Pro-inflammatory cytokines involvement in the hesperidin antihyperalgesic effects at peripheral and central levels in a neuropathic pain model.

Emerging evidence proposes a link between immune changes and pain, which is consistent with the inflammation theory and the increased incidence of neurodegenerative diseases. Flavonoids have long been used because of their anti-inflammatory potential activity and they are considered a promising alternative to alleviate neuropathic pain. The aim of this study was to investigate the antihyperalgesic effect of hesperidin and the presence of pro-inflammatory cytokines evaluated at peripheral and central levels in the chronic constriction injury as model of neuropathic pain in rats. Mechanical and thermal hyperalgesia were assessed in the aesthesiometer and plantar tests, respectively, as related to the presence of cytokines concentrations (TNF-α, IL-1ß and IL-6) in sciatic nerve and segments of the spinal cord after 15 days chronic constriction injury model in rats receiving vehicle or hesperidin. Antihyperalgesic response of hesperidin (100 mg/kg) was associated to the presence of cytokines mainly at several sections of the spinal cord suggesting not only peripheral but also its involvement in central sensitization in the experimental neuropathic pain.

Evaluation of the antinociceptive effect of Rosmarinus officinalis L. using three different experimental models in rodents.

The rationale of this investigation was to examine the antinociceptive effect of an ethanol extract of Rosmarinus officinalis (RO) aerial parts, using three different experimental models: acetic acid-induced writhing test and formalin test in mice; and a model of arthritic pain: "pain-induced functional impairment model in the rat (PIFIR model)". The antinociceptive efficacies were evaluated using several dose-response curves and time courses. The antinociceptive effects from RO extract were compared with the antinociceptive effect of either tramadol (TR: 3.16-50 mg/kg, i.p. in mice, and 1.0-31.62 mg/kg, i.p. in rats) or acetylsalicylic acid (AA: 31.62-562.32 mg/kg, p.o.). RO extract (10-300 mg/kg, p.o.) significantly (P < 0.001) reduced the number of writhing movement induced by the i.p. administration of acetic acid solution in a dose-dependent way (ED50 = 108.84 mg/kg, whereas, TR showed an ED50 = 12.38 mg/kg). In addition, RO extract (30-300 mg/kg) significantly (P < 0.001) inhibited licking and shaking behaviours in both early (neurogenic pain) and in the late (inflammatory pain) phases of the formalin test. These effects were like those produced by TR. Concerning the results using the PIFIR model, RO extract (30-3000 mg/kg, p.o.) like either TR or AA, produced a significant (P < 0.001) and dose-dependent antinociceptive response in rats (RO: ED50 = 222.78 mg/kg versus TR: ED50 = 11.06 mg/kg and AA: ED50 = 206.13 mg/kg). These results strongly suggest that aerial parts of RO possess antinociceptive and anti-inflammatory activity, and reinforce the use of this plant in folk medicine.

Influence of inflammatory nociception on the anxiolytic-like effect of diazepam and buspirone in rats.

RATIONALE: The effect of anxiety on nociception has been evaluated but not that of nociception on anxiety. OBJECTIVE: The study was conducted to analyse the influence of nociception on basal levels of anxiety-like behaviour and on the action of anxiolytic drugs. METHODS: Nociception was induced by an intra-articular injection of uric acid at 3.75 or 7.5%. Experimental anxiety was determined in the rat burying behaviour and the elevated plus maze tests. To separate specific anxiety-related drug actions, a spontaneous ambulatory test was included. The anxiolytics, buspirone (2.5 and 5.0 mg/kg, i.p.) and diazepam (0.5, 1.0 and 2.0 mg/kg, i.p.), were used. RESULTS: In the nociception test, the pain-induced functional impairment rat model, uric acid at 3.75 and 7.5% had an effect of around 35 and 75%, respectively. Uric acid (UA) at the lower dose (3.75%) lacked an effect on burying behaviour but significantly increased the time spent and number of entries to the open arms; the higher UA dose (7.5%) produced a significant increase in the time spent and number of entries to the open arms and a statistically significant reduction in cumulative burying. Diazepam and buspirone produced a clear dose-dependent reduction in cumulative burying. In the plus maze, diazepam also induced an increase in the time spent and number of entries to the open arms. In the burying behaviour test, rats with a mild level of nociception (uric acid at 7.5%) were insensitive to the anxiolytic-like effect of these anxiolytic drugs. In the plus maze test, the anxiolytic-like effect of diazepam (1.0 mg/kg) was blocked under both levels of nociception. CONCLUSIONS: These data demonstrate that nociception modifies the response to anxiolytic drugs. The role of factors with anxiogenic properties produced during inflammation, which may modify diazepam and buspirone effects, is discussed.

Pharmacological profile of the receptors that mediate external carotid vasoconstriction by 5-HT in vagosympathectomized dogs.

1. 5-Hydroxytryptamine (5-HT) can produce vasodilatation or vasoconstriction of the canine external carotid bed depending upon the degree of carotid sympathetic tone. Hence, external carotid vasodilatation to 5-HT in dogs with intact sympathetic tone is primarily mediated by prejunctional 5-HT1-like receptors similar to the 5-HT1D subtype, which inhibit the carotid sympathetic outflow. The present investigation is devoted to the pharmacological analysis of the receptors mediating external carotid vasoconstriction by 5-HT in vagosympathectomized dogs. 2. Intracarotid (i.c.) infusions for 1 min of 5-HT (0.3, 1, 3, 10, 30 and 100 micrograms) resulted in dose-dependent decreases in both external carotid blood flow and the corresponding conductance; both mean arterial blood pressure and heart rate remained unchanged during the infusions of 5-HT. These responses to 5-HT were resistant to blockade by antagonists at 5-HT2 (ritanserin) and 5-HT3/5-HT4 (tropisetron) receptors, but were partly blocked by the 5-HT1-like and 5-HT2 receptor antagonist, methiothepin (0.3 mg kg-1); higher doses of methiothepin (1 and 3 mg kg-1) caused little, if any, further blockade. These methiothepin (3 mg kg-1)-resistant responses to 5-HT were not significantly antagonized by MDL 72222 (0.3 mg kg-1) or tropisetron (3 mg kg-1). 3. The external carotid vasoconstrictor effects of 5-HT were mimicked by the selective 5-HT1-like receptor agonist, sumatriptan (3, 10, 30 and 100 micrograms during 1 min, i.c.), which produced dose-dependent decreases in external carotid blood flow and the corresponding conductance; these effects of sumatriptan were dose-dependently antagonized by methiothepin (0.3, 1 and 3 mg kg-1), but not by 5-HT1D-like receptor blocking doses of metergoline (0.1 mg kg-1). 4. The above vasoconstrictor effects of 5-HT remained unaltered after administration of phentolamine, propranolol, atropine, hexamethonium, brompheniramine, cimetidine and haloperidol, thus excluding the involvement of alpha- and beta-adrenoceptors, muscarinic, nicotinic, histamine and dopamine receptors. Likewise, inhibition of either 5-HT-uptake (with fluoxetine) or cyclo-oxygenase (with indomethacin), depletion of biogenic amines (with reserpine) or blockade of calcium channels (with verapamil) did not modify the effects of 5-HT. 5. Taken together, the above results support our contention that the external carotid vasoconstrictor responses to 5-HT in vagosympathectomized dogs are mainly mediated by activation of sumatriptan-sensitive 5-HT1-like receptors. It must be emphasized, notwithstanding, that other mechanisms of 5-HT, including an interaction with a novel 5-HT receptor (sub)type and/or an indirect action that may lead to the release of a known (or even unknown) neurotransmitter substance cannot be categorically excluded.

Antinociceptive effects of S(+)-ketoprofen and other analgesic drugs in a rat model of pain induced by uric acid.

We investigated the antinociceptive properties of dexketoprofen trometamol [S(+)-ketoprofen tromethamine salt; SKP], a new analgesic, antiinflammatory drug, using the pain-induced functional impairment model in the rat (PIFIR), an animal model of arthritic pain. SKP was compared with racemic ketoprofen tromethamine salt (rac-KP), R(-)-ketoprofen tromethamine salt (RKP), ketorolac (KET), and morphine (MOR). We also assessed the effects of flurbiprofen (rac-FB) and its enantiomers (SFB and RFB) in the same model. Groups of six rats received either vehicle or analgesic drug and antinociception was evaluated by evaluating the dose-response curves over time. SKP was an effective antinociceptive drug in this model and was almost equally potent by either oral or intracerebroventricular administration. The oral potency of SKP was similar to that of oral KET and greater than that of oral MOR. No significant differences were observed between racemic ketoprofen and its enantiomers when administered orally. In the rat, significant bioinversion of RKP to SKP occurs when RKP is given orally. After oral administration of RKP, SKP was detectable in 30 min and surpassed the concentration of RKP after 3 h. Nevertheless, when the compounds were given intracerebroventricularly, some stereoselectivity in favor of SKP was observed. Stereoselectivity was observed with flurbiprofen, an analogue of ketoprofen that does not undergo significant metabolic inversion. Whereas SFB was an effective antinociceptive, RFB had no antinociceptive effect at the doses tested when given either orally or intracerebroventricularly.

Evidence for the involvement of nitric oxide in the antinociceptive effect of ketorolac.

The involvement of nitric oxide in the antinociception produced by ketorolac was assessed using the pain-induced functional impairment model in the rat: 800 micrograms of NG-nitro-L-arginine methyl ester, an inhibitor of nitric oxide synthesis, or saline was injected intra-articularly in a hind limb joint previously injured with uric acid. Animals then received ketorolac, dipyrone or no drug. Ketorolac and dipyrone produced a significant antinociceptive effect which was reduced by pretreatment with NG-nitro-L-arginine methyl ester, but not with saline. It is concluded that the antinociceptive effect of both drugs involves the local participation of nitric oxide.

Effect of caffeine coadministration and of nitric oxide synthesis inhibition on the antinociceptive action of ketorolac.

The effects of caffeine and nitric oxide synthesis inhibition on the antinociceptive action of ketorolac were assessed using the pain-induced functional impairment model in the rat. Nociception was induced by the intra-articular injection of uric acid. Ketorolac, but not caffeine, produced an antinociceptive effect which was reduced by NG nitro-L-arginine methyl ester (L-NAME), an inhibitor of nitric oxide synthesis. Caffeine coadministration potentiated the ketorolac effect. L-NAME induced a dose-dependent reduction of this potentiation. The results suggest the participation of the L-arginine-nitric oxide-cyclic GMP pathway in the caffeine potentiation of ketorolac-induced antinociception.

Effect of coadministration of caffeine and either adenosine agonists or cyclic nucleotides on ketorolac analgesia.

Caffeine potentiation of ketorolac-induced antinociception in the pain-induced functional impairment model in rats was assessed. Caffeine alone was ineffective, but increased the effect of ketorolac without affecting its pharmacokinetics. Intra-articular administration of adenosine and N6-cyclohexyladenosine (CHA, an adenosine A1 receptor agonist), but not 2-p-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxamidoadenosine hydrochloride (CGS-21680, an adenosine A2A receptor agonist), significantly increased ketorolac antinociception. This effect was not local, as contralateral administration was also effective. Ipsilateral and contralateral administration of adenosine and CHA also increased antinociception by ketorolac-caffeine. Intra-articular 8-Bromo-adenosine cyclic 3',5'-hydrogen phosphate sodium or 8-Bromo-guanosine-3',5'-cyclophosphate sodium (cGMP) given ipsilaterally or contralaterally did not affect ketorolac-induced antinociception. Nevertheless, ipsilateral, but not contralateral, administration of 8-Br-cGMP significantly increased antinociception by ketorolac-caffeine, suggesting a local effect. The results suggest that caffeine potentiation of ketorolac antinociception is mediated, at least partially, by a local increase in cGMP and rule out the participation of adenosine receptor blockade.

External carotid effects of 2-(2-aminoethyl)-quinoline (D-1997) in vagosympathectomized dogs.

Serotonin (5-hydroxytryptamine; 5-HT) elicits external carotid vasoconstriction in vagosympathectomized dogs via 5-HT1B/1D receptors and a mechanism unrelated to the 5-HT1, 5-HT2, 5-HT3 and 5-HT4 types. In order to further explore the nature of this novel mechanism, the canine external carotid effects of 2-(2-aminoethyl)-quinoline (D-1997), a novel 5-HT1 receptor agonist, were analyzed and compared with those of 5-HT and sumatriptan. Intracarotid (i.c.) infusions of 5-HT, D-1997 and sumatriptan to vagosympathectomized dogs dose-dependently decreased external carotid conductance, the rank order of agonist potency being 5-HT > sumatriptan > D-1997. The effects to D-1997 were resistant to intravenous (i.v.) pretreatment with 5-HT2 and 5-HT3/5-HT4 receptor antagonists. Remarkably, the effects induced by lower (10-100 microg/min), but not higher (300-1000 microg/min), doses of D-1997 were blocked by high doses of methiothepin (1 and 3 mg/kg, i.v.), as previously shown with 5-HT. In addition, GR-127935 (1-10 microg/kg, i.v.), partially and dose-dependently antagonized D-1997-induced responses. However, the effects of D-1997 remained unaltered after blockade of alpha- and beta-adrenoceptors, muscarinic, nicotinic, histamine and dopamine receptors, or inhibition of 5-HT-uptake or cyclo-oxygenase, depletion of biogenic amines or blockade of Ca2+ channels. These results may support our previous contention that lower doses of 5-HT elicit external carotid vasoconstriction in vagosympathectomized dogs by activation of 5-HT1B/1D receptors, whilst higher doses of 5-HT stimulate a novel vasoconstrictor mechanism.

5-hydroxytryptamine inhibits pressor responses to preganglionic sympathetic nerve stimulation in pithed rats.

5-Hydroxytryptamine (5-HT) inhibits contractile responses to adrenergic nerve stimulation in several blood vessels and organs. We have now investigated the potential ability of 5-HT to inhibit the pressor responses caused by preganglionic sympathetic stimulation (T7-T9) in pithed rats. Sympathetic stimulation (0.03, 0.1, 0.3, 1 and 3 Hz) resulted in frequency-dependent increases in diastolic blood pressure; these effects were augmented after i.v. treatment with desipramine (50 micrograms/kg). During continuous infusions of 5-HT (1.8, 3.1, 5.6 and 10 micrograms/kg.min, i.v.), but not of saline, the pressor responses were dose-dependently inhibited in both control and desipramine-pretreated rats; this inhibitory effect of 5-HT was significantly more pronounced at lower frequencies of stimulation. In contrast, the above infusions of 5-HT did not inhibit the pressor responses induced by i.v. bolus injections of exogenous norepinephrine (up to 3 micrograms/kg). Taken together, the above findings suggest an operative 5-HT-induced prejunctional inhibition of sympathetic nerve activity on the systemic vasculature in vivo.

Effect of caffeine on antinociceptive action of ketoprofen in rats.

BACKGROUND: To assess a possible synergistic antinociceptive interaction, the antinociceptive effects of ketoprofen (KET), and caffeine (CAF) administered either separately or in combinations were determined in a model of arthritic pain. METHODS: Antinociceptive activity was assayed using "ellipsis pain-induced functional impairment in the rat" (PIFIR model). The antinociceptive efficacies were evaluated using several dose-response curves and time courses. The antinociceptive effects from the combination that produced the greater effect were compared with the maximal antinociceptive effect of either morphine, acetylsalicylic acid (ASA), or KET alone. The animals were administered with 0.05 mL intra-articular (i.a.) of uric acid to induce nociception. Groups of six rats received orally either ASA, morphine (MOR), KET, CAF, or a combination KET + CAF (24 combinations). RESULTS: ASA (ED(50) 465.2 +/- 1.5 mg/kg), MOR (ED(50) 71.0 +/- 1.6 mg/kg), and KET (ED(50) 7.2 +/- 1.4 mg/kg) alone induced dose-dependent antinociception, whereas CAF alone showed no activity at the assayed doses. Nine combinations showed various degrees of potentiation (p <0.01), while the remainder exhibited the antinociceptive effect of KET only. Combinations of 17.8 mg/kg CAF with either 1.0, 1.8, 3.2, 5.6, or 10.0 mg/kg KET yielded the highest antinociceptive potentiations. For example, antinociceptive effect was 125.6 +/- 21.4 area units (au) with KET (3.2 mg/kg) alone, but the combination with CAF (17.8 mg/kg) showed 309.5 +/- 10.3 au. The median effective dose (ED(50)) of KET alone was 7.2 +/- 1.4 mg/kg, whereas the ED(50) of KET + CAF 17.8 mg/kg was 0.4 +/- 0.6 mg/kg: KET in the presence of CAF was approximately 18 times more potent than the analgesic drug without CAF. CONCLUSIONS: These results showed that CAF was able to potentiate the analgesia of KET, but only at selected dose combinations: CAF in the doses of 10.0 and 17.8 mg/kg was able to potentiate the analgesic effect of KET, the most efficacious drug combination being CAF 17.8 mg/kg + KET 3.2 mg/kg. The combination of analgesic drugs and CAF can produce better antinociceptive effects than the analgesic drug alone. This knowledge will permit the selection of the therapeutically most effective combination ratio of drugs, employing lower doses of each drug.

Usefulness of the pain-induced functional impairment model to relate plasma levels of analgesics to their efficacy in rats.

In this work we show that the pain-induced functional impairment model (PIFIR) can be used with cannulated rats as a useful procedure for pharmacokinetic/pharmacodynamic modelling. This model evaluates analgesia by measuring motor impairment of the right limb after intra-articular administration of uric acid. Time of contact with a rotating cylinder is referred to the control limb. We studied the pharmacokinetic and pharmacodynamics of naproxen after six peroral doses to Wistar rats, and we examined the adjuvant action of caffeine with naproxen. Surgery and blood sampling did not produce any difference on functional impairment either in rats without uric acid or in the dysfunction produced by uric acid. The relation between naproxen plasma concentration and the analgesic effect was obtained with few rats. Caffeine alone did not produce any significant modification in functional impairment but the co-administration significantly increased the effect of naproxen. Plasma levels of naproxen did not change when caffeine was co-administered. The PIFIR model with blood sampling is a suitable method for pharmacokinetic/pharmacodynamic relationship studies and is specially useful to characterize drug-drug interactions.

Evidence against the participation of mu- and kappa-opioid receptors in the analgesic activity of ketorolac in rats.

The possibility that activation of opioid receptors is involved in the analgesic activity of ketorolac was explored. The analgesic effects of ketorolac, of ketocyclazocine, the prototype kappa-agonist, and of morphine, the prototype mu-agonist, were assayed in the pain-induced functional impairment model in the rat. All three drugs induced a significant analgesic effect in this model. Naloxone was able to antagonize the effects of ketocyclazocine and morphine. However, the effect of ketorolac was not blocked by naloxone, although a high dose, 3.2 mg kg-1, capable of blocking kappa-receptors was used. It is concluded that activation of mu- or kappa-opioid receptors, by either a direct or an indirect mechanism, does not play a role in the analgesic activity of ketorolac.

Characterization of the analgesic effect of paracetamol and caffeine combinations in the pain-induced functional impairment model in the rat.

The analgesic activities of paracetamol (100, 178, 316 and 562 mg kg-1), caffeine (10, 18, 32 and 56 mg kg-1) and combinations of these doses were tested on a pain-induced functional impairment model in the rat. Dysfunction of the right hind limb was induced by an intra-articular injection of 30% uric acid in the knee. Drugs were given orally and the recovery of functionality over time was considered as an expression of analgesia. Paracetamol alone induced a dose-dependent analgesic effect whereas caffeine alone did not show any activity at the assayed doses. Combinations of 316 mg kg-1 paracetamol with either 10, 18, 32 or 56 mg kg-1 caffeine yielded analgesic effects significantly greater than that of paracetamol alone. The highest potentiation was observed with a paracetamol-caffeine mixture of 316-32 mg kg-1. Caffeine coadministration, however, did not significantly change paracetamol plasma levels. No potentiation was obtained with other combinations. Paracetamol plasma levels and analgesic effect observed with administration of 316 mg kg-1 paracetamol alone or 316-32 mg kg-1 of paracetamol-caffeine were fitted to the sigmoidal Emax model according to the Hill equation. The curves obtained were parallel, but that of the combination was shifted to the left. It is concluded that caffeine is able to potentiate the analgesic effect of paracetamol by a pharmacodynamic mechanism, but this only occurs at certain dose combinations.

Relationship between paracetamol plasma levels and its analgesic effect in the rat.

The relationship between plasma levels of paracetamol and its analgesic effect was studied in the rat using a model of pain-induced functional impairment (PIFI). Female Wistar rats received an intraarticular injection of 30% uric acid in the knee of the right hind limb, inducing its dysfunction. Animals then received oral paracetamol at doses of 178, 316 or 562 mg kg-1 and the recovery of functionality over time was considered as an expression of analgesia. Paracetamol plasma levels were determined by HPLC. Results showed that there is a direct relationship between paracetamol plasma levels and its analgesic effect that follows a sigmoidal model according to the Hill equation. The PIFI model appears to be a useful tool to establish pharmacokinetic/pharmacodynamic relationships for non-narcotic analgesics.

Determination of analgesic interaction between acetaminophen and d-propoxyphene obtained by means of the surface of synergistic interaction.

The analgesic effects of acetaminophen, p.o., (ACE) and d-propoxyphene, s.c., (PROP) administered either separately or in 24 different combinations were determined in a model of pain-induced functional impairment in the rat. This allowed us to detect the analgesic interaction profile of the combinations. Furthermore, we set out to determine the optimal degree of enhancement obtained with a specific combination of the above drugs by means of the surface of synergistic interaction (SSI) of the combinations. This parameter was calculated from the total analgesic effect produced by the combination after having subtracted the analgesic effect produced by each drug alone. The ED50s for ACE and PROP were 286.1 +/- 1.4 mg/kg and 66.3 +/- 1.2 mg/kg, respectively. Over the dose ranges used, the analgesic activities of both ACE and PROP tended to be smaller than those of their respective combinations. Furthermore, 11 combinations showed various degrees of enhancement (p<0.01), while the others (13) exhibited additive analgesic effects. The combination of ACE (562.3 mg/kg) and PROP (56.2 mg/kg) produced the maximum analgesic effect. However,5 combinations of ACE with PROP (177.8-56.2, 316.2-10.0, 316.2-17.8, 316.2-56.2 and 562.3-10.0 mg/kg) produced the highest enhancement. The SSI clearly showed which combination of these analgesic drugs produced the highest degree of enhancement in the rat. This study shows that a specific combination ratio of analgesic drugs can produce optimum enhancement of their analgesic effects.

Analysis of antinociceptive effects of flurbiprofen enantiomers in a rat model of arthritic pain.

The potential antinociceptive effects of the S(+)- and R(-)-enantiomers of flurbiprofen (SFB and RFB, respectively) were investigated when given intravenously to rats using the pain-induced functional impairment model in the rat (PIFIR), an animal model of arthritic pain. Groups of 6 rats received either vehicle or the enantiomer in turn and antinociception was determined by evaluating the dose-response curves over time. Although SFB and RFB produced dose-dependent effects with similar efficacy (SFB: 277.4 +/- 29.9 au and RFB: 293.5 +/- 20.1 au), the R(-)-enantiomer was unable to produce any antinociceptive action when assessed at the same dose ranges as SFB. It was necessary to increase the dose of RFB by 100 times to produce similar antinociception. Accordingly, S(+)-flurbiprofen was 100-fold more potent (ED50 = 0.33 +/- 0.13 mg/kg) than its antipode R(-)-(ED50 = 30.0 +/- 1.7 mg/kg). SFB generated from metabolic inversion (> 1%) after i.v. dosage of RFB, as well as impurities of SFB present in RFB preparations, tend to confirm the hypothesis that the efficacy of RFB achieved at 100 mg/kg, similar to that observed with 1 mg/kg of SFB, is attributable to SFB.

Evidence of mechanism of action of anti-inflammatory/antinociceptive activities of acacetin.

BACKGROUND: Acacetin is a bioflavonoid with pharmacological properties such as antinociceptive/anti-inflammatory activities. However, scientific evidence of its spectrum activity and mechanisms of action is unknown. METHODS: Acacetin administered via i.p. was assessed using several nociceptive experimental models such as the writhing test, the formalin test and carrageenan paw oedema in the thermal plantar tests (Hargreaves method) in mice, as well as the pain-induced functional impairment model in rat (PIFIR model). RESULTS: Acacetin produced a significant and dose-dependent inhibition of the writhes with an ED50 = 20 mg/kg. Furthermore, acacetin inhibited licking and shaking associated with nociceptive behaviour mainly in the inflammatory phase of the formalin test. No significant differences were observed in the plantar test in mice, but a minor response was obtained in the PIFIR model. Animals receiving pre-treatment of WAY100635 (0.1 mg/kg, s.c.), flumazenil (3 mg/kg, i.p.) or naloxone (1 mg/kg, i.p.) partially reduced the antinociceptive response of acacetin in the writhing test. Presence of the inhibitors in the NO-cGMP-K(+) channel pathway did not modify the antinociceptive effect of acacetin in the writhing or the formalin test. CONCLUSIONS: Our data showed that systemic administration of acacetin decreased visceral and inflammatory nociception and prevented the formalin-induced oedema. In the mechanism of the acacetin antinociceptive effect, 5-HT1A, GABA/BDZs and opioid receptors but not the NO-cGMP-K(+) channel pathway seem to be involved. The data presented prove acacetin to be potentially useful in the therapy of pain-related diseases.

Relationship between pharmacokinetics and the analgesic effect of ketorolac in the rat.

The relationship between the pharmacokinetic properties and the analgesic effect of ketorolac was evaluated with the pain-induced functional impairment model in the rat. Female Wistar rats were injected with uric acid in the knee of the right hind limb to produce dysfunction. Then, animals received an oral dose of 0.3, 1, 1.8, 3.2 or 5.6 mg/kg of ketorolac tromethamine and analgesic effect and blood concentration, determined by high-performance liquid chromatography, were evaluated at selected times for a period of 4 hr. Ketorolac produced a dose-dependent analgesic effect, measured as a recovery of the functionality of the injured limb, which reached its maximal effect at doses of 3.2 mg/kg or higher. When functionality index was plotted against ketorolac blood concentration, a direct relationship was observed that was well described by the sigmoidal maximal effect model. The data strongly suggest that ketorolac's analgesic effect depends on the blood concentration of the drug.

2-(2-Aminoethyl)-quinoline (D-1997): a novel agonist at 5-hydroxytryptamine1-like receptors in the canine basilar artery.

This study aimed to investigate the mechanisms involved in the contractile effects produced by the novel quinoline derivative, 2-(2-aminoethyl)-quinoline (D-1997), in the canine isolated basilar artery. For comparison, the effects of D-1997 were also evaluated on rat aorta. Canine basilar artery and rat aortic rings were prepared and mounted in organ baths to record isometric tension changes. The contractile effects of D-1997 in the basilar artery were compared with those produced by 5-hydroxytryptamine (5-HT) and the 5-HT receptor agonist quipazine. Thus, 4-HT (10(-10)-10(-6)M), D-1997 (3.1 x 10(-8)-10(-4) M) and quipazine (3.1 x 10(-7)-10(-4) M) each caused concentration-dependent contractions of the canine basilar artery with a rank order of agonist potency of 5-HT > D-1997 > quipazine. 5-HT and D-1997 exhibited similar maximum effects which were higher than that of quipazine. Similar concentrations of D-1997 failed to produce contraction in rat aorta. The effects of D-1997 in the basilar artery were not modified by incubation with either the 5-HT2 receptor antagonist ketanserin (0.01-1 microM), the 5-HT3 and 5-HT4 receptor antagonist ICS205930 (tropisetron; 0.1-10 microM), the 5-HT1A receptor antagonist spiroxatrine (0.01-1 microM), the beta-adrenoceptor blocker with high affinity for 5-HT1A and 5-HT1B binding sites (+/-)-pindolol (0.01-1 microM), or the alpha 1-adrenoceptor antagonist prazosin (0.01-1 microM). In contrast, the D-1997-induced responses were potently and concentration-dependently antagonized by the mixed 5-HT1-like and 5-HT2 receptor antagonist methiothepin (0.01-1 microM). It is concluded that D-1997 contracts the canine basilar artery by stimulating 5-HT1-like receptors unrelated to either the 5-HT1A or 5-HT1B receptor subtypes. The compound seems to be devoid of 5-HT2 receptor agonist properties in rat aorta.