Tolerance to Non-Opioid Analgesics is Opioid Sensitive in the Nucleus Raphe Magnus

Tsagareli, Merab G.; Nozadze, Ivliane; Tsiklauri, Nana; Gurtskaia, Gulnaz

doi:10.3389/fnins.2011.00092

Cited by 15 publications

(17 citation statements)

References 29 publications

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“…The data reported in this study demonstrate that microinjection of commonly used NSAIDs, diclofenac, ketorolac and xefocam into the rostral part of ACC induces antinociception. These findings are in resemblance with the results of our and other colleagues’ previous investigations in an acute pain model with TF and HP tests, and in which metamizol, xefocam, ketorolac or lysine-acetylsalicylate were given systemically or microinjected into the PAG [ 10 , 11 , 16 – 18 , 25 ], into the CeA [ 13 , 21 ], and the NRM [ 13 , 20 , 26 ]. In the other investigation, responses of spinal dorsal horn wide-dynamic range neurons of rats to mechanical noxious stimulation of a hindpaw were strongly inhibited by intravenous metamizol [ 27 ].…”

Section: Discussionsupporting

confidence: 89%

“…Diclofenac (diclofenac sodium, 75 μg/0.5 μl, Hemofarm, Serbia), ketorolac (ketorolac tromethamine, 90 μg/0.5 μl, Grindex, Latvia) or xefocam (lornoxicam, 12 μg/0.5 μl, Nycomed, Austria) were injected through the microinjection cannula as we used in previous works [ 19 , 20 ]. The guide cannula was then plugged with a stainless steel stylet.…”

Section: Methodsmentioning

confidence: 99%

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Antinociceptive tolerance to NSAIDs in the anterior cingulate cortex is mediated via endogenous opioid mechanism

Tsiklauri¹,

Pirkulashvili²,

Nozadze³

et al. 2018

BMC Pharmacol Toxicol

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BackgroundIn the past decade several studies have reported that in some brain areas, particularly, in the midbrain periaqueductal gray matter, rostral ventro-medial medulla, central nucleus of amygdala, nucleus raphe magnus, and dorsal hippocampus, microinjections of non-steroidal anti-inflammatory drugs (NSAIDs) induce antinociception with distinct development of tolerance. Given this evidence, in this study we investigated the development of tolerance to the analgesic effects of NSAIDs diclofenac, ketorolac and xefocam microinjected into the rostral part of anterior cingulate cortex (ACC) in rats.MethodsMale Wistar experimental and control (saline) rats were implanted with a guide cannula in the ACC and tested for antinociception following microinjection of NSAIDs into the ACC in the tail-flick (TF) and hot plate (HP) tests. Repeated measures of analysis of variance with post-hoc Tukey-Kramer multiple comparison tests were used for statistical evaluations.ResultsTreatment with each NSAID significantly enhanced the TF and HP latencies on the first day, followed by a progressive decrease in the analgesic effect over a 4-day period, i.e., developed tolerance. Pretreatment with an opioid antagonist naloxone completely prevented the analgesic effects of the three NSAIDs in both behavioral assays.ConclusionsThese findings support the concept that the development of tolerance to the antinociceptive effects of NSAIDs is mediated via an endogenous opioid system possibly involving descending pain modulatory systems.

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Section: Discussionsupporting

confidence: 89%

Section: Methodsmentioning

confidence: 99%

Antinociceptive tolerance to NSAIDs in the anterior cingulate cortex is mediated via endogenous opioid mechanism

Tsiklauri¹,

Pirkulashvili²,

Nozadze³

et al. 2018

BMC Pharmacol Toxicol

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“…In the other experiments in rats, responses of spinal dorsal horn wide-dynamic range neurons to mechanical noxious stimulation of a hindpaw were strongly inhibited by intravenous NSAID dipyrone (metamizole) [30]. Importantly, repeated microinjections of NSAIDs into the DH resulted in a progressive decrease in antinociceptive effectiveness, that is, induced tolerance similar to that observed with intra-PAG, CeA, and NRM injections [16, 17, 19–22], and reminiscent of the effect of opiates.…”

Section: Discussionmentioning

confidence: 99%

Is Hippocampus Susceptible to Antinociceptive Tolerance to NSAIDs Like the Periaqueductal Grey?

Tsiklauri¹,

Nozadze²,

Gurtskaia³

et al. 2014

Pain Research and Treatment

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Emotional distress is the most undesirable feature of painful experience. Numerous studies have demonstrated the important role of the limbic system in the affective-motivational component of pain. The purpose of this paper was to examine whether microinjection of nonsteroidal anti-inflammatory drugs (NSAIDs), Clodifen, Ketorolac, and Xefocam, into the dorsal hippocampus (DH) leads to the development of antinociceptive tolerance in male rats. We found that microinjection of these NSAIDs into the DH induces antinociception as revealed by a latency increase in the tail-flick (TF) and hot plate (HP) tests compared to controls treated with saline into the DH. Subsequent tests on consecutive three days, however, showed that the antinociceptive effect of NSAIDs progressively decreased, suggesting tolerance developed to this effect of NSAIDs. Both pretreatment and posttreatment with the opioid antagonist naloxone into the DH significantly reduced the antinociceptive effect of NSAIDs in both pain models. Our data indicate that microinjection of NSAIDs into the DH induces antinociception which is mediated via the opioid system and exhibits tolerance.

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“…Since tolerance, antinociception at the spinal level, and increased latency in the tail-flick test are very typical of opioids [28], we propose that the endogenous opioidergic system is involved in the analgesia induced by compound 3g. Involvement of this system in the antinociception caused by NSAIDs is supported by data from recent studies, which propose that gamma-aminobutyric acid (GABA)-containing synapses act as sites where NSAIDs converge with endogenous opioids [29]. Multiple intraperitoneal administration of non-opioid analgesics in rats induces antinociception and causes tolerance, as well as cross-tolerance to morphine.…”

Section: Discussionmentioning

confidence: 96%

Biological Screening of Novel Structural Analog of Celecoxib as Potential Anti-Inflammatory and Analgesic Agent

et al. 2019

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Background and objectives: The clinical use of non-steroidal anti-inflammatory drugs is limited due to high incidence of adverse drug reactions. The pyrrole heterocycle is included in the chemical structure of a number of drugs with various activities and shows relatively good tolerability and safety. The objectives of our study were to evaluate the analgesic and anti-inflammatory activity, as well as possible organ toxicity, of 2-[3-acetyl-5-(4-chloro-phenyl)-2-methyl-pyrrol-1-yl]-3-(1H-indol-3-yl)-propionic acid (compound 3g), a novel N-pyrrolylcarboxylic acid structurally similar to celecoxib. Materials and methods: All experiments were performed on 6-week-old male Wistar rats divided into parallel groups (n = 8). Antinociception was assessed using animal pain models with thermal and chemical stimuli (paw withdrawal, tail-flick, and formalin tests). Criteria for the analgesic effect were increased latency in the paw withdrawal and tail-flick tests and decreased paw licking time in the formalin test compared to animals treated with saline (control). Anti-inflammatory activity was measured using a carrageenan-induced paw edema model; the criterion for anti-inflammatory effect was decreased edema compared to control. Blood samples were obtained after animals were sacrificed to assess possible organ toxicity. Statistical analysis was performed with IBM SPSS 20.0. Results: 2-[3-Acetyl-5-(4-chloro-phenyl)-2-methyl-pyrrol-1-yl]-3-(1H-indol-3-yl)-propionic acid had analgesic action against chemical stimulus after single and multiple administration and against thermal stimulus after single administration. Compound 3g significantly suppressed carrageenan-induced paw edema after both single and continuous administration. After continuous administration, hematological tests showed that compound 3g decreased leukocyte and platelet levels and elevated serum creatinine levels. Conclusions: Antinociception with the tested compound is most likely mediated by spinal, peripheral, and anti-inflammatory mechanisms. Possible tolerance of the analgesic action at the spinal level develops after continuous administration. Anti-inflammatory activity is significant and probably the leading cause of antinociception. After multiple administration, compound 3g showed signs of potential nephrotoxicity and antiplatelet activity, as well as suppression of leukocyte levels.

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Tolerance to Non-Opioid Analgesics is Opioid Sensitive in the Nucleus Raphe Magnus

Cited by 15 publications

References 29 publications

Antinociceptive tolerance to NSAIDs in the anterior cingulate cortex is mediated via endogenous opioid mechanism

Antinociceptive tolerance to NSAIDs in the anterior cingulate cortex is mediated via endogenous opioid mechanism

Is Hippocampus Susceptible to Antinociceptive Tolerance to NSAIDs Like the Periaqueductal Grey?

Biological Screening of Novel Structural Analog of Celecoxib as Potential Anti-Inflammatory and Analgesic Agent

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