Risperidone in analgesia induced by paracetamol and meloxicam in experimental pain.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the best therapeutic options to treat pain. Their use in combination with other drugs may broaden their applicability in analgesia if their ceiling and adverse effects are reduced. The aim of this study was to evaluate the pharmacological interaction of two NSAIDs, paracetamol and meloxicam, with the antipsychotic drug risperidone in mice, in several experimental tests of nociceptive and inflammatory pain. Antinociception was assessed by dose-response curves to paracetamol and meloxicam before and after the i.p. administration of 0.5 mg/kg of risperidone. Results are presented as means ± SEM and differences were calculated by one-way ANOVA followed by Tukey's post-test. Paracetamol and meloxicam produced a dose-related antinociceptive effect with diverse potencies. Risperidone increased the analgesia mediated by paracetamol and meloxicam only in the tonic tests that detected inflammatory pain. This suggests that COX inhibition is only a partial explanation of the increased analgesic potency of paracetamol and meloxicam since the effects of NSAIDs in the CNS are mediated by multiple mechanisms. These results indicate that the combination of risperidone with paracetamol or meloxicam could be a new and effective alternative for the management of inflammatory pain.

The Antinociceptive Activities of Certain NSAIDS Combinations in Murine Orofacial Test.

Pain models are mostly in rodents and between them formalin orofacial test allow discrimination among antinociception and anti-inflammation. This assay use a formalin solution injected into the upper right lip of each mouse which produces two periods of pain separated by an inactive period. The aims of the present study were to evaluate, by means of the isobolographic analysis, the antinociception and anti-inflammatory activities of the following NSAIDs: dexketoprofen, diclofenac, piroxicam and metamizole in an orofacial. The NSAIDs administered intraperitoneally produced a dose-dependent activity with the following order of potency of the rubbing behavior, in phase I: diclofenac>dexketoprofen>piroxicam>metamizole and in the phase II: metamizole>diclofenac>piroxicam>dexketoprofen. The coadministration of NSAIDs resulted in a synergistic interaction, which according to the value of the potency of the combination (II) presents the following range: dexketoprofen plus metamizole>dexketoprofen plus diclofenac>dexketoprofen plus piroxicam, in phase I and dexketoprofen plus metamizole>dexketoprofen plus piroxicam>dexketoprofen plus diclofenac, on the phase II. Data obtained in this work corroborate that NSAIDs alone or in combination inducing activities by additional mechanism of action supplementary to inhibition of COXs. This fact represent a novel approach that could be used as multimodal management of orofacial pain, since with this treatment strategies, by the reduction of doses, can help to diminish side effects of other dugs such opioids.

Involvement of NO in Antinociception of NSAIDS in Murine Formalin Hind Paw Assay.

There are different animal models to evaluate pain among them the formalin hind paw assay which is widely used since some of its events appear to be similar to the clinical pain of humans. The assay in which a dilute solution of formalin is injected into the dorsal hindpaw of a murine produces two 'phases' of pain behavior separated by a inactive period. The early phase (Phase I) is probably due to direct activation of nociceptors and the second phase (Phase II) is due to ongoing inflammatory input and central sensitization. Mice were used to determine the potency antinociceptive of piroxicam (1,3,10,and 30 mg/kg), parecoxib (0.3, 1,3,10 and 30 mg/kg), dexketoprofen (3,10,30 and 100 mg/kg) and ketoprofen (3,10,30 and 100 mg/kg). Dose-response for each NSAIDs were created before and after 5 mg/kg of L-NAME i.p. or 5 mg/kg i.p. of 7-nitroindazole. A least-squares linear regression analysis of the log dose-response curves allowed the calculation of the dose that produced 50% of antinociception (ED50) for each drug. The ED50 demonstrated the following rank order of potency, in the phase I: piroxicam > dexketoprofen > ketoprofen > parecoxib and in the phase II: piroxicam > ketoprofen > parecoxib > dexketoprofen. Pretreatment of the mice with L-NAME or 7-nitroindazol induced a significant increase of the analgesic power of the NSAIDs, with a significant reduction of the ED50. It is suggested that NO may be involved in both phases of the trial, which means that nitric oxide regulates the bioactivity of NSAIDs.

Nitric Oxide and Opioids Involvement in Isobolographic Nsaids Antinociception.

Different NSAIDs are used as antinociceptive in various analgesic assays, among which should be mentioned: ibuprofen, ketorolac , ketoprofen, meloxicam , paracetamol and others. It has been shown that NSAIDs possess antinociceptive activity by blocking cyclooxygenase enzymes (COXs). The present study was designed to evaluate the possible involvement of the nitridergic pathway due to L-NAME and the opioidergic route by NTX in the antinoception induced by NSAIDs using a murine pain model the tail flick test in an automatic tail flick algesiometer. The antinociception was evaluated by means of isobolographic analysis. The interaction between the combination of NSAIDs, via i.p., on basis of their ED25, demonstrated that the coadministration of the drugs were synergistic with the exception of the lack of effect in combination of meloxicam with ibuprofen and with ketorolac, since the result was additive. These data validate that the NSAIDs administered alone or in combinations produce antinociception in which other mechanisms of action must be added to the simple inhibition of COXs. In addition, the pretreatment of the mice with L-NAME and NTX does not change previous isobolographic parameters of the mixture of NSAIDs.

Non-steroidal Anti-inflammatory Drugs in Tonic, Phasic and Inflammatory Mouse Models.

The principal mechanism of action of non-steroidal anti-inflammatory drugs (NSAIDs) is the inhibition of ciclooxigenases. In this study was evaluated if NSAIDs could induce antinociceptive differences according to the type of murine pain model. Male mice were injected intraperitoneally with meloxicam, diclofenac, piroxicam, metamizol, ibuprofen, naproxen and paracetamol in the writhing, tail flick and formalin orofacial tests and dose-response were analyzed to obtain the ED50 of each drugs. Administration of NSAIDs produced in a dose-dependent antinociception with different potency in the tests. The relative potency of NSAIDs among the tests shows a value of 5.53 in the orofacial formalin test in phase I and 6.34 in phase II between meloxicam and paracetamol; of 7.60 in the writhing test between meloxicam and paracetamol and of 8.46 in the tail flick test between ibuprofen and paracetamol. If the comparison is made for each NSAID in the different tests, the minimum value was 0.01 for between writhing and phase II of the orofacial formalin. Meanwhile, the highest power ratio was 11.71 for diclofenac between writhing and tail flick tests. In conclusion, the results suggests that intraperitoneal NSAIDs administration induce antinociceptive activity depending on the type of pain. The results support that NSAIDs administration, induce a wide variety of antinociceptive effect, depending on the type of pain. This suggest the participation of different mechanisms of action that can be added to the simple inhibition of COXs controlled by NSAIDs.

Pharmacological interaction between NSAIDS with clomipramine and risperidone in mice visceral pain.

Nonsteroidal anti-inflammatory drugs (NSAIDs) possess as primary action mechanism the inhibition of cyclooxygenases (COX-1, COX-2, and COX-3), thus producing a decreasing prostaglandin synthesis. This study was designed to evaluate whether the antinociception induced by NSAIDs could be modulated by clomipramine or risperidone using a chemical model of inflammatory acute visceral pain, the abdominal acetic acid induced a writhing test in mice. Dose-response curves, intraperitoneal, or intrathecal for the antinociceptive activity displayed by ketoprofen, piroxicam, nimesulide, parecoxib, and paracetamol were analyzed in order to obtain the ED50 of each drug. Pretreatment of mice with either clomipramine or risperidone, increased antinociceptive potency of ketoprofen, piroxicam, nimesulide, parecoxib, and paracetamol, expressed by a decrease in the values of antinociceptive ED50. The results that were obtained are in line with those where the inhibition of COXs provides a justification for most of the pharmacological actions. Nevertheless, several findings suggest other molecular mechanisms, among which may be mentioned, L-selecting shedding; inhibition of i-NOS; inhibition of NF-Kappa B; suppression metaloproteinasas; inhibition of ß2 integrin activation; activation of α2 -adrenoceptor; increase of IL-1ß; upregulation IL-6. In conclusion, the data generated in this study demonstrated that risperidone and clomipramine, separately, increase antinociceptive potency of NSAIDs in a chemical model of inflammatory acute visceral tonic pain.

Synergism between gabapentin-tramadol in experimental diabetic neuropathic pain.

Neuropathic pain is associated with several conditions such as surgery, cancer, and diabetes and can be induced experimentally. Among the drugs used as monotherapy are gabapentin and tramadol. The purpose of this study was to evaluate the coadministration of gabapentin and tramadol, by isobolographic analysis, in three different algesiometric assays in experimental diabetic neuropathic pain induced by streptozocin in mice. In all the behavioral tests, gabapentin or tramadol produced a dose-dependent antinociception and their coadministration resulted in a positive interaction. This effect can be explained by principles of multimodal analgesia, whereby the different mechanisms of action of each drug contribute to the combined effect in a supra-additive manner. The findings of the present study suggest that the combination of gabapentin and tramadol could be a useful strategy for the treatment of pain induced by diabetic neuropathy.

Antinociception induced by rosuvastatin in murine neuropathic pain.

BACKGROUND: Neuropathic pain, and subsequent hypernociception, can be induced in mice by paclitaxel (PTX) administration and partial sciatic nerve ligation (PSNL). Its pharmacotherapy has been a clinical challenge, due to a lack of effective treatment. In two models of mouse neuropathic pain (PTX and PSNL) the antinociception induced by rosuvastatin and the participation of proinflammatory biomarkers, interleukin (IL)- 1ß, TBARS and glutathione were evaluated. METHODS: A dose-response curve for rosuvastatin ip was obtained on cold plate, hot plate and Von Frey assays. Changes on spinal cord levels of IL-1ß, glutathione and lipid peroxidation were measured at 7 and 14days in PTX and PSNL murine models. RESULTS: PTX or PSNL were able to induce in mice peripheral neuropathy with hypernociception, either to 7 and 14days. Rosuvastatin induced a dose dependent antinociception in hot plate, cold plate and Von Frey assays. The increased levels of IL-1ß or TBARS induced by pretreatment with PTX or PSNL were reduced by rosuvastatin. The reduction of spinal cord glutathione, by PTX or PSNL, expressed as the ratio GSH/GSSG, were increased significantly in animals pretreated with rosuvastatin. The anti-inflammatory properties of statins could underlie their beneficial effects on neuropathic pain by reduction of proinflammatory biomarkers and activation of glia. CONCLUSION: The findings of this study suggest a potential usefulness of rosuvastatin in the treatment of neuropathic pain.

Pharmacological profile of dexketoprofen in orofacial pain.

BACKGROUND: Non-steroidal anti-inflammatory drugs (NSAIDs) may act through others mechanisms, in addition to inhibition of prostaglandin synthesis. These includes cholinergic, NO, serotonergic and opioids pathways. METHODS: The aim of this work was to evaluate the effect of systemic action of (S)-+-ketoprofen (dexketoprofen, DEX) on pain behaviors using the orofacial formalin test in mice and the potential involvement of cholinergic, NO, serotonergic and opioids pathways. RESULTS: The pretreatment of the mice with 1mg/kg ip of atropine or opoid antagonists: 1mg/kg, ip of NTX or 1mg/kg ip of NTI or 1mg/kg of NOR-BNI ip, did not produce significant change in the ED50 values of the antinociception to orofacial test induced by DEX. The pretreatment of the mice with 0.5mg/kg ip tropisetron, increased in a significant fashion the values of ED50 of DEX. When the mice were treated with 5mg/kg ip of L-NAME or 25mg/kg ip of aminoguanidine or 50mg/kg ip of 7-nitroindazole reversed the antinociception of DEX. CONCLUSION: The findings of this study demonstrate activation of NO and 5-HTpathways play important roles in the systemic antinociceptive effect of DEX in a murine model of inflammatory pain.

Antinociceptive Interaction of Tramadol with Gabapentin in Experimental Mononeuropathic Pain.

Neuropathic pain is the result of injury to the nervous system, and different animal models have been established to meet the manifestations of neuropathy. The pharmacotherapy for neuropathic pain includes gabapentin and tramadol, but these are only partially effective when given alone. The aim of this study was to assess the antinociceptive interaction between both drugs using the isobolographic analysis and changes of the IL-1ß concentration in a mouse model of neuropathic pain (partial sciatic nerve ligation or PSNL). The i.p. administration of gabapentin (5-100 mg/kg) or tramadol (12.5-100 mg/kg) displayed a dose-dependent antinociception in the hot plate assay of PSNL mice, and effects induced by gabapentin with tramadol were synergistic. Administration of gabapentin or tramadol reversed significantly the increase in the concentration of IL-1ß induced by PSNL after either 7 or 14 days and their combination was significantly more potent in reversing the elevated concentration of IL-1ß. The synergism obtained by the co-administration of gabapentin and tramadol is proposed to result from action on different mechanisms in pain pathways. Gabapentin or tramadol or their combination modulates the expression of pro-inflammatory cytokine, IL-1ß, in a model of mice PSNL which could be due to an inhibition of glial function.

Involvement of nitridergic and opioidergic pathways in the antinociception of gabapentin in the orofacial formalin test in mice.

BACKGROUND: Pain is one of the most common problems in clinical medicine. There is considerable evidence that pharmacologic approaches are the most widely used therapeutic options to ameliorate persistent or chronic pain. In this study it was evaluated the effect of l-NAME and naltrexone in the antinociception induced by administration of gabapentin in the orofacial formalin test of mice. METHODS: The algesiometer assay was performed by the administration of 20 µl of 2% formalin solution injected into the upper right lip of each mouse. RESULTS: The dose of gabapentin that produces the 50% of the maximum possible effect (ED50) was significantly increased by the pretreatment with l-NAME or naltrexone. CONCLUSIONS: These results suggest that gabapentin produce antinociception partly via the activation nitridergic pathways and opioid system.

Antinociceptive synergism of gabapentin and nortriptyline in mice with partial sciatic nerve ligation.

BACKGROUND AND METHODS: Neuropathic pain results from nerve injury, and gabapentin, an antiepileptic drug, has been approved for the treatment of several types of neuropathic pain. On the other hand, nortriptyline, an antidepressant drug, has been suggested as an alternative treatment. In partial sciatic nerve ligation (PSNL) mice, the interaction of gabapentin with nortriptyline was evaluated by the hot plate assay using isobolographic analysis. RESULTS: Gabapentin (3-100 mg/kg, i.p.) or nortriptyline (1-30 mg/kg, i.p.) induced dose-dependent antinociception, with an ED50 of 11.60 ± 0.54 mg/kg for gabapentin and of 5.16 ± 0.21 mg/kg for nortriptyline. The potency of gabapentin and nortriptyline in PSNL mice at 7 and 14 days after ligation was significantly increased (p < 0.05). Coadministration of gabapentin with nortriptyline, at a 1:1 ratio of their ED50, had a synergistic effect, with an interaction index of 0.311 and 0.348 for these mice at 7 and 14 days, respectively. CONCLUSION: The data showed a synergy in antinociception at a gabapentin-to-nortriptyline ratio of 1:1 in PSNL mice. This finding suggests that this combination could provide a therapeutic alternative that can be used for neuropathic pain management.

Isobolographic analysis of the opioid-opioid interactions in a tonic and a phasic mouse model of induced nociceptive pain.

BACKGROUND: Opioids have been used for the management of pain and coadministration of two opioids may induce synergism. In a model of tonic pain, the acetic acid writhing test and in a phasic model, the hot plate, the antinociceptive interaction between fentanyl, methadone, morphine, and tramadol was evaluated. RESULTS: The potency of opioids in the writhing test compared to the hot plate assay was from 2.5 (fentanyl) to 15.5 (morphine) times, respectively. The ED50 was used in a fixed ratio for each of the six pairs of opioid combinations, which, resulted in a synergistic antinociception except for methadone/tramadol and fentanyl/tramadol which were additive, in the hot plate. The opioid antagonists naltrexone, naltrindole and nor-binaltorphimine, suggests that the synergism of morphine combinations are due to the activation of MOR subtypes with partially contribution of DOR and KOR, however fentanyl and methadone combinations are partially due to the activation of MOR and DOR subtypes and KOR lack of participation. The antinociceptive effects of tramadol combinations, are partially due to the activation of MOR, DOR and KOR opioid subtypes. CONCLUSION: These results suggets that effectiveness and magnitude of the interactions between opioids are dependent on pain stimulus intensity.

Systemic synergism between codeine and morphine in three pain models in mice.

BACKGROUND: The combination of two analgesic agents offers advantages in pain treatment. Codeine and morphine analgesia is due to activation of opioid receptor subtypes. METHODS: This study, performed in mice using isobolographic analysis, evaluated the type of interaction in intraperitoneal (ip) or intrathecal (it) coadministration of codeine and morphine, in three nociceptive behavioral models. RESULTS: Intrathecal morphine resulted to be 7.5 times more potent than ip morphine in the writhing test, 55.6 times in the tail flick test and 1.7 times in phase II of the orofacial formalin test; however, in phase I of the same test ip was 1.2 times more potent than it morphine. Intrathecal codeine resulted being 3.4 times more potent than ip codeine in the writhing test, 1.6 times in the tail flick test, 2.5 times in phase I and 6.7 times in phase II of the orofacial formalin test. Opioid coadministration had a synergistic effect in the acute tonic pain (acetic acid writhing test), acute phasic pain (tail flick test) and inflammatory pain (orofacial formalin test). The interaction index ranged between 0.284 (writhing ip) and 0.440 (orofacial formalin phase II ip). CONCLUSION: This synergy may relate to the different pathways of pain transmission and to the different intracellular signal transduction. The present findings also raise the possibility of potential clinical advantages in combining opioids in pain management.

Synergism between fentanyl and tramadol in tonic inflammatory pain: the orofacial formalin test.

Opioids have been used for long time to management of pain, the coadministration of two opioids may induce synergism. The present study was conducted to determine the antinociceptive interaction between the dual mechanism of action of tramadol compared to the main of fentanyl antinociception in the orofacial formalin which represents a model of persistent cutaneous nociception in the region innervated by the trigeminal nerve. The i.p. administration of tramadol and fentanyl induced a dose-dependent antinociception with an ED(50) of 2.97 ± 0.32 mg/kg for phase I and 1.79 ± 0.30 mg/kg for phase II and 0.062 ± 0.0040 mg/kg in phase I and 0.041 ± 0.0039 mg/kg in phase II, respectively. The coadministration of fentanyl with tramadol induced synergism in both phases of the test with an interaction index of 0.343 and 0.163 for phase I and phase II, respectively. This finding could be explained by the more complex pharmacology of tramadol compared to fentanyl.

Antinociception and anti-inflammation induced by simvastatin in algesiometric assays in mice.

Statins, belonging to a well-known drug class used for lowering cholesterol through competitive inhibition of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, also have other pleiotropic properties, such as anti-inflammatory action. The purpose of this study was to evaluate the antinociceptive and anti-inflammatory effects of simvastatin in five models of nociceptive behaviour. Oral gavage administration of simvastatin induced a dose-dependent inhibition of nociception for 1 day in the acetic acid writhing (ED(50) = 5.59 ± 0.07), tail-flick (ED(50) = 112.96 ± 8.00), hot-plate (ED(50) = 134.87 ± 2.20), formalin hind paw (ED(50) = 19.86 ± 1.12 in phase I and 23.30 ± 2.05 in phase II) and orofacial formalin (ED(50) = 5.54 ± 2.74 in phase I and 11.48 ± 1.88 in phase II) tests. However, after 3 days, the values were in the acetic acid writhing (ED(50) = 6.14 ± 0.51), tail-flick (ED(50) = 154 ± 8.88), hot-plate (ED(50) = 136.14 ± 2.94), formalin hind paw (ED(50) = 15.93 ± 0.42 in phase I and 17.10 ± 1.80 in phase II) and orofacial formalin (ED(50) = 6.79 ± 0.66 in phase I and 5.80 ± 1.49 in phase II) tests. This study demonstrated the antinociceptive and anti-inflammatory activities of simvastatin in five models of tonic or phasic pain. These actions seem to be related to the inhibition of cytokine and prostanoid release and stimulation of nitric oxide synthesis. A possible clinical role of simvastatin could be related to the potentially beneficial effects in the neuropathic pain, and by their pleiotropic properties, they could play a clinical role in anti-inflammatory disease.

Analgesia induced by morphine microinjected into the nucleus raphe magnus: effects on tonic pain.

One of the possible sites of action of the analgesic effect of morphine is the Nucleus Raphe Magnus, as morphine injected into this structure induces analgesia in transient pain models. In order to test if morphine in the Nucleus Raphe Magnus is also analgesic in a tonic pain model, 5 microg of morphine or saline (control) were microinjected into the Nucleus Raphe Magnus of the rat. Analgesic effects were assessed following nociceptive stimulation using transient heating of the tail (phasic pain) and subcutaneous orofacial injection of 1.5 % formalin (tonic pain). While morphine was strongly analgesic for the tail-flick response (p <0.0001 compared to control), analgesia on the response to formalin was also observed for both early (p = 0.007) and late responses (p = 0.02). However, the response to formalin was not completely blunted. These results suggest that the Nucleus Raphe Magnus is not the exclusive site of action of morphine-induced analgesia in clinical conditions.

Neostigmine interactions with non steroidal anti-inflammatory drugs.

1. The common mechanism of action of non-steroidal anti-inflammatory drugs (NSAIDs) is the inhibition of the enzyme cyclo-oxygenase (COX), however, this inhibition is not enough to completely account for the efficacy of these agents in several models of acute pain. 2. It has been demonstrated that cholinergic agents can induce antinociception, but the nature of the interaction between these agents and NSAIDs drugs has not been studied. The present work evaluates, by isobolographic analysis, the interactions between the cholinergic indirect agonist neostigmine (NEO) and NSAIDs drugs, using a chemical algesiometric test. 3. Intraperitoneal (i.p.) or intrathecal (i.t.) administration of NEO and of the different NSAIDs produced dose-dependent antinociception in the acetic acid writhing test of the mouse. 4. The i.p. or i.t. co-administration of fixed ratios of ED(50) fractions of NSAIDs and NEO, resulted to be synergistic or supra-additive for the combinations ketoprofen (KETO) and NEO, paracetamol (PARA) and NEO) and diclofenac (DICLO) and NEO administered i.p. However, the same combinations administered i.t. were only additive. In addition, the combinations meloxicam (MELO) and NEO and piroxicam (PIRO) and NEO, administered either i.p. or i.t., were additive. 5. The results suggest that the co-administration of NEO with some NSAIDs (e.g. KETO, PARA or DICLO) resulted in a synergistic interaction, which may provide evidence of supraspinal antinociception modulation by the increased acetylcholine concentration in the synaptic cleft of cholinergic interneurons. The interaction obtained between neostigmine and the NSAIDs could carry important clinical implications.

Influence of 6-hydroxydopamine on ethanol narcosis in mice

Se estudian los efectos de la administración de 6-hidroxidopamina (6-OHDA0, 100 Y 200 microng i.c.v., en la duración de la narcosis por etanol en ratones sin o con tratamiento de alfa-metil-p-tirosina (AMPT), p-cloro-fenilalanina (PCPA) o 5-hidroxitriptófano (5-HTP). La narcosis por etanol fue significativamente más prolongada en los ratones que recibieron 200 microng de 6-OHDA i.c.v. que en los testigos. La duración de la narcosis en los ratones tratados con ambas dosis de 6-OHDA fue significativamente más larga cuando éstos recibieron previamente AMPT (inhibidor de la biosíntesis de seotonina). En 5-HTP (precursor de la biosíntesis de serotonina). En cambio, en los pretratados con PCPA (inhibidor de la triptófano hidroxilasa), la 6-OHDA no modificó la duración de la narcosis por etanol. Las alcoholemias al momento de despertar no cambiaron significativamente por la 6-OHDA. Estos resultados son consistentes con la hipótesis de que la disminución de noradrenalina así como el aumento de serotonina cerebrales prolongan la narcosis por etanol y, en cambio, el aumento de noradrenalina o la disminución de serotonina en el cerebro reducen la narcosis por etanol