European journal of pharmacology
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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. ⋯ 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.
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Spinal cord dorsal horn N-methyl-D-aspartate (NMDA) receptors have been implicated in central sensitization, enhanced responsiveness to peripheral stimuli following peripheral injury. Since hyperalgesia is a behavioral consequence of central sensitization, it should be attenuated at the level of the dorsal horn with NMDA receptor antagonists. However, responsiveness to thermal and mechanical hyperalgesia may be distinct, and have thus far not been directly compared in chronic inflammatory pain models. ⋯ The NMDA receptor antagonists dose-dependently ameliorated mechanical hyperalgesia, but had marginal effects on thermal hyperalgesia. In ranges near antihyperalgesic doses, significant disruption of motor coordination was observed for both antagonists. These results suggest that, depending on the stimulus, NMDA receptors may have variable significance for central sensitization-mediated hyperalgesia, and that NMDA receptor antagonists may have therapeutic potential for some, but not all components in the clinical manifestation of inflammatory pain.
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Comparative Study
A comparison of the antinociceptive effects of voltage-activated Na+ channel blockers in two rat models of neuropathic pain.
The pain-relieving effects of various voltage-activated Na(+) channel blockers have been evaluated in two rat models of neuropathic pain; the photochemically induced nerve injury model (Gazelius) and spared nerve injury model. Lidocaine (up to 40 mg/kg, i.p.) and lamotrigine (up to 60 mg/kg, i.p.) had no effect on mechanical or cold allodynia in either model. ⋯ The present results show that these voltage-activated Na(+) channel blockers have broadly similar antinociceptive effects in these two models of neuropathic pain. They also show that these drugs can have markedly different effects on distinct neuropathic pain-related behaviours within models.
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Previously, enhanced levels of spermine which stimulates N-methyl-D-aspartate (NMDA) receptors, particularly those containing the NR2B subunit, were found in brains of dt(sz) mutant hamsters, a model of paroxysmal dyskinesia in which dystonic episodes occur in response to stress. Therefore, the effects of the NR2B selective NMDA receptor antagonist Ro 25-6981 ([R-(R,S)]-alpha-(4-hydroxyphenyl)-beta-methyl-4-phenyl-methyl)-1-piperidine-propanol] on severity of dystonia were investigated in the dt(sz) hamster. ⋯ This result indicates that overstimulation of receptors that include the NR2B subunit by polyamines is not involved in the dystonic syndrome. NR2B-selective NMDA receptor antagonists seem not to provide a novel approach in the treatment of hereditary paroxysmal dyskinesias.
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In the present study, the effects of intra-ventral tegmental area injection of L-arginine, a nitric oxide (NO) precursor, and N(G)-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthase (NOS) inhibitor, on morphine-induced conditioned place preference in male Wistar rats were investigated. Our data showed that subcutaneous (s.c.) injection of morphine sulphate (0.5-10 mg/kg) significantly increased the time spent in the drug-paired compartment in a dose-dependent manner. Intra-ventral tegmental area administration of a low dose of L-arginine (0.05 microg/rat) with an ineffective dose of morphine (0.5 mg/kg) elicited significant conditioned place preference; however, a higher dose of L-arginine (0.1 microg/rat) reduced the morphine response. ⋯ L-Arginine and L-NAME by themselves did not elicit any effect on place conditioning; however, intra-ventral tegmental area administration of L-arginine (0.01-0.1 microg/rat) and a higher dose of L-NAME (0.1 microg/rat) significantly decreased the expression of morphine (7.5 mg/kg)-induced place preference. The attenuation of already established morphine-induced place preference on the test day by L-arginine was inhibited by L-NAME (0.03 microg/rat). The results indicate that NO may be involved in the acquisition and expression of morphine-induced place preference.