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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. [ABSTRACT FROM AUTHOR]

Aims: To evaluate the nature of the antinociceptive interaction of systemic administration of a combination of the anticonvulsant gabapentin with the antidepressant nortriptyline, by isobolographic analysis in the formalin orofacial pain test of mice. Methods: The study was carried out in 168 male CF-1 mice weighing 30 g, and the protocol was to test each drug (at dosages of 1, 3, 10, 30, and 100 mg/kg of gabapentin and 0.1, 1, 3, 10, and 30 mg/kg of nortriptyline; ip) alone and in combination. The isobolographic assay has two phases: phase 1 corresponds to the 5-minute period starting immediately after the formalin injection and reflects a tonic acute pain due to peripheral nociceptor sensitization; phase 2 is recorded as the 10-minute period starting 20 minutes after the formalin injection and reflects an inflammatory pain state. Results were analyzed by Student t test for independent means. Results: Gabapentin was 1.61 times more potent in phase 2 than in phase 1, and nortriptyline 1.37 times more potent in phase 2 than in phase 1. The combination of both drugs was synergic, with an index of interaction of 0.134 and 0.148 for phase 1 and phase 2, respectively. Differences in the pharmacological profiles of gabapentin and nortriptyline could underlie the synergism of the two drugs. Conclusion: The findings of this study are important, because they are concordant with some clinical studies and also raise the possibility of potential clinical advantages of combining gabapentin and nortriptyline in pain management, since the low doses of the components may potentially have a lower incidence of adverse reactions. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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-1β 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-1β induced by PSNL after either 7 or 14 days and their combination was significantly more potent in reversing the elevated concentration of IL-1β. 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-1β, in a model of mice PSNL which could be due to an inhibition of glial function. [ABSTRACT FROM AUTHOR]

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. © 2015 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Neosaxitoxin (NeoSTX) is a specific reversible blocker of voltage gated sodium channels on excitable cells. In the last decade, it has been tested in a number of interesting clinical trials, however there is still little information available on mammalian toxicity. Rats were treated for 12 weeks with doses of 1, 3 or 6 μg/kg of subcutaneous NeoSTX. At weeks 12 and 17, animals were sacrificed and blood samples collected for hematological and biochemical analysis. Organs were harvested for weight determination and histopathological assessments. The lowest acute toxicity via the intraperitoneal (ip) route was (30.35 μg/kg) and there was no significant difference between intramuscular and subcutaneous routes (11.4 and 12.41 μg/kg). The NeoSTX adiministration did not produce lethality at week 12 and after five weeks of suspension. NeoSTX 6 μg/kg ip produced reductions (p < 0.05) in body weight and food intake, and increased blood level of total and direct bilirubin, GGT and SGOT at week 12; all of these were reversed in the recovery period. NeoSTX 1 and 3 μg/kg ip did not show significant changes with the control group. Histopathological presentations were normal in all groups. This study revealed that NeoSTX is safe in vivo, giving a reliable security margin for its use like a local anesthetic. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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 (hat 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 lest of the mouse. 4 The i.p or i.t. co-administration of fixed ratios of ED50 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. [ABSTRACT FROM AUTHOR]

Ethnopharmacological relevance: Quillaja saponaria bark contains a high percentage of triterpene saponins and has been used for centuries as a cleansing and analgesic agent in Chilean folk medicine. Aim of the study: The topical and systemic analgesic effects of a commercial partially purified saponin extract, 3β,16α-dihydroxy-23-oxoolean-12-en-28-oic acid (quillaic acid), methyl 3β,16α-dihydroxy-23-oxoolean-12-en-28-oate and methyl 4-nor-3,16-dioxoolean-12-en-28-oate. Materials and methods: The samples were assessed in mice using the topical tail-flick and i.p. hot-plate tests, respectively. Results: All the samples showed activity in both analgesic tests in a dose-dependent manner. The most active against tail flick test was commercial partially purified saponin extract (EC50 27.9mg%, w/v) and more than the ibuprofen sodium. On hot-plate test, methyl 4-nor-3, 16-dioxoolean-12-en-28-oate was the most active (ED50 12.2mg/kg) and more than the ibuprofen sodium. Conclusions: The results of the present study demonstrated that Quillaja saponaria saponins, quillaic acid, its methyl ester, and one of the oxidized derivatives of the latter, elicit dose-dependent antinociceptive effects in two murine thermal models. [Copyright &y& Elsevier]

Background: Quillaja saponaria Mol. bark contains a high concentration of triterpene saponins that have been used for centuries as a cleansing, antiinflammatory and analgesic agent in Chilean folk medicine. In earlier studies, in mice, both the anti-inflammatory as well as the antinociceptive effect of the major sapogenin, quillaic acid have been demonstrated (QA)., Objective: To determine the antihyperalgesic effect of QA one and seven days after itpl administration of complete Freund's adjuvant (CFA) in male mice using the hot plate test in the presence of complete Freund's adjuvant (HP/CFA) as an acute and chronic skeletal muscle pain model., Methods: The present study evaluated the antihyperalgesic activity of QA against acute and chronic skeletal muscle pain models in mice using the hot plate test in the presence of complete Freund's adjuvant (HP/CFA), at 24 h (acute assay) and 7 days (chronic assay) , with dexketoprofen (DEX) as the reference drug., Results: In acute and chronic skeletal muscle pain assays, QA at 30 mg/kg ip elicited its maximal antihyperalgesic effects (65.0% and 53.4%) at 24 h and 7 days, respectively. The maximal effect of DEX (99.0 and 94.1 at 24 h and 7 days, respectively) was induced at 100 mg/kg., Conclusion: QA and DEX elicit dose-dependent antihyperalgesic effects against acute and chronic skeletal muscle pain, but QA is more potent than DEX in the early and late periods of inflammatory pain induced by CFA., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Objective: The effects of the co-administration of fenoldopam (FD) or levodopa (LD) with dopamine (DA) on arterial blood pressure were studied in rats to assess the possibility of synergic effects that might be of some clinical importance., Methods and Results: Mean arterial blood pressure (MBP) in the carotid artery of anaesthetized rats was registered. All agents induced dose-dependent reductions in mean arterial blood pressure when administered in a non-cumulative schedule to rats pretreated with phentolamine. For each drug, the doses that induced a 50% of reduction in basal mean arterial blood pressure, (ED50) calculated by standard linear regression analysis of the log dose-response curve and were 5.49 mg/kg, (n=10), 2.86 mg/kg, (n=11) and 0.445 mg/kg, (n=12), for FD, LD and DA, respectively. The interactions were evaluated by simultaneous administration of different fixed ratios of DA with FD (1:12.3) or DA with LD (1:6) and obtaining dose-response curves and ED50's for each mixture. An isobolographic analysis was then performed, which demonstrated that the co-administration had synergistic effects as illustrated by statistically higher reductions of blood pressure under each combination as compared to theoretical calculated additive effects., Conclusions: The present results show that in the rat, after alpha-adrenergic blockade, the association of DA and FD could inappropriately potentiate the hypotension induced by both drugs.