Merab G. Tsagareli

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

Publications

  • Source
    [show abstract] [hide abstract]
    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.
  • Source
    [show abstract] [hide abstract]
    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.
  • Source
    Merab G. Tsagareli
    [show abstract] [hide abstract]
    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.
    09/2013: pages 118-145; , ISBN: 978-1-60805-768-9
  • Source
    [show abstract] [hide abstract]
    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. · 0.38 Impact Factor
  • Source
    Merab G. Tsagareli
    [show abstract] [hide abstract]
    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.
  • Source
    Merab G. Tsagareli
    [show abstract] [hide abstract]
    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.
  • Source
    Merab G Tsagareli
    [show abstract] [hide abstract]
    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.
  • Source
    [show abstract] [hide abstract]
    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 01/2012; 7(13):1029-1039. · 0.14 Impact Factor
  • Source
    Merab G. Tsagareli
    01/2012: pages 15-33; , ISBN: 978-1-61942-101-1
  • Source
    Tsagareli M.G. and Tsiklauri N
    [show abstract] [hide abstract]
    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
  • Source
    Merab G Tsagareli
    [show abstract] [hide abstract]
    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.
    01/2012: pages 183-204; , ISBN: 978-1-61470-171-2
  • [show abstract] [hide abstract]
    ABSTRACT: Our recent investigations demonstrated that microinjections of three nonsteroidal anti-inflammatory drugs (NSAIDs), Analgin, ketorolac, or xefocam, into the central nucleus of the amygdala produce tolerance to these drugs and cross-tolerance to morphine. We observed the same phenomenon in the midbrain peri- aqueductal gray matter. In this report, we show that microinjections of NSAIDs into the nucleus raphe magnus (NRM) produces antinociception, as indicated by latency increases in both tail-flick (TF) and hot-plate (HP) reflexes compared to controls with saline microinjected into the same nucleus. Furthermore, microinjection of the μ-opioid antagonist naloxone into the NRM significantly decreased antinociceptive effects of NSAIDs characterized by the TF and HP latencies on the 1st experimental day. On the 2nd day, naloxone also provided some trend effects in both TF and HP tests. These results strongly support the suggestion that the endogenous opioid system is significantly involved in NSAID-induced antinociception and tolerance.
    Neurophysiology 06/2011; 43(3):213-216. · 0.38 Impact Factor
  • European Journal of Pain Supplements 01/2011; 5(1):208-208.
  • European Neuropsychopharmacology - EUR NEUROPSYCHOPHARMACOL. 01/2011; 21.
  • Source
    [show abstract] [hide abstract]
    ABSTRACT: Repeated injection of opioid analgesics can lead to a progressive loss of effect. This phenomenon is known as tolerance. Several lines of investigations have shown that systemic, intraperitoneal administration or the microinjection of non-opioid analgesics, non-steroidal anti-inflammatory drugs (NSAIDs) into the midbrain periaqueductal gray matter induces antinociception with some effects of tolerance. Our recent study has revealed that microinjection of three drugs analgin, ketorolac, and xefocam into the central nucleus of amygdala produce tolerance to them and cross-tolerance to morphine. Here we report that repeated administrations of these NSAIDs into the nucleus raphe magnus (NRM) in the following 4 days result in progressively less antinociception compare to the saline control, i.e., tolerance develops to these drugs in male rats. Special control experiments showed that post-treatment with the μ-opioid antagonist naloxone into the NRM significantly decreased antinociceptive effects of NSAIDs on the first day of testing in the tail-flick (TF) reflex and hot plate (HP) latency tests. On the second day, naloxone generally had trend effects in both TF and HP tests and impeded the development of tolerance to the antinociceptive effect of non-opioid analgesics. These findings strongly support the suggestion of endogenous opioid involvement in NSAIDs antinociception and tolerance in the descending pain-control system. Moreover, repeated injections of NSAIDs progressively lead to tolerance to them, cross-tolerance to morphine, and the risk of a withdrawal syndrome. Therefore, these results are important for human medicine too.
    Frontiers in Neuroscience 01/2011; 5:92.
  • European Journal of Pain Supplements 01/2011; 5(1):18-18.
  • [show abstract] [hide abstract]
    ABSTRACT: Our recent investigations have shown that microinjection of three non-steroidal anti-inflammatory drugs (NSAIDs) analgin, ketorolac and xefocam into the central nucleus of amygdala produce tolerance to these drugs and cross-tolerance to morphine. We have observed the same phenomenon in midbrain periaqueductal grey matter and nucleus raphe magnus. The medullar nucleus raphe magnus (NRM) is one of important parts of CNS circuit that controls nociceptive transmission at the level of spinal cord. It is functionally involved in descending pain modulation, and mainly consists of serotoninergic neurons. The aim of this study was to examine opioid sensitivity of NSAIDs action in NRM of male rats. For this purpose 30 minutes later of NSAIDs administrations we microinjected μ-opioid antagonist naloxone and tested rats for tail flick and hot plate latencies. Our investigation showed that microinjection of naloxone in NRM significantly decreased antinociceptive effects of NSAIDs at the first day in the TF and HP latencies. At the second day, naloxone generally had trend effects in both TF and HP tests. These results strongly support the suggestion on endogenous opioid involvement in NSAIDs antinociception and tolerance. On the other hand, our evidence confirms once more that NRM is involved in the descending pain control circuit inhibiting spinal nocifensive reflexes.
    Georgian medical news 01/2011;
  • Source
    Robert W. Doty, Merab G. Tsagareli
    [show abstract] [hide abstract]
    ABSTRACT: This short review is devoted to vicissitudes of life one of the outstanding physiologist of the 20th century Ivane S. Beritashvili (1884-1974). He was graduated from St. Petersburg University (1910) and for five years worked at the University Laboratory under supervision of N. Wedensky. Unfortunately, Beritashvili was afflicted by an adversity seldom encountered, the rejection of his thesis by his mentor. Beritashvili, therefore, had to leave St. Petersburg and move to Odessa (1916). After returning to homeland, he founded Department of Physiology (1919) and Institute of Physiology (1935) at the University of Tbilisi. Among his many contributions is the discovery of the rhythmical course of reciprocal inhibition in spinal reflexes (1911). Beritashvili was the first to demonstrate the excitatory and inhibitory reactions of brain stem reticular formation (1937). After important studies on the psycho-neural mechanisms of animal behavior, he made his most significant contribution by suggesting that such behavior is mediated by the image-driven memory (1947). For his unorthodox doctrine, (vis-à-vis Pavlov) Beritashvili was removed from his position of Director of Physiology Institute as being “anti-Pavlovian” and endured five years of isolation from science. Fortunately, in 1955 after Stalin’s death, he returned to his research and extensive work for the remaining 20 years was crowned by the publication of his most known volumes.
    Bulletin of Georgian National Academy of Sciences, New Series. 12/2010; 4(3):103-106.
  • Source
    [show abstract] [hide abstract]
    ABSTRACT: Menthol is used in analgesic balms and also in foods and oral hygiene products for its fresh cooling sensation. Menthol enhances cooling by interacting with the cold-sensitive thermoTRP channel TRPM8, but its effect on pain is less well understood. We presently used behavioral methods to investigate effects of topical menthol on thermal (hot and cold) pain and innocuous cold and mechanical sensitivity in rats. Menthol dose-dependently increased the latency for noxious heat-evoked withdrawal of the treated hindpaw with a weak mirror-image effect, indicating antinociception. Menthol at the highest concentration (40%) reduced mechanical withdrawal thresholds, with no effect at lower concentrations. Menthol had a biphasic effect on cold avoidance. At high concentrations (10% and 40%) menthol reduced avoidance of colder temperatures (15 degrees C and 20 degrees C) compared to 30 degrees C, while at lower concentrations (0.01-1%) menthol enhanced cold avoidance. In a -5 degrees C cold plate test, 40% menthol significantly increased the nocifensive response latency (cold hypoalgesia) while lower concentrations were not different from vehicle controls. These results are generally consistent with neurophysiological and human psychophysical data and support TRPM8 as a potential peripheral target of pain modulation.
    Behavioural Brain Research 10/2010; 212(2):179-86. · 3.33 Impact Factor
  • Source
    9th "Gagra Talks", Intl. Conference Fundamental Problems Neuroscience; 10/2010

11 Following View all

13 Followers View all