Merab G. Tsagareli

Dr. Biol. Sci.
Laboratory Head
I.Beritashvili Center of Exper... · Neurophysiology of Pain and Analgesia

Publications

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    ABSTRACT: Acute pain is associated with tissue damage, which results in the release of inflammatory mediators. Recent studies point to the involvement of epigenetic mechanisms (DNA methylation) in the development of pain. We have found that during acute inflammatory pain induced by the application of 10% mustard oil on the tongues of rats, levels of DNMT3a and 3b were elevated markedly (36 and 42 % respectively), whereas the level of DNMT1 was not changed significantly. Previous injection of Xefocam with 0,4 mg/kg dose decreased levels of DNMT3a and 3b (25 and 24% respectively). The level of DNMT1 was not changed significantly compared to the control group. The findings support the idea that inhibitors of DNA-methyltransferases could be useful for pain management. Our data suggest that NSAIDs (alone or in combination with DNMT inhibitors) may be proposed as possible epigenetic regulatory agents, which may play a role in epigenetic mechanisms indirectly through altering the activity of inflammatory mediators involved in pain development.
    Georgian medical news 10/2014; 10(235):78-81.
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    ABSTRACT: Aim of Investigation: Pain is the most unpleasant symptom of illness, which is mediated by a variety agents released from local inflammatory cells. Recent studies points to the involvement of epigenetic mechanisms both in the development and maintenance of pain states. One of the most fundamental epigenetic marks is the methylation of cytosine residues in DNA, catalyzed by DNA-methyltransferase enzymes. The aim of the present study was to analyze the changes of DNMT1, DNMT3a and DNMT3b in the trigeminal ganglia (TG) neurons during the maintenance phase of pain states. Methods: Mustard oil ( 10%) or capsaicin at concentrations of 0.4%,- 0.6% (Sigma-Aldrich, USA) was applied to four- month-age male rats to induce acute inflammatory pain and responses to mechanical stimuli were assessed. All animal studies confirmed to the Guidelines of International Association for the study of Pain regarding investigations. The levels of DNMT1, DNMT3a and DNMT3b were measured in nuclear extracts of Trigeminal ganglia (TGs) neurons in study and control groups. DNMTs assay kits were used to measure the amount of DNAmethyltransferases. Results and Conclusions: Mustard oil-evoked pain increased the levels of DNMT3a and DNMT3b, Mustard oil has no significant effect on levels of DNMT1, while capsaicin induced pain increased the levels of DNMT3a and DNMT3b,as well as levels of DNMT1, in the same regions compare to control sample. This study provides the evidence that epigenetic modification,such as DNA methylation plays a role in development of pain in animal models. Epigenetic analysis may identify mechanisms critical to the transition from acute to persistent pain.
    IBNS 23rd Annual Meeting, Las Vegas, Nevada; 06/2014
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    European Human Genetics Conference, Milan, Italy; 05/2014
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    ABSTRACT: 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.
    Pain research and treatment. 04/2014; 2014:654578.
    This article is viewable in ResearchGate's enriched format
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    ABSTRACT: Pain is characterized as a complex experience, dependent not only on the regulation of nociceptive sensory systems, but also on the activation of mechanisms that control emotional processes in limbic brain areas such as the amygdala and the hippocampus. Several lines of investigations have shown that in some brain areas, particularly the midbrain periaqueductal gray matter, rostral ventro-medial medulla, central nucleus of amygdala and nucleus raphe magnus, microinjections of non-steroidal anti-inflammatory drugs (NSAIDs) induce antinociception with distinct development of tolerance. The present study was designed to examine whether microinjection of NSAIDs, clodifen, ketorolac and xefocam into the dorsal hippocampus (DH) leads to the development of antinociceptive tolerance in male rats. The experiments were carried out on experimental and control (with saline) white male rats. Animals were implanted with a guide cannula in the DH and tested for antinociception following microinjection of NSAIDs into the DH 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. We found that microinjection of these NSAIDs into the DH induces antinociception as revealed by a latency increase in the TF and HP tests compared to controls treated with saline into the DH. Subsequent tests on days 2 and 3, however, showed that the antinociceptive effect of NSAIDs progressively decreased, suggesting tolerance developed to this effect of NSAIDs. Both pretreatment and post-treatment with the opioid antagonist naloxone into the DH significantly reduced the antinociceptive effect of NSAIDs in both pain models. Our results indicate that microinjection of NSAIDs into the DH induces antinociception which is mediated via the opioid system and exhibits tolerance.
    BMC pharmacology & toxicology. 02/2014; 15(1):10.
    This article is viewable in ResearchGate's enriched format
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    ABSTRACT: Purpose of Review: One of the vital functions of the nervous system is to provide information about the threat of injury. The sensation of pain by its inherent aversive nature, contributes to this function. The mainstay of medical pain therapy remains drugs that have been around for decades, like opiates and non-opioid drugs. However, adverse effects of opiates, particularly tolerance, limit their clinical use. Several lines of investigations have shown that systemic administration of non-opioid, non-steroidal anti-inflammatory drugs (NSAIDs) induces antinociception with some effects of tolerance. In this review, we report that repeated microinjections of NSAIDs analgin, clodifen, ketorolac and xefocam into the central nucleus of amygdala, the midbrain periaqueductal grey matter and nucleus raphe magnus in the following 4 days result in progressively less antinociception compared to the saline control testing in the tail-flick reflex and hot plate latency tests. Hence, tolerance develops to these drugs and cross-tolerance to morphine in male rats. Conclusions: Presented data show that repeated microinjections of NSAIDs into the central nucleus of amygdala, the midbrain periaqueductal grey matter and nucleus raphe magnus induce antinociception and then exhibit tolerance. These findings strongly support the suggestion of endogenous opioid system involvement in NSAIDs antinociception, as it is blocked by an opioid antagonist naloxone. Moreover, the descending pain-control system, the periaqueductal grey – rostral ventro-medial part of medulla circuit should be viewed as a pain-modulation system.
    Annual Research and Review in Biology. 02/2014; 4(12):1887-1901.
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    Merab G. Tsagareli
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    ABSTRACT: Transient receptor potential (TRP) ion channels have been extensively investigated over the past few years and they are being ardently pursued as targets for drug discovery. Several factors make TRP ion channels appealing as drug targets. First,they are the largest group of noxious stimulus detectors in pain receptors (nociceptors). Second, although pain is currently the most advanced TRP channel-related field, an increasing number of gene deletion researches in animals and genetic association studies in humans have demonstrated that the pathophysiological roles of TRP channels extend well beyond the sensory nervous system (vision, olfaction, taste, mechano- and thermosensation, and osmoregulation). Many studies implicate them in other body systems, including pulmonary, cardiovascular, renal, and bladder systems. Many TRP channels are expressed by the central nervous system; some are expressed at the spinal cord level (for example TRPA1, TRPM8 and TRPV1 channels), whereas others are expressed at high levels in the cerebrum (e.g., TRPC3 in cerebellar Purkinje cells, and TRPC5 in the hippocampus and amygdala). TRPM2 and TRPM7 are expressed in brain neurons and microglia and are implicated in various pathologies related to oxidative stress, including the focal ischemia model of stroke. Therefore,TRPM7 antagonists may have a role in the treatment of stroke. The TRPM2 gene is also a candidate risk factor gene for bipolar disorder. Recent findings in the field of pain have established a subset of TRP channels that are activated by temperature (the so-called thermoTRP ion channels) and are capable of initiating sensory nerve impulses following the detection of thermal, as well as mechanical and chemical irritant stimuli. At least, a family of six thermoTRP channels (TRPA1, TRPM8, TRPV1, TRPV2, TRPV3, and TRPV4) exhibits sensitivity to increases or decreases in temperature as well as to chemical substances that elicit similar hot or cold sensations. Such irritants include menthol from mint, cinnamaldehyde, gingerol, capsaicin from chili peppers, mustard oil, camphor, eugenol from cloves, and others. This review focuses on recent developments in the TRP ion channel-related area and highlights evidence supporting TRP channels as promising targets for new analgesic drugs at the periphery and central levels and opportunities for therapeutic intervention.
    Frontiers in CNS Drug Discovery, Vol. 2 09/2013: chapter 5: pages 118-145; Benthan Science Publisher., ISBN: 978-1-60805-768-9
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    ABSTRACT: It was recently found that transient receptor potential (TRP) channels play an important role in the transduction of thermal, mechanical, and chemical stimuli underlying the somatic sensation. Several types of TRP channels exhibit sensitivity to increases or decreases in temperature, as well as to the action of chemical ligands that elicit similar thermal or painful sensations. These agents include menthol, mustard oil, cinnamaldehyde (CA), gingerol, capsaicin, camphor, eugenol, and others. Cinnamaldehyde is a pungent chemical obtained from cinnamon, which acts as an agonist of the TRPA1 channels; these channels were originally reported to be activated by cold temperatures (below 18°C). TRPA1 is also implicated in cold nociception. However, its role in the formation of cold pain is more controversial, with discrepant reports that TRPA1s do or do not respond to intense cooling. Menthol derived from plants of the mint family enhances the feeling of coldness by interacting with the cold-sensitive TRPM8 channels, but its effect on pain is less well understood. Using behavioral methods, we showed that unilateral intraplantar injection of CA (5 to 20%) induced a significant concentration-dependent decrease in the latency for ipsilateral paw withdrawal from a noxious heat stimulus, i.e., heat hyperalgesia. Cinnamaldehyde also significantly reduced mechanical withdrawal thresholds for the injected paw, i.e., evoked mechanical allodynia. Bilateral intraplantar injections of CA resulted in a significant cold hyperalgesia (cold plate test) and a weak enhancement of innocuous cold avoidance (thermal preference test). In contrast to CA, menthol in a dose-dependent manner increased the latency for noxious heat-evoked withdrawal, i.e., exerted an antinociceptive effect. Menthol did not affect mechanosensation except for a weak allodynic effect when applied in the highest concentration used (40 %), indicating that it did not exert a local anesthetic effect. Menthol had a biphasic effect on cold avoidance. High concentrations of menthol reduced cold avoidance, i.e., induced cold hypoalgesia, while low menthol concentrations significantly intensified cold avoidance. The highest menthol concentration provided cold hypoalgesia (cold plate test), while lower concentrations had no effect. Taken together, our data support the idea that TRPA1 and TRPM8 channels represent promising peripheral targets for pain modulation.
    Neurophysiology 07/2013; 43(4):329-339. · 0.17 Impact Factor
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    ABSTRACT: Transient receptor potential channels (TRP) have been extensively investigated over the past few years. Recent findings in the field of pain have established a family of six thermoTRP channels (TRPA1, TRPM8, TRPV1, TRPV2, TRPV3, and TRPV4) that exhibits sensitivity to increases or decreases in temperature, as well as to chemical substances eliciting the respective hot or cold sensations. Such irritants include menthol, cinnamaldehyde, gingerol, mustard oil, capsaicin, camphor, eugenol, and others. In this study, we used behavioral and electrophysiological methods to investigate if mustard oil (allyl isothiocyanate, AITC) and capsaicin affect the sensitivity to thermal, innocuous cold, and mechanical stimuli in male rats. Unilateral intraplantar injections of AITC and capsaicin induced significant decreases in the latency for ipsilateral paw withdrawal from a noxious heat stimulus, i.e., heat hyperalgesia. These agents also significantly reduced the mechanical withdrawal thresholds of the injected paw, i.e., mechanical allodynia. Bilateral intraplantar injections of AITC resulted in a twophase effect on cold avoidance (thermal preference test). A low concentration of AITC (5%) did not change cold avoidance similarly to the vehicle control, while higher AITC concentrations (10 and 15%) significantly reduced cold avoidance, i.e., induced cold hypoalgesia. Capsaicin acted in almost the same manner. These results indicate that TRPA1 channels are clearly involved in pain reactions, and the TRPA1 agonist AITC enhances the heat pain sensitivity, possibly by indirectly modulating TRPV1 channels co-expressed in nociceptors with TRPA1s. In electrophysiological experiments, neuronal responses to electrical and graded mechanical and noxious thermal stimulations were tested before and after cutaneous application of AITC. Repetitive application of AITC initially increased the firing rate of spinal wide-dynamic range neurons; this was followed by rapid desensitization that persisted when AITC application was reapplied 30 min later. The responses to noxious thermal (but not to mechanical) stimuli were significantly enhanced irrespective of whether the neuron was directly activated by AITC. These findings indicate that AITC produced peripheral sensitization of heat nociceptors. Overall, our data support the role of hermosensitive TRPA1 and TRPV1 channels in pain modulation and show that these thermoTRP channels are promising targets for the development of a new group of analgesic drugs.
    Neurophysiology 07/2013; 45(4). · 0.17 Impact Factor
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    Merab G. Tsagareli
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    ABSTRACT: Pain receptors, nociceptors inputs to the spinal cord and supra spinal structures triggering a prolonged but reversible increase in the excitability and synaptic efficacy of neurons in central nociceptive pathways, is the phenomenon of central sensitization. Key processes for pain memory stabilizing could be considering processes of peripheral and central sensitizations. Mechanical hypersensitivity and allodynia to light touch after central sensitization are pathological in that they are evoked by Aβ low threshold mechanoreceptors, which normally do not produce painful sensations. Peripheral sensitization allows low-intensity stimuli to produce pain by activating Aδ and C nociceptors whereas central sensitization allows normal low- threshold Aβ mechanoreceptors to produce pain as a result of changes in sensory processing in the spinal cord. During peripheral and central sensitization, the receptive fields of dorsal horn neurons expand beyond the site of injury into surrounding non-injured tissue. The clinical result of all above changes is hyperalgesia, allodynia, spontaneous pain, referred pain and sympathetically maintained pain. Therefore, these persistent sensory responses to noxious stimuli are a form of memory, the memory for pain. Long lasting synaptic plasticity as the long-term potentiation at spinal and supra-spinal levels could undergo hyperalgesia and allodynia. The latter could be providing neuronal basis for persistent pain and pain memory. Thus, it will be particularly important to know how to regulate long-lasting plastic changes in spinal cord, thalamus and cortex. Molecular mechanisms of these plastic processes could be main targets for new therapeutic drugs in pain relief.
    World Journal of Neuroscience 02/2013; 3(1):39-48.
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    Merab G. Tsagareli
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    ABSTRACT: One of the crucial cellular processes for major symptoms of pain, like hyperalgesia and allodynia, is considered as a phenomenon of sensitization. Key processes for pain memory stabilizing are peripheral and central sensitizations. Mechanical hypersensitivity and allodynia to light touch after central sensitization are pathologic in that they are evoked by Aβ low threshold mechanoreceptors, which normally do not produce painful sensations. Peripheral sensitization allows low-intensity stimuli to produce pain by activating Aδ and C nociceptors whereas central sensitization allows normal low-threshold Aβ mechanoreceptors to produce pain as a result of changes in sensory processing in the spinal cord. During peripheral and central sensitization, the receptive fields of dorsal horn neurons expand beyond the site of injury into surrounding uninjured tissue. The clinical result of all above changes is hyperalgesia, allodynia, spontaneous pain, referred pain and sympathetically maintained pain. These persistent sensory responses to noxious stimuli are a form of memory, the memory for pain. Long-lasting synaptic plasticity as long-term potentiation at spinal and supraspinal levels could be providing the neuronal basis for persistent pain and pain memory. Thus, it will be particularly important to know how to regulate long-lasting plastic changes in the spinal cord, thalamus and cortex. Molecular mechanisms of these plastic processes could be main targets for new therapeutic drugs in pain relief. This review presents findings from recent studies that examined the possibility of relations between pain and memory.
    Journal of Biological Physics and Chemistry 12/2012; 12(6):174-181.
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    ABSTRACT: Background / Purpose: A family of six thermo-transient receptor potential (TRP) channels (TRPA1, TRPM8, TRPV1, TRPV2, TRPV3, and TRPV4) exhibits sensitivity to increases or decreases in temperature as well as to chemical substances that elicit similar hot or cold sensations. Such irritants include menthol from mint, cinnamaldehyde, gingerol, capsaicin from chili peppers, mustard oil, camphor, eugenol from cloves, and others. In this study, we have used behavioral and electrophysiological methods to investigate if cinnamaldehyde (CA), mustard oil (allyl isothiocyanate, AITC) and menthol affect sensitivity to thermal (hot and cold) changes, innocuous cold, and mechanical sensitivity in male rats. Main conclusion: Presented data support the role of thermosensitive TRPA1 and TRPM8 channels in pain modulation. These thermo-TRP channels represent promising targets for the development of a new group of analgesic drugs.
    International Workshop on Transient Receptor Potential (TRP) Channels 2012; 10/2012
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    Merab G Tsagareli
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    ABSTRACT: This article is dedicated to one of the outstanding scientists of the nineteenth century: Ivane Tarkhnishvili (Tarchanoff), a Russian physiologist of Georgian origin who graduated from the St. Petersburg Medico-Surgical Academy and worked under the supervision of the founder of Russian physiology, Ivan Sechenov. Among his numerous contributions was the discovery of the skin galvanic reflex; however, Tarkhnishvili's most significant contribution was the discovery of the influence of X-rays on the central nervous system, animal behavior, the heart and circulation, and embryonic development. Indeed, these works have given rise to a new field in science (radiobiology).
    Journal of the History of the Neurosciences. 10/2012; 21(4):393-408.
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    ABSTRACT: Pain is a sensation related to potential or actual damage in some tissue of the body. The mainstay of medical pain therapy remains drugs that have been around for decades, like non-steroidal anti-inflammatory drugs (NSAIDs), or opiates. However, adverse effects of opiates, particularly tolerance, limit their clinical use. Several lines of investigations have shown that systemic (intraperitoneal) administration of NSAIDs induces antinociception with some effects of tolerance. In this review, we report that repeated microinjection of NSAIDs analgin, clodifen, ketorolac and xefocam into the central nucleus of amygdala, the midbrain periaqueductal grey matter and nucleus raphe magnus in the following 4 days result in progressively less antinociception compared to the saline control testing in the tail-flick reflex and hot plate latency tests. Hence, tolerance develops to these drugs and cross-tolerance to morphine in male rats. These findings strongly support the suggestion of endogenous opioid involvement in NSAIDs antinociception and tolerance in the descending pain-control system. Moreover, the periaqueductal grey-rostral ventro-medial part of medulla circuit should be viewed as a pain-modulation system. These data are important for human medicine. In particular, cross-tolerance between non-opioid and opioid analgesics should be important in the clinical setting.
    Neural Regeneration Research 05/2012; 7(13):1029-1039. · 0.23 Impact Factor
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    Merab G Tsagareli
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    ABSTRACT: Traditionally the term Cognition is applied to processes such as association and memory, language and concept formation, attention and perception, problem solving and action, and mental imagery as well. The first steps toward a study of cognition were taken in the late 19th century when it was discovered that many such higher mental functions could be selectively impaired by relatively focal brain lesions. Subsequent works had been devoted to obtaining a more detailed picture of possible behavior fractionations and more precise anatomical correlations by computerized tomography and magnetic resonance imaging. At the same time, localization of higher brain functions for sensory, perceptive and motor elements has not been at issue since the close of 19th century, but the interpretation of high-level deficits and hence of nature and extent of specialization within associative cortex is more contentious. In this regard, the role of cerebral hemispheres and their interaction is a very interesting problem in mental activity and cognitive processes. The basic concept of complementary specialization in which the left hemisphere plays the leading role in language and the right in visual and spatial ideation continues to receive qualified support. This chapter presents findings from recent studies that examined the possibility of hemispheric specialization and interaction in cognitive processes.
    Advances in Psychology Research, 01/2012: chapter No. 7: pages 183-204; Nova Science Publisher, Inc.., ISBN: 978-1-61470-171-2
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    Tsagareli M.G. and Tsiklauri N
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    ABSTRACT: Pain is a sensation related to potential or actual damage in some tissue of the organism. This alarm sign represents the beginning of a chain of biological events one purpose of which is to provide a warning to the organism. Pain perception in higher order species, including humans, also involves the activation of areas of the brain associated with emotions, such that we feel anxiety, anger, and fear as a result of pain. However when the pain signals remain over long periods of time they generate chronic pain. Despite the investment of significant resources by the pharmaceutical industry to identify novel analgesic drugs, chronic pain, which is most commonly defined as pain lasting longer than 3 months (i.e., outlasting the usual healing process), still represents a difficult treatment challenge in a large sector of the population. The mainstay of medical pain therapy remains drugs that have been around for decades, like non- steroidal anti-inflammatory drugs (NSAIDs), or drugs that have been around even for centuries, such as opiates. The latter are very powerful painkillers, but adverse effects limit their clinical use. The interaction of opioids and NSAIDs is of utmost interest. NSAIDs belong to the inhibitors of cyclo-oxygenases. They through the inhibition of cyclo-oxygenases inhibit synthesis of prostaglandins, which in their turn cause sensitization, and enhance of pain signals. For the last decade, it has been revealed that non-opioid drugs NSAIDs also could induce tolerance such as opioids. In this book, we consider in detail the effects of tolerance widely used NSAIDs by behavioral test models in rats.
    01/2012; Nova Biomedical, Nova Science Publishers, Inc., New York., ISBN: 978-1-62100-033-4
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    Merab G. Tsagareli
    Opioids: Pharmacology, Clinical Uses and Adverse Effects, 01/2012: chapter Pain concepts and treatment by opioids: Historic review: pages 15-33; Nova Science Publishers, Inc.., ISBN: 978-1-61942-101-1
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    ABSTRACT: Background / Purpose: The aim of this study was to examine opioid sensitivity of NSAIDs action in the nucleus raphe magnus (NRM) of male rats. 20 minutes after NSAIDs administration, we microinjected mu-opioid antagonist naloxone and tested rats for tail-flick (TF) and hot plate (HP) latencies. Main conclusion: Our results strongly suggest that endogenous opioid release plays a crucial role in NSAIDs antinociception. On the other hand, our evidence confirms once more that NRM is involved in the descending pain control circuit inhibiting spinal nocifensive reflexes.
    7th Congress of the European Federation of IASP Chapters (EFIC) 2011; 11/2011
  • European Journal of Pain Supplements 09/2011; 5(1):208-208.
  • European Neuropsychopharmacology 09/2011; 21. · 5.40 Impact Factor

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