side effects.

Adrenergic Agents↗

PubMed2001

NSAID antinociception measured in a chemical and a thermal assay in mice.

The antinociceptive activity of several nonsteroidal anti-inflammatory drugs (NSAIDs) that were administered either intraperitoneally or intrathecally was assessed in mice by two algesiometric tests. The first was the writhing test, which assessed the abdominal constrictions that were induced by intraperitoneal acetic acid (a chemical test), and the second was the tail flick test, which measured pain responses to heat stimuli. The corresponding effective doses and their relative potencies were compared because these tests use different nociceptive stimuli with different transmission pathways. The intraperitoneal and intrathecal dose-response curves for the antinociception induced by every NSAID that was tested were parallel in the writhing test. In the tail flick test, however, only the intraperitoneal and intrathecal dose-response curves for ketoprofen, piroxicam, naproxen, nimesulide, paracetamol and diclofenac were parallel. The results obtained in this study confirm that NSAIDs possess different abilities to induce inhibition of cyclooxygenase, and they can be indirectly assessed by their different antinociceptive activities, depending on the algesiometric assays that are used. The antinociception of most NSAIDs might involve central mechanisms. The findings demonstrate the increasing importance of the spinal cord in processing and modulating nociceptive input, because intrathecal administration of NSAIDs is always more effective (in terms of potency) than systemic administration; thus, the antinociceptive efficacy of NSAIDs strongly depends on the algesiometric assay that is used and on the type of the nociceptive stimulus to which the test subject is exposed.

Animals↗

PubMed2000

Isobolographic analysis of the interaction between fenoldopam and levodopa on arterial blood pressure of the rat.

Fenoldopam (FD) and levodopa (LD) injected intravenously in rats in a noncumulative schedule induced dose-dependent reductions in mean arterial blood pressure. The doses that induced a 50% reduction in the initial control mean arterial pressure (referred as ED50) were calculated by linear regression analysis of the corresponding parallel dose-response curves and were 0.88 and 0.068 mg/kg, respectively. The interaction between the effects of FD and LD on pressure reduction was evaluated by simultaneous administration of different fixed ratios of FD and LD (16:1) and obtaining a dose-response curve. An isobolographic analysis was then performed, which showed that the experimental point for the effect of the simultaneous administration of FD and LD was significantly different from the theoretically calculated additive point, denoting supradditivity. It was concluded that the effect of the combination of FD and LD on mean blood pressure reduction was synergic and was probably due to an activation of D1 vascular receptors by both drugs, in conjunction with an activation of beta2 adrenoceptors by LD and a blocking action of FD on postsynaptic alpha1-adrenoceptors.

Animals↗

PubMed2000

Progesterone and testosterone modulate the convulsant actions of pentylenetetrazol and strychnine in mice.

The influence of progesterone and testosterone on the incidence of seizures after administration of intraperitoneal pentylenetetrazol and subcutaneous strychnine was evaluated in mice. Pentylenetetrazol and strychnine were administered in doses that induced seizures in 40-50% of control mice in dioestrus (48 and 0.9 mg/kg, respectively). The percentage of seizures induced by pentylenetetrazol and strychnine was significantly lower in female mice in prooestrus/oestrus, when progesterone levels are high, than in dioestrus, when progesterone levels are low. Pretreatment of pentylenetetrazol-challenged mice with progesterone (250 microg/kg) increased the incidence of seizures in prooestrus/oestrus, without affecting seizures in dioestrus. The same pretreatment in strychnine-challenged mice also increased the incidence of seizures in prooestrus-dioestrus, but significantly reduced the incidence of seizures in dioestrus. In addition, progesterone pretreatment significantly increased the percentage of deaths induced by strychnine in prooestrus-oestrus, reducing deaths in dioestrus. Orchidectomized male mice had a significantly higher incidence of seizures after administration of pentylenetetrazol and strychnine than control mice. Administration of 11 daily doses of 250 microg/kg of testosterone to castrated mice significantly reduced the incidence of seizures induced by pentylenetetrazol. These results confirm the modulatory influence of reproductive steroids on the excitability of the central nervous system and the possible clinical importance of progesterone and testosterone in the management of partial epilepsy.

Animals↗

PubMed1998

Antinociception, tolerance, and physical dependence comparison between morphine and tramadol.

The mechanism of action of tramadol includes the activation of opioid receptors, and the potential ability of the drug to induce tolerance and physical dependence has been evaluated in different animal species and humans. This work was designed to study the involvement of opioid receptors in the antinociceptive activity and the potential ability to develop tolerance, crosstolerance, and/or physical dependence of tramadol. The writhes induced by acetic acid administration was used as algesiometric test. After chronic administration of tramadol, tolerance was evaluated by measuring the antinociceptive activity, and physical dependence was measured by naloxone administration. Morphine was used as drug of comparison. The i.p. administration of tramadol produced a dose-dependent antinociception with an ED50 value of 7.82 +/- 1.16 mg/kg, which was unchanged after chronic administration of either tramadol (39.1 or 100 mg/kg) or morphine (1.05 or 100 mg/kg). By contrast, the ED50 for morphine (0.21 +/- 0.08 mg/kg) was significantly reduced only by chronic pretreatment with both doses of morphine (tolerance). Physical dependence was developed only in mice pretreated with morphine, as evidenced by the presence of jumps, wet-dog shakes, tachypnea, piloerection, seizures, diarrhea, and urination after the administration of naloxone (1 mg/kg). These findings suggest that the antinociceptive activity of tramadol in mice is due to activation of opioid and nonopioid mechanisms, and as opposed to morphine, is not likely to induce tolerance and physical dependence.

Analgesics, Opioid↗

PubMed1998

Interactions in the antinociceptive effect of tramadol in mice: an isobolographic analysis.

Tramadol is a widely-used analgesic for pre- and post-operative pain which has a different pharmacological profile to that of classical opioids, since it does not induce respiratory depression, constipation, sedation, tolerance or dependence. However, tramadol frequently produces nausea and vomiting as side-effects. In the present study, the interactions between tramadol and several adrenergic and serotonergic compounds with antinociceptive activity were studied by isobolographic analysis. Antinociceptive activity was evaluated using the acetic acid writhing test in mice. Dose-response curves for the antinociceptive effect of tramadol, prazosin, clonidine, xylamine, clomipramine and cyproheptadine were obtained, and ED(50)s were calculated for isobolographic analysis, which was performed by administration of fixed-ratios of tramadol with each of these drugs, given both systemically and intrathecally. The isobolograms of all combinations tested, either systemically or intrathecally showed superadditivity. The synergies observed with these combinations suggest a complex modulation of the descending noradrenergic and serotonergic systems that exert inhibitory influences on the transmission of nociceptive information, probably in addition to effects on receptors in the primary neurons of the spinal cord. The co-administration of analgesic drugs that produce superadditive effects constitutes a significant new avenue for the treatment of pain, since a similar level of antinociception can be obtained with considerable reductions in the dose of each analgesic. Copyright 1998 European Federation of Chapters of the International Association for the Study of Pain.

Journal Article↗

PubMed1996

alpha-Adrenoceptor and opioid receptor modulation of clonidine-induced antinociception.

1. The antinociceptive action of clonidine (Clon) and the interactions with alpha 1, alpha 2 adrenoceptor and opioid receptor antagonists was evaluated in mice by use of chemical algesiometric test (acetic acid writhing test). 2. Clon produced a dose-dependent antinociceptive action and the ED50 for intracerebroventricular (i.c.v.) was lower than for intraperitoneal (i.p.) administration (1 ng kg-1 vs 300 ng kg-1). The parallelism of the dose-response curves indicates activation of a common receptor subtype. 3. Systemic administration of prazosin and terazosin displayed antinociceptive activity. Pretreatment with prazosin produced a dual action: i.c.v. Clon effect did not change, and i.p. Clon effect was enhanced. Yohimbine i.c.v. or i.p. did not induce antinonciception, but antagonized Clon-induced activity. These results suggest that alpha 1- and alpha 2-adrenoceptors, either located at the pre- and/or post-synaptic level, are involved in the control of spinal antinociception. 4. Naloxone (NX) and naltrexone (NTX) induced antinociceptive effects at low doses (microgram kg-1 range) and a lower antinociceptive effect at higher doses (mg kg-1 range). Low doses of NX or NTX antagonized Clon antinociception, possibly in relation to a preferential mu opioid receptor antagonism. In contrast, high doses of NX or NTX increased the antinociceptive activity of Clon, which could be due to an enhanced inhibition of the release of substance P. 5. The results obtained in the present work suggest the involvement of alpha 1-, alpha 2-adrenoceptor and opioid receptors in the modulation of the antinociceptive activity of clonidine, which seems to be exerted either at spinal and/or supraspinal level.

Adrenergic alpha-Agonists↗

PubMed1996

Progesterone modulation of diazepam withdrawal syndrome in mice.

The influence of progesterone and oestrogens on the benzodiazepine withdrawal syndrome in mice was studied. The intraperitoneal administration of 15 mg/kg of flumazenil induced a withdrawal syndrome in chronic diazepam-treated mice, characterized by jerks, usually accompanied by tail lifts, and seizures. The principal finding of the present work is that the intensity of diazepam withdrawal syndrome was significantly reduced by acute administration of progesterone as revealed by a low incidence of jerks and seizures. The action of progesterone could be due to a modulatory role of the hormone on neuronal activity as an anxiolytic agent. The modulatory activity of progesterone appears to be related to changes in the pharmacological properties of benzodiazepine receptors.

Animals↗

PubMed1995

Interaction of opioids with antidepressant-induced antinociception.

The antinociceptive activity of antidepressant drugs is poorly understood. In this study, using the acetic acid writhing test in mice, the antinociception produced by clomipramine (CLO), maprotiline (MAP), imipramine (IMI), and zimelidine (ZIM) was tested and correlated with opioid drugs. All the compounds displayed a significant dose-dependent antinociception, which was not antagonized by naloxone (NX) or naltrexone (NTX). The administration of morphine (M) plus CLO, MAP, IMI or ZIM resulted in a significant additive effect that was antagonized by 1 or 10 mg/kg NX or NTX, except in the case of IMI. This finding suggests that the additive effect seems to be partially due to activation of opioid receptors, except for the case of imipramine. However, aminophylline, a non-selective blocker of A1/A2 adenosine receptors, significantly antagonized the antinociceptive activity of CLO, IMI, MAP and ZIM, demonstrating an interaction at the level of adenosine receptors. This work suggests that the antinociceptive activity of antidepressants could be dependent on critical levels of free 5-HT and NE at receptor(s) site(s) in CNS and on their interaction with opioid and adenosine receptors.

Animals↗