Pharmacokinetics and Pharmacodynamics of (S)-Ketoprofen Co-Administered with Caffeine: A Preclinical Study in Arthritic Rats.

The purpose of the present study was to determine whether caffeine modifies the pharmacokinetics and pharmacodynamics of (S)-ketoprofen following oral administration in a gout-type pain model. 3.2 mg/kg of (S)-ketoprofen alone and combined with 17.8 mg/kg of caffeine were administered to Wistar rats and plasma levels were determined between 0.5 and 24.0 h. Additionally, antinociception was evaluated based on the protocol of the PIFIR (pain-induced functional impairment in the rat) model before blood sampling between 0.5 and 4.0 h. Significant differences in Cmax, AUC0-24, and AUC0-∞ values were observed with caffeine administration (p < 0.05). Also, significant differences in Emax, Tmax, and AUC0-4 values were determined when comparing the treatments with and without caffeine (p < 0.05). By relating the pharmacokinetic and pharmacodynamic data, a counter-clockwise hysteresis loop was observed regardless of the administration of caffeine. When the relationship between AUCe and AUCp was fitted to the sigmoidal Emax model, a satisfactory correlation was found (R² > 0.99) as well as significant differences in Emax and EC50 values (p < 0.05). With caffeine, Emax and EC50 values changed by 489.5% and 695.4%, respectively. The combination studied represents a convenient alternative for the treatment of pain when considering the advantages offered by using drugs with different mechanisms of action.

Antihyperalgesic Effect of Hesperidin Improves with Diosmin in Experimental Neuropathic Pain.

Neuropathic pain is caused by a primary lesion, dysfunction, or transitory perturbation in the peripheral or central nervous system. In this study, we investigated the hesperidin antihyperalgesic effects alone or combined with diosmin in a model of neuropathic pain to corroborate a possible synergistic antinociceptive activity. Mechanical and thermal hyperalgesia were assessed in the aesthesiometer and plantar tests, respectively, after chronic constriction injury (CCI) model in rats receiving hesperidin (HS, 5 doses from 10 to 1000 mg/kg) alone or combined with diosmin (DS, 10 and 100 mg/kg) in comparison to gabapentin (31.6 mg/kg). UHPLC-MS analysis of cerebral samples was used to recognize the central concentrations of these flavonoids. Participation of different receptors was also investigated in the presence of haloperidol, bicuculline, and naloxone antagonists. Acute hesperidin administration significantly decreased mechanical and thermal hyperalgesia in CCI rats. Antihyperalgesic response of hesperidin, improved by a combination with diosmin (DS10/HS100) in both stimuli, was blockaded by haloperidol, bicuculline, and naloxone, but not WAY100635, antagonists. Both flavonoids were detected in brain samples. In conclusion, hesperidin alone and combined with diosmin produces antihyperalgesic response in the CCI model in rats. Antihyperalgesic effect of DS10/HS100 combination involves central activity partially modulated by D2, GABAA, and opioids, but not by 5-HT1A, receptors.

Endogenous opioids participation in the effect of Rosmarinus officinalis L. in the visceral, inflammatory and gout arthritis nociception in rodents / Participación de los opioides endógenos en el efecto de Rosmarinus officinalis L. en la nocicepción visceral, inflamatoria y artritis gotosa en roedores

The aim of this study was to investigate the endogenous opioid participation in the antinociceptive effect of R. officinalis aerial parts in experimental models of visceral, inflammatory and gout arthritis nociception. Acid-acetic induced writhing and formalin tests as well as the pain-induced functional impairment model in the rat (PIFIR) assay were studied. Antinociceptive doses of R. officinalis via oral, alone and in presence of an opioid antagonist were evaluated in comparison to the reference analgesic drug tramadol (31.6 and 50mg/kg i.p., in mice and rats, respectively). The antinociceptive effect of R. officinalis at a 300mg/kg dosage was significantly reverted in presence of 1.0mg/ kg s.c. of naloxone in writhing and formalin tests. Concerning PIFIR model, significant antinociceptive response produced for 1000 and 3000mg/kg was not inhibited in presence of 1.0 or 3.16mg/kg, s.c. of naloxone. In the antinociceptive effect of tramadol, naloxone produced partial inhibition in all models tested. These results suggest that antinociceptive and anti-inflammatory activities of R. officinalis aerial parts involve endogenous opioids, but activation of these mediators depends on the experimental model and the physiological process of the induced nociception.

El objetivo de este estudio fue investigar la participación de los opioides endógenos en el efecto antinociceptivo producido por un extracto preparado con las partes aéreas de Rosmarinus officinalis en modelos experimentales de nocicepción visceral, inflamatoria y tipo artritis gotosa. Para la inducción de nocicepción visceral e inflamatoria se utilizaron los modelos de estiramiento abdominal "writhing" y de formalina intraplantar al 1 %, respectivamente, en ratones. A su vez, para la nocicepción de tipo artritis gotosa se utilizó el modelo de disfunción inducida por ácido úrico al 20% intraarticular en ratas conocido como PIFIR (por sus siglas en inglés). Dosis antinociceptivas de R. officinalis vía oral se evaluaron solas y en presencia del antagonista de opioides endógenos naloxona. Adicionalmente, dicho efecto se comparó con el fármaco analgésico de referencia tramadol (31.6 y 50mg/kg i.p., en ratones y ratas, respectivamente). El efecto antinociceptivo de R. officinalis significativo en la dosis de 300mg/kg se revirtió en presencia de 1mg/kg s.c. de naloxona en las pruebas de estiramiento abdominal y formalina. En cuanto al modelo PIFIR, la respuesta antinociceptiva producida por 1000 y 3000mg/kg no se inhibió en presencia de 1 o 3.16mg/kg, s.c. de naloxona. En el efecto de tramadol, opioide atípico, la naloxona produjo inhibición parcial de la respuesta antinociceptiva en todos los modelos probados. Los resultados sugieren que la actividad antinociceptiva producida por el extracto de las partes aéreas de R. officinalis involucra al sistema de opioides endógenos, pero la presencia de estos mediadores depende del tipo de estímulo y del proceso fisiológico involucrado en la nocicepción inducida.

Anti-nociceptive and anti-inflammatory activities of the Agastache mexicana extracts by using several experimental models in rodents.

ETHNOPHARMACOLOGICAL RELEVANCE: Agastache mexicana is a plant that has long been used in large demand in Mexican folk medicine to treat pain, among others affections. Nevertheless, no scientific data confirming its use have been reported. The aim of this investigation was to examine the spectrum of antinociceptive activity of A. mexicana by using different experimental models of nociception in rodents. MATERIAL AND METHODS: Nociceptive activity was induced 30 min post treatment of different doses of hexane, ethyl acetate and methanol extracts from A. mexicana aerial parts. The writhing test in mice, and the formalin and plantar tests as well as the pain-induced functional impairment assay in rats (PIFIR model) were the experimental nociceptive models used. Antinociceptive response of the organic extracts was compared to that observed with the analgesic drug tramadol. RESULTS: A. mexicana organic extracts produced a dose-dependent and significant inhibition of the abdominal constrictions caused by 1% acetic acid injection (i.p.) in mice. A maximal antinociceptive effectiveness obtained with tramadol was also observed with the administration of hexane and ethyl acetate extracts in comparison to less effectiveness obtained with the methanol extract. At the same range of doses, A. mexicana organic extracts inhibited the behavioral responses in both phases of the formalin pain test, in which a more intense effect was observed in the inflammatory phase than in the neurogenic stage. With regard to the plantar test and PIFIR model, a significant but not dose-dependent antinociceptive response was observed at specific doses that depended on the organic extract evaluated. CONCLUSION: The antinociceptive activity of A. mexicana aerial parts depends on the intensity of the painful stimulus induced and involves different kinds of constituents. Our present results reinforce the use of this species in traditional medicine and its utility for pain treatment mainly associated with inflammation.

Hesperidin produces antinociceptive response and synergistic interaction with ketorolac in an arthritic gout-type pain in rats.

Hesperidin occurs in greatest concentration in plants from the Rutaceae and Lamiaceae families. In human nutrition it contributes to the integrity of blood vessels and its deficiency in the diet has been linked to abnormal capillary leakiness as well as pain. In this study, the bioflavonoid hesperidin was identified as an active compound in an ethanol extract of the Rosmarinus officinalis aerial parts tested in the pain-induced functional impairment model in the rat (PIFIR) as an assay of inflammatory and chronic nociception similar to that observed in clinical gout. Hesperidin produced a dose-dependent and significant response with an ED25=1666.72 mg/kg in comparison to an ED25=302.90 mg/kg for the extract or an ED25=0.47 mg/kg for the reference drug ketorolac in the PIFIR model. Although the antinociceptive response of R. officinalis was reverted in presence of the opioid antagonist naloxone (10 mg/kg, s.c.) and the 5HT(1A) antagonist WAY100635 (0.12 mg/kg, s.c.), the hesperidin response was not modified by naloxone (10 mg/kg), WAY100635 (0.12 mg/kg), bicuculline (1 mg/kg, s.c.), flumazenil (10 mg/kg, i.p.) or caffeine (1 mg/kg, s.c.). Nevertheless, it was reduced in presence of capsazepine (10 or 20 mg/kg, s.c.) suggesting the participation of the TRPV1 receptor, which was reinforced when hesperidin significantly reduced the capsaicin-induced nociceptive response. A synergistic interaction was also observed when antinociceptive doses of hesperidin were combined with those of ketorolac producing 15 combinations mainly in additive and supra-additive responses. These results provide evidence for the antinociceptive activity of hesperidin and demonstrate synergistic response when combined with ketorolac, possibly by involvement of the TRPV1 receptor, suggesting their clinical potential in pain therapy.

Insular cortex lesion diminishes neuropathic and inflammatory pain-like behaviours.

Injury to the insular cortex in humans produces a lack of appropriate response to pain. Also, there is controversial evidence on the lateralization of pain modulation. The aim of this study was to test the effect of insular cortex lesions in three models of pain in the rat. An ipsilateral, contralateral or bilateral radiofrequency lesion of the rostral agranular insular cortex (RAIC) was performed 48h prior to acute, inflammatory or neuropathic pain models in all the experimental groups. Acute pain was tested with paw withdrawal latency (PWL) after thermal stimulation. Inflammation was induced with carrageenan injected in the paw and PWL was tested 1h and 24h afterwards. Neuropathic pain was tested after ligature of the sciatic nerve by measuring mechanical nociceptive response after stimulation with the von Frey filaments. Another model of neuropathy consisted of thermo stimulation followed by right sciatic neurectomy prior to the recording of autotomy behaviour. Acute pain was not modified by the RAIC lesion. All the RAIC lesion groups showed diminished pain-related behaviours in inflammatory (increased PWL) and neuropathic models (diminished mechanical nociceptive response and autotomy score). The lesion of the RAIC produces a significant decrease in pain-related behaviours, regardless of the side of the lesion. This is a clear evidence that the RAIC plays an important role in the modulation of both inflammatory and neuropathic - but not acute - pain.

Antinociceptive activity of Annona diversifolia Saff. leaf extracts and palmitone as a bioactive compound.

Annonas are consumed as fresh fruits, but are also widely used in folk medicine for treating pain and other ailments. Antinociceptive properties of the Annona diversifolia ethanol crude extract were tested using the pain-induced functional impairment model in rat (PIFIR) and the writhing test in mice. The ethanol extract caused a 25% recovery of limb function in rats; this response was significant and dose-dependent. Furthermore, this extract produced a similar antinociceptive response (ED(50)=15.35 mg/kg) to that of the reference drug tramadol (ED(50)=12.42 mg/kg) when evaluated in the writhing test in mice. Bio-guided fractionation yielded hexane and acetone active fractions from which the presence of palmitone and flavonoids was respectively detected. Palmitone produced an antinociceptive response with an ED(50)=19.57 mg/kg in the writhing test. Antinociceptive responses from ethanol extract and tramadol were inhibited in the presence of either naloxone (1mg/kg, s.c.)--an antagonist of endogenous opioids--or WAY100635 (0.8 mg/kg, s.c.)--a 5-HT(1A) serotonin receptor antagonist. These results provide evidence that A. diversifolia possesses antinociceptive activity, giving support to their traditional use for treatment of spasmodic and arthritic pain. In addition, our results suggest the participation of endogenous opioids and 5-HT(1A) receptors in this antinociceptive response.

D-propoxyphene and dipyrone co-administration produces greater antinociception and fewer adverse effects than single treatments in rats.

D-propoxyphene is a commonly prescribed opiate analgesic. Its use is limited by unwanted side effects at high doses and tolerance development after chronic administration. Dipyrone (also known as metamizol) is a non-steroidal anti-inflammatory drug extensively used in Latin America and Europe. The objective of this work was to evaluate the antinociceptive efficacy of a dipyrone/D-propoxyphene combination and the development of tolerance to its repeated administration in the tail flick test in rats. Male Wistar rats (200+/-20 g) were i.v. injected twice daily (8 h apart) with 0.31 mg/kg D-propoxyphene, 400 mg/kg dipyrone, or the combination of these drugs, at the same doses, until complete tolerance was observed. A time course of the effects for each administration was determined. At the doses tested, D-propoxyphene and dipyrone produced mild antinociception per se. Repeated administration resulted in complete tolerance to their antinociceptive effects by the sixth dose. The D-propoxyphene/dipyrone combination produced more antinociception than expected by the sum of individual drug effects. With this treatment, tolerance developed at the 15th administration. In animals already tolerant to D-propoxyphene or dipyrone alone, subsequent administration of the combination partially restored the antinociceptive effect. These results suggest that the use of this combination provides advantages over single drug therapies.

Antinociceptive effect and GC/MS analysis of Rosmarinus officinalis L. essential oil from its aerial parts.

The rationale of this investigation was to examine the antinociceptive properties of the essential oil obtained from Rosmarinus officinalis aerial parts, using a rat model of arthritic pain. The essential oil (100, 300 and 600 mg/kg, I. P.) produced a dose-dependent antinociceptive effect, manifested as a significant reduction in the dysfunction in the pain-induced functional impairment model in the rat (PIFIR model), mainly at high doses. Chemical constituents of the essential oil were further analyzed by gas chromatography-mass spectrometry (GC/MS). The major compounds in the essential oil were alpha-pinene (14.10 %), camphene (11.47 %), beta-pinene (12.02 %), myrcene (3.31 %), alpha-phellandrene (7.87 %), eucalyptol (8.58 %), 2-bornanone (3.42 %), camphor (8.75 %), isoborneol (3.48 %), borneol (4.85 %) and borneol acetate (6.49 %). The antinociceptive effects of R. officinalis essential oil were tested in combination with 0.12 mg/kg WAY100635, s. c. (an antagonist of 5-HT(1A) receptors) or 1 mg/kg naloxone, i. p. (an antagonist of endogenous opioids receptors), demonstrating in both cases an inhibition of the antinociceptive response. This study suggests an involvement, at least in part, of the serotonergic system via 5-HT(1A) receptors and endogenous opioids in the antinociceptive effect of R. officinalis essential oil in the PIFIR model.

Absence of histological changes after the administration of a continuous intrathecal clonidine in Wistar rats.

BACKGROUND: The administration of epidural and spinal clonidine has demonstrated an antinociceptive effect in animals and humans. For that reason, its spinal administration has been proposed as an adjuvant in chronic pain management. However, there is limited information about its possible neurotoxic effect after its continuous neuraxial administration. METHOD: Twelve male Wistar rats were randomly divided into two groups. Using an osmotic mini-pump a continuous infusion of intrathecal clonidine, (21.4 micrograms/day, Group A) or saline solution (Group B), was administered for 14 consecutive days. For evaluating the neurological damage a neuropathological analysis of the spinal cord was performed by light microscopy. RESULTS: Neurohistopathologic examination of the spinal cord specimens failed to show evidence of neurotoxic damage in either group. CONCLUSIONS: These findings showed that continuous intrathecal administration of clonidine did not produce evidence of histological neurotoxicity; therefore it is possible that continuous administration of intrathecal clonidine might be a safe option for treatment of chronic intractable pain; however, further investigations are necessary for evaluating diverse doses and periods of time, and to define its possible behavioral effects.

Antinociceptive activity of Tilia americana var. mexicana inflorescences and quercetin in the formalin test and in an arthritic pain model in rats.

Tilia species are well known around the world for their properties in traditional medicine. Antinociceptive activity of hexane, methanol and aqueous extracts from Tilia americana var. mexicana inflorescences was evaluated in the pain-induced functional impairment model in rats (PIFIR). A preliminar 300 mg/kg dosage of aqueous extracts i.p., but not the same dose of methanol or hexane extract, produced an antinociceptive response in rats similar to that of tramadol (17.8 mg/kg i.p.). A dose-response curve from aqueous extract allowed the determination of ED(50) = 364.97 mg/kg in comparison to ED(50) = 10.35 mg/kg for tramadol in this model. A previous HPLC-DAD analysis corroborated by an HPLC-MS technique in this study demonstrated the flavonoid composition in this Tilia aqueous extract revealing the presence of glycosides mainly derived from quercetin. Thus, Tilia aqueous extract and quercetin were tested at 30 and/or 100 mg/kg dosages i.p. in the PIFIR and formalin models producing a significant and dose-dependent antinociceptive response resembling that produced by a total and a partial agonist of 5-HT(1A) receptors like 8-OH-DPAT (0.1 mg/kg, s.c.) and buspirone (5 mg/kg, i.p.), respectively. In all the treatments, antinociceptive response was inhibited in the presence of WAY 100635 (0.12 mg/kg, i.p.). Our results support the analgesic activity of T. americana var. mexicana inflorescences attributed by folk medicine; they also indicate that quercetin is partly responsible for this pharmacological activity that is likely mediated by serotonin 5-HT(1A) receptors.

Effect of acute gouty arthritis on sleep patterns: a preclinical study.

BACKGROUND: It has been demonstrated that the interrelation between pain and sleep produces changes in sleep patterns and pain perception. Although some evidences suggest that sleep and pain may interact in a complex way, polysomnographic studies in animals with acute nociception are limited in number. AIMS: This study was carried out in order to evaluate the effect of intra-articular knee injection of uric acid on sleep-wake patterns. METHODS: Surgical electrode implantation was performed in seven anesthetized Wistar rats to carry out 10 h polysomnographic recordings. Acute nociception was induced by the intra-articular administration of 30% uric acid crystals into the knee joint of the right hind limb. Two recordings before and after intra-articular drug administration were obtained. Sleep-wake parameters were classified as (i) wakefulness (W), (ii) slow wave sleep (SWS), and (iii) rapid eye movement (REM) sleep. Frequency and duration from each parameter were evaluated under the two above-mentioned conditions. RESULTS: Intra-articular administration of uric acid induced: (i) an increased duration of wakefulness (p=0.014), (ii) a decrement in the duration (p=0.001) and number of events (p=0.027) in REM sleep, and (iii) a decrement in the total sleep time (p=0.001). SWS did not present statistical differences between groups. CONCLUSIONS: These data suggest that a nociceptive stimulus, induced by the intra-articular administration of uric acid, alters the sleep-wake equilibrium with REM sleep being particularly altered. However, further research concerning pain-sleep interaction is needed.

Pharmacological study of antispasmodic activity of Mirabilis jalapa Linn flowers.

INTRODUCTION: Mirabilis jalapa Linn is a well-studied plant. The indigenous people of Mexico use Mirabilis jalapa to cure many infirmities including dysentery, diarrhea, muscular pain and abdominal colic. In the present investigation, we have further characterized some pharmacological properties of an extract of Mirabilis jalapa flowers; therefore, we intend to contribute to understand the pharmacological effects and clarify the complex use of this medicinal plant. RESULTS: The extract of Mirabilis jalapa (1-1000 mug/mL) exhibits an inhibitory effect (IC(50)=18+/-0.7 micorg/mL) on gut smooth muscle contractility whereas it stimulates the contraction of rabbit aortic muscle (EC(50)=11.60+/-0.26 micorg/mL) in a concentration-dependent manner. CONCLUSIONS: These effects were not due to either ACh or HIS receptors blockage, IP(3), cAMP, cGMP, Ca(2+) release from intracellular storage, or protein kinase mediated contraction-relaxation mechanisms. The effects inducted by the Mirabilis jalapa extract may involve a serotoninergic mechanism, which, in turn, interacts with other adrenergic systems. Further studies are necessary to identify the active compounds within the extract and to elucidate the mechanism of action.

Dopamine receptors in the anterior insular cortex modulate long-term nociception in the rat.

The rostral agranular insular cortex (RAIC) receives dopaminergic projections from the mesolimbic system, which has been involved in the modulation of nociceptive processes. In this study we determined the contribution of dopamine D(1) and D(2) receptors in the RAIC regarding nociception processing in a neuropathic pain model, as well as inflammatory articular nociception measured as pain-induced functional impairment in the rat (PIFIR). Microinjection of vehicle or substances into the RAIC was performed after the induction of nociception. The groups were treated with: a dopamine D(1) receptor antagonist (SCH-23390), a dopamine D(1) receptor agonist (SKF-38393), a dopamine D(2) receptor agonist (TNPA) and a dopamine D(2) receptor antagonist (spiperone). Chronic nociception, induced by denervation, was measured by the autotomy score in which onset and incidence were also determined. The SCH-23390 and TNPA groups showed a decrease in the autotomy score and a delay on the onset as compared to control, whereas the PIFIR groups did not show statistical differences. This work shows the differential role of dopamine receptors within the RAIC in which the activation of D(2) or the blockade of D(1) receptors elicit antinociception.

Chronic subarachnoid administration of 1-(4chlorobenzoyl)-5methoxy-2methyl-1H-indole-3 acetic acid (indomethacin): an evaluation of its neurotoxic effects in an animal model.

Neuraxial administration of nonsteroid antiinflammatory drugs has been suggested as an alternative in the management of intractable pain, but there is little evidence that the neurotoxic effects of indomethacin by this route of administration have been evaluated. In this study, we evaluated histological neurotoxicity of indomethacin after its subarachnoid administration in guinea pigs. The hypothesis tested was "Does subarachnoid administration of indomethacin produce damage in the spinal cord of guinea pigs?" Ten male guinea pigs were anesthetized, and a polyamide catheter connected to a subcutaneous osmotic micro-pump was implanted at the L2-3 level. Animals were randomly assigned in 2 groups of 5 animals each. Indomethacin or saline solution was administered by continuous infusion (0.5 microL/h) for 14 days. Neurotoxicity was determined by spinal cord histopathology. There was no evidence of toxicity in the histological examinations of either group. These data suggest that subarachnoid administration of indomethacin infusion, at these doses, did not produce lesions typical of neurotoxicity in the spinal cord. We have concluded that epidural administration of indomethacin may be considered an alternative for application in human pain management, although more studies to determine its safety are required.

Peripheral involvement of the nitric oxide-cGMP pathway in the indomethacin-induced antinociception in rat.

The role of nitric oxide (NO) in the antinociceptive effect of indomethacin was assessed in the pain-induced functional impairment model in the rat (PIFIR model), a model of inflammatory and chronic pain similar to that observed in clinical gout. Oral administration of indomethacin (5.6 mg/kg), a nonselective cyclooxygenase inhibitor, significantly decreased the nociceptive response elicited by uric acid injected into the knee joint of the right hind limb (2.0+/-3.0 and 149.7+/-18.0 area units [au], in the absence and the presence of indomethacin, respectively). This effect of indomethacin was reduced in nearly 50% by local pretreatment with the nonselective inhibitor of NO synthase, N G-L-nitro-arginine methyl ester (L-NAME) (72.9+/-10.7 vs. 149.7+/-18.0 au, P<0.05). On the other hand, local administration of L-arginine (a NO synthase substrate) or sodium nitroprusside (a non-enzymatic NO donor) each increased in almost 40% the antinociceptive effect of indomethacin (230.9+/-12.6 and 226.6+/-9.7 vs. 149.7+/-18.0 au, P<0.05), whereas D-arginine (the inactive isomer of arginine) had no effect on the indomethacin antinociceptive response (208.0+/-34.9 vs. 149.7+/-18.0 au). These results suggest that, the antinociceptive effect of indomethacin involves, at least in part, the NO-cyclic GMP pathway at peripheral level.

Participation of the L-arginine-nitric oxide-cyclic GMP-ATP-sensitive K+ channel cascade in the antinociceptive effect of rofecoxib.

The antinociceptive effect of rofecoxib, a preferential inhibitor of cyclooxygenase-2, was assessed in the pain-induced functional impairment model in the rat. Systemic administration of rofecoxib generated a dose-dependent antinociceptive effect in rats injected with uric acid into the knee joint of the right hindlimb in order to produce nociception. Ipsilateral intra-articular pretreatment with N(G)-L-nitro-arginine methyl ester (L-NAME, an inhibitor of nitric oxide (NO) synthesis), 1H-(1,2,4)-oxadiazolo (4,2-a)quinoxalin-1-one (ODQ, an inhibitor soluble guanylyl cyclase), and the ATP-sensitive potassium channel blocker glibenclamide reversed the antinociceptive effect of rofecoxib p.o. However, ipsilateral intra-articular pretreatment with L-arginine (a NO substrate), or 3-morpholino-sydnonimine-HCl (SIN-1, a non-enzymatic donor of NO), potentiated the antinociceptive effect induced by rofecoxib. The present results suggest that, in addition to cyclooxygenase-2 inhibition, the antinociceptive effect of rofecoxib could also involve activation of the L-arginine-NO-cyclic GMP (cGMP) pathway, followed by opening of ATP-sensitive K+ channels at the peripheral level.

Morphine and dipyrone co-administration delays tolerance development and potentiates antinociception.

This work analyses the time course of tolerance development and antinociceptive potentiation throughout repeated co-administration of morphine (an opioid receptor agonist) plus dipyrone (a non-steroidal anti-inflammatory drug) in the tail-flick test. Male Wistar rats were i.v. injected with morphine (3.1 mg/kg), dipyrone (600 mg/kg) or the combination morphine/dipyrone twice a day for 5 days. Dipyrone produced antinociceptive effects with a trend towards tolerance development at the end of the treatment. Morphine was initially effective, but complete tolerance developed after its fifth administration. The combination of morphine plus dipyrone produced a significant potentiation and longer duration of antinociceptive effects. The antinociceptive efficacy of morphine and dipyrone co-administration gradually decreased after the sixth injection. An additional group of rats treated with dipyrone for 11 days developed complete tolerance after the 19th administration. These data suggest that repeated co-administration of morphine plus dipyrone results in a delay of tolerance development and in a potentiation of their individual antinociceptive effects.

Enhancement of antinociception by co-administration of an opioid drug (morphine) and a preferential cyclooxygenase-2 inhibitor (rofecoxib) in rats.

Synergism has been used to obtain analgesia at doses at which side effects are minimal. In addition, it has been demonstrated that inhibition of cyclooxygenase-2 is responsible for the therapeutic effects of nonsteroidal anti-inflammatory drugs (NSAIDs). The aim of this study was to evaluate the antinociceptive interaction between the preferential COX-2 inhibitor, rofecoxib and morphine. Several combinations were evaluated using the pain-induced functional impairment model (PIFIR), a rat model of arthritic pain. Surface of synergistic interaction (SSI) analysis and an isobolographic method were used to detect the antinociceptive potency of the drugs, given either individually or in combination. The surface of synergistic interaction was calculated from the total antinociceptive effect produced by the combination after subtraction of the antinociceptive effect produced by each individual drug. Male rats received orally morphine alone (10, 17.8, 31.6, 56.2 and 100.0 mg/kg), rofecoxib alone (3.2, 5.6, 10, 31.6, 56.2 and 74.0 mg/kg) or 12 different combinations of morphine and rofecoxib. Three combinations exhibited potentiation of antinociceptive effects (10 mg/kg of morphine with either 5.6, 10 or 31.6 mg/kg of rofecoxib), whereas the other nine combinations showed additive antinociceptive effects. The combination of morphine, 56.2 mg/kg (p.o.), and rofecoxib, 31.6 mg/kg (p.o.), produced the maximum antinociceptive effect (P<0.05). This combination caused gastric injuries less severe than those observed with indomethacin, i.e. it reduced ulcers and erosion formation. The synergistic antinociceptive effects of rofecoxib and morphine are important and suggest that combinations with drugs may decrease the side effects associated with the use of nonselective NSAIDs. Furthermore, the present results suggest that combinations containing opioid drugs and selective COX-2 inhibitors may have clinical utility in pain therapy.