Dexketoprofen (DEX) is the dextrorotatory enantiomer of S (+) configuration with a high antinociceptive activity of ketoprofen. The aim of this study was to evaluate the pharmacological interaction of DEX with the noradrenergic antagonist's prazosin, yohimbine, propranolol and atenolol in the formalin orofacial pain in mice. Analgesia to nociceptive and inflammatory pain was evaluated by dose response curves to DEX before and after the i.p. administration of 1.0 mg/kg of prazosin, or yohimbine, or propranolol or atenolol. Results are presented as means ± SEM and differences were calculated by one-way ANOVA, followed by Tukey’s post-test. DEX produced a dose-related antinociceptive effect with varying potencies in both trial phases, with prazosin and yohimbine increasing the efficacy of DEX and propranolol and atenolol having no effect. These findings suggests that the increased efficacy of DEX cannot be explained by only inhibition of COXs, since it may be a consequence of multiple pharmacodynamic interactions induced by the activation of a-adrenoceptors in the opioidergic, cannabinoid, nitrergic or serotonergic mechanisms involved in pain. These results indicate that the combination of DEX with prazosin or yohimbine could be a new and effective alternative for the management of pain.
Pain is an unpleasant sensation that causes mild or severe physical discomfort, by which induces the use of analgesics which are basically of two types: opioids or NSAIDs. The objectives of the present study was to evaluate the antinociception activity induced by NSAIDs and opioids in a thermal model of animal pain, the tail flick assay, and to determine the effect of the MOR antagonist, naltrexone. Antinociception was assessed by the tail flick test using an digital algesiometer. The rank orden of potency was fentanyl > morphine > ibuprofen > tramadol > codeine > meloxicam > paracetamol and the antinociceptive ratio, compared with paracetamol, was between 460 for fentanyl and 1 for meloxicam. Pretreatment with the opioid receptor antagonist, naltrexone, 1 mg/kg i.p., significant reversed the antinociceptive effect of NSAIDs and opioids. The results obtained with naltrexone in this assay confirm the antagonism of this agent on opioids. However, the antagonism over NSAIDs is a new finding since that has not been previously reported. This study test that NSAIDs and opioids induce antinociceptive activity in a thermal murine phasic pain with the following rank orden of potency fentanyl > morphine > ibuprofen > tramadol > codeine > meloxicam > paracetamol. Although the mechanisms of action of these drugs are different, naltrexone, a MOR antagonist, blocked the effects of both agents, suggesting that inhibition of pain seem partially mediated by MOR with association to central mechanisms.
Pain is a complex entity that can be described in several dimensions, such as, acute pain and chronic pain, characterized by its duration. After the tissue injury, the activation of the sensory nervous tissue occurs from where the different pro-inflammatory mediators are released with the consequent nociceptive transmission that characterizes the genesis of inflammatory pain. The main objective of this study was to review the role of the opioid system, using morphine and MOR opioid receptors as paradigm, in the antinociceptive modulation of inflammatory pain, by means of the formalin test as a model. Various pieces of evidence are compiled that establish the fundamental role of morphine in the inflammatory pain. Morphine has noticeable antinociceptive efficacy in to decrease the inflammatory pain. This review demonstrates the fundamental role that morphine plays in inflammatory pain states and that it could serve as the basis for a new pharmacotherapy of inflammatory pain.
Abstract: The role of para‐chlorophenylalanine and α‐methyl‐DL‐p‐tyrosine in the antinociceptive effects of the intracerebroventricular administration of the antidepressant drugs clomipramine, zimelidine, imipramine and maprotiline was studied using the acetic acid writhing test in mice. The results demonstrated an antinociceptive effect for all these antidepressants. Pretreatment with para‐chlorophenylalanine significantly reduced the antinociception induced by the ED 50 's of imipramine and maprotiline, and did not modify the effects of zimelidine and clomipramine, pretreatment with α‐methyltyrosine did not modify the antinociception induced by these drugs except maprotiline. Pretreatment with para‐chlorophenylanine plus α‐methyltyrosine significantly reduced the antinociceptive effect of all the antidepressants tested. The main finding of the present study is that the association of para‐chlorophenylanine plus α‐methyltyrosine reduced the antinociceptive action of all the antidepressants. This means that critical levels of both 5‐HT and NA are responsible for mediating the antinociceptive effects of antidepressants on the writhing test in mice.
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.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.These results suggets that effectiveness and magnitude of the interactions between opioids are dependent on pain stimulus intensity.
Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used in pain whose mechanism of action is the inhibition of cyclooxygenase enzymes (COXs), however, there are evidence of other mechanisms of action, such as the inhibition of substance P, interaction with systems NO, monoaminergic and others. The objective of the present work was to study the participation of a-1 (prazosin) and a-2 (yohimbine) adrenoceptors antagonists in the antinociception of dexketoprofen, the S (+) enantiomer of ketoprofen. The antinociception evaluation was thru the mice orofacial formalin assay. Dexketoprofen (DEX) induced a dose-related antinociception 3.40 times more potent in phase I than in phase II. Prazosin i.p. decreased of the antinociception of DEX, 2.01 times in phase I and 4.02 times in phase II. Administered i.t. reduced the antinociception 5.30 times in phase I and 6.20 times in phase II. Yohimbine i.p. induced a reduction of the ED50 of 3.40 times in phase I and 4.50 times in phase II, after i.t. administration the reduction was 5.30 times in phase I and 6.20 times in phase II. The mechanism of antinociception induced by DEX is mediated by the activation of α-1 and α-2 adrenergic receptors at supraspinal and spinal levels.
Pain is a common unpleasant sensory and emotional experience, in which are frequently used in their treatment the nonsteroidal anti-inflammatory drugs (NSAIDs). A group of agents with antipyretic, analgesic, and anti-inflammatory properties due to the inhibition of cyclooxygenase enzymes (COXs). Among these drugs there are a group of selective inhibitors of COX-2 named coxib that include to parecoxib, celecoxib, rofecoxib and etoricoxib. Pharmacological information on the mechanism of action of coxibs is insufficient to determine the analgesic and anti-inflammatory efficacy of these agents. There are contradictory reports regarding the antinociceptive effects of the various coxibs at the preclinical level as well as the nitridergic modulation of such actions. The objective of the present study was to evaluate the antinociceptive efficacy of parecoxib, rofecoxib, celecoxib, and etoricoxib using the formalin hind paw assay in mice and the possible contribution of the nitridergic system in the efficacy of COX-2 agents. Antinociception was assessed in a murine formalin assay using dose-response curves to coxibs before and after i.p. administration of 5 mg/kg of L-NAME. Coxibs produced dose-dependent analgesia and anti-inflammation. L-NAME administration reduced the analgesic and anti-inflammatory effectiveness of parecoxib, rofecoxib, celecoxib, and etoricoxib. These findings suggest that the effect of these agents, in addition to COX-2 inhibition, would be mediated by other mechanisms, among which nitridergic modulation would be compromised.
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