scholarly journals mTOR Kinase: A Possible Pharmacological Target in the Management of Chronic Pain

2015 ◽  
Vol 2015 ◽  
pp. 1-13 ◽  
Author(s):  
Lucia Lisi ◽  
Paola Aceto ◽  
Pierluigi Navarra ◽  
Cinzia Dello Russo
Keyword(s):  
Chronic Pain ◽  
Neuropathic Pain ◽  
Mammalian Target Of Rapamycin ◽  
Public Health Problem ◽  
Experimental Models ◽  
Major Public Health Problem ◽  
Major Mechanism ◽  
Mtor Kinase ◽  
Pain Transmission ◽  
Pharmacological Target

Chronic pain represents a major public health problem worldwide. Current pharmacological treatments for chronic pain syndromes, including neuropathic pain, are only partially effective, with significant pain relief achieved in 40–60% of patients. Recent studies suggest that the mammalian target of rapamycin (mTOR) kinase and downstream effectors may be implicated in the development of chronic inflammatory, neuropathic, and cancer pain. The expression and activity of mTOR have been detected in peripheral and central regions involved in pain transmission. mTOR immunoreactivity was found in primary sensory axons, in dorsal root ganglia (DRG), and in dorsal horn neurons. This kinase is a master regulator of protein synthesis, and it is critically involved in the regulation of several neuronal functions, including the synaptic plasticity that is a major mechanism leading to the development of chronic pain. Enhanced activation of this pathway is present in different experimental models of chronic pain. Consistently, pharmacological inhibition of the kinase activity turned out to have significant antinociceptive effects in several experimental models of inflammatory and neuropathic pain. We will review the main evidence from animal and human studies supporting the hypothesis that mTOR may be a novel pharmacological target for the management of chronic pain.

scholarly journals Animal Models of Undernutrition and Enteropathy as Tools for Assessment of Nutritional Intervention.

Nutrients ◽  
2019 ◽  
Vol 11 (9) ◽  
pp. 2233 ◽  
Author(s):  
Salameh ◽  
Morel ◽  
Zeilani ◽  
Déchelotte ◽  
Marion-Letellier
Keyword(s):  
Growth Failure ◽  
Public Health Problem ◽  
Nutritional Intervention ◽  
Experimental Models ◽  
Major Public Health Problem ◽  
Gut Function ◽  
Environmental Enteric Dysfunction ◽  
Clinical Models ◽  
Novel Therapeutic Strategies ◽  
The Impact

: Undernutrition is a major public health problem leading to 1 in 5 of all deaths in children under 5 years. Undernutrition leads to growth stunting and/or wasting and is often associated with environmental enteric dysfunction (EED). EED mechanisms leading to growth failure include intestinal hyperpermeability, villus blunting, malabsorption and gut inflammation. As non-invasive methods for investigating gut function in undernourished children are limited, pre-clinical models are relevant to elucidating the pathophysiological processes involved in undernutrition and EED, and to identifying novel therapeutic strategies. In many published models, undernutrition was induced using protein or micronutrient deficient diets, but these experimental models were not associated with EED. Enteropathy models mainly used gastrointestinal injury triggers. These models are presented in this review. We found only a few studies investigating the combination of undernutrition and enteropathy. This highlights the need for further developments to establish an experimental model reproducing the impact of undernutrition and enteropathy on growth, intestinal hyperpermeability and inflammation, that could be suitable for preclinical evaluation of innovative therapeutic intervention.

scholarly journals ANIMAL MODELS FOR THE STUDY OF LEISHMANIASIS IMMUNOLOGY

2014 ◽  
Vol 56 (1) ◽  
pp. 1-11 ◽  
Author(s):  
Elsy Nalleli Loria-Cervera ◽  
Fernando Jose Andrade-Narvaez
Keyword(s):  
Animal Models ◽  
Human Disease ◽  
Public Health Problem ◽  
Leishmania Species ◽  
Experimental Models ◽  
Sand Fly ◽  
Leishmania Infection ◽  
Major Public Health Problem ◽  
Wild Rodents ◽  
Experimental Conditions

Leishmaniasis remains a major public health problem worldwide and is classified as Category I by the TDR/WHO, mainly due to the absence of control. Many experimental models like rodents, dogs and monkeys have been developed, each with specific features, in order to characterize the immune response to Leishmania species, but none reproduces the pathology observed in human disease. Conflicting data may arise in part because different parasite strains or species are being examined, different tissue targets (mice footpad, ear, or base of tail) are being infected, and different numbers (“low” 1×102 and “high” 1×106) of metacyclic promastigotes have been inoculated. Recently, new approaches have been proposed to provide more meaningful data regarding the host response and pathogenesis that parallels human disease. The use of sand fly saliva and low numbers of parasites in experimental infections has led to mimic natural transmission and find new molecules and immune mechanisms which should be considered when designing vaccines and control strategies. Moreover, the use of wild rodents as experimental models has been proposed as a good alternative for studying the host-pathogen relationships and for testing candidate vaccines. To date, using natural reservoirs to study Leishmania infection has been challenging because immunologic reagents for use in wild rodents are lacking. This review discusses the principal immunological findings against Leishmania infection in different animal models highlighting the importance of using experimental conditions similar to natural transmission and reservoir species as experimental models to study the immunopathology of the disease.

scholarly journals Pathogenesis of Cerebral Malaria: Recent Experimental Data and Possible Applications for Humans

2001 ◽  
Vol 14 (4) ◽  
pp. 810-820 ◽  
Author(s):  
Jinning Lou ◽  
Ralf Lucas ◽  
Georges E. Grau
Keyword(s):  
Endothelial Cells ◽  
Cerebral Malaria ◽  
Public Health Problem ◽  
Major Complication ◽  
Experimental Models ◽  
Soluble Form ◽  
Recent Experimental Data ◽  
Major Public Health Problem

SUMMARY Malaria still is a major public health problem, partly because the pathogenesis of its major complication, cerebral malaria, remains incompletely understood. Experimental models represent useful tools to better understand the mechanisms of this syndrome. Here, data generated by several models are reviewed both in vivo and in vitro; we propose that some pathogenic mechanisms, drawn from data obtained from experiments in a mouse model, may be instrumental in humans. In particular, tumor necrosis factor (TNF) receptor 2 is involved in this syndrome, implying that the transmembrane form of TNF may be more important than the soluble form of the cytokine. It has also been shown that in addition to differences in immune responsiveness between genetically resistant and susceptible mice, there are marked differences at the level of the target cell of the lesion, namely, the brain endothelial cell. In murine cerebral malaria, a paradoxical role of platelets has been proposed. Indeed, platelets appear to be pathogenic rather than protective in inflammatory conditions because they can potentiate the deleterious effects of TNF. More recently, it has been shown that interactions among platelets, leukocytes, and endothelial cells have phenotypic and functional consequences for the endothelial cells. A better understanding of these complex interactions leading to vascular injury will help improve the outcome of cerebral malaria.

Chronic Oral Gabapentin Reduces Elements of Central Sensitization in Human Experimental Hyperalgesia

2004 ◽  
Vol 101 (6) ◽  
pp. 1400-1408 ◽  
Author(s):  
Hanne Gottrup ◽  
Gitte Juhl ◽  
Anders D. Kristensen ◽  
Robert Lai ◽  
Boris A. Chizh ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Central Sensitization ◽  
Human Subjects ◽  
Clinical Signs ◽  
Experimental Models ◽  
Human Model ◽  
Chronic Neuropathic Pain ◽  
Double Blind ◽  
Pain Transmission ◽  
Parallel Group Design

Background In chronic pain, increased activity from intact or damaged peripheral nerve endings results in an enhanced response in central pain transmission systems, a mechanism known as central sensitization. Central sensitization can also be invoked in human experimental models. Therefore, these models may be useful to characterize novel analgesics in humans. The anticonvulsant gabapentin has demonstrated efficacy in patients with neuropathic pain, but its mode of action remains unclear. This study examined the effects of gabapentin on signs of central sensitization (brush and pinprick hyperalgesia) in a human model of capsaicin-evoked pain, using a gabapentin dosing regimen similar to that used in the clinic. The aims were to determine whether gabapentin, dosed in a manner similar to that used in the clinic, affected the various components of central sensitization and to assess the utility of this model for characterizing novel analgesics. Methods Intradermal capsaicin (100 microg/20 microl) was administered in the volar forearm of 41 male human volunteers to induce pain and clinical signs of central sensitization. Gabapentin (titrated to 2,400 mg daily) or placebo was given orally for 15 days in a randomized, double-blind, parallel-group design. The capsaicin test was conducted at baseline and after gabapentin or placebo. Endpoints were the size of areas of brush-evoked allodynia (with cotton gauze) and pinprick hyperalgesia (with von Frey filament), and the intensity of ongoing brush- and pinprick-evoked pain. Results Gabapentin significantly reduced the area of brush allodynia compared with placebo (P </= 0.05) and insignificantly attenuated the area of pinprick hyperalgesia. Gabapentin had no significant effect on spontaneous and evoked pain intensity. Conclusion Oral gabapentin, administered to healthy volunteers in a regimen similar to that used in treating chronic neuropathic pain, reduces measures of central sensitization evoked by intradermal capsaicin. This suggests that the pain-relieving effect in chronic neuropathic pain condition is linked to the effect of gabapentin on central sensitization. The ability of the capsaicin model to detect the efficacy of this standard treatment of neuropathic pain suggests that it may have a predictive value for detection of efficacy in human subjects.

scholarly journals ERK activation in noradrenergic and serotonergic brainstem nuclei in chronic pain upon noxious stimulation and antidepressants treatment

2009 ◽  
Vol 15 (S3) ◽  
pp. 7-8
Author(s):  
G. Borges ◽  
E. Berrocoso ◽  
A. Ortega-Alvaro ◽  
J. A. Micó ◽  
F. L. Neto
Keyword(s):  
Chronic Pain ◽  
Neuropathic Pain ◽  
Chronic Constriction Injury ◽  
Noxious Stimulation ◽  
Analgesic Action ◽  
Chronic Neuropathic Pain ◽  
Erk Activation ◽  
Pain Transmission ◽  
Extracellular Signal ◽  
Brainstem Nuclei

AbstractChronic neuropathic pain is a pathology that affects thousands of people worldwide. Antidepressants have been prescribed for the treatment of this sort of pain but the mechanisms underlying their analgesic action remain unknown. Extracellular-signal regulated kinases (ERKs) are being implicated in pain transmission and modulation as well as in the pathophysiology of depression. In order to clarify some of the mechanisms which might be related to the analgesic effect of antidepressants, we started by evaluating possible changes in the pattern of activation of ERKs in rats with chronic constriction injury (CCI), an experimental model of chronic

scholarly journals Controlled activation of cortical astrocytes can reverse neuropathic chronic pain

2021 ◽  
Author(s):  
Ikuko Takeda ◽  
Kohei Yoshihara ◽  
Dennis Cheung ◽  
Masakazu Agetsuma ◽  
Makoto Tsuda ◽  
...  
Keyword(s):  
Public Health ◽  
Chronic Pain ◽  
Sciatic Nerve ◽  
Peripheral Nerves ◽  
Treatment Options ◽  
Public Health Problem ◽  
Afferent Input ◽  
Major Public Health Problem ◽  
Partial Sciatic Nerve Ligation ◽  
Spine Plasticity

Abstract Chronic pain is a major public health problem that currently lacks effective treatment options. Here, we report a novel combination therapy that can effectively reverse chronic pain induced by nerve injury in mice. By combing transient nerve block to inhibit noxious afferent input from injured peripheral nerves, with transient concurrent activation of astrocytes in the somatosensory cortex (S1) by either transcranial direct current stimulation (tDCS) or via the chemogenetic DREADD system, we could reverse allodynia previously established by partial sciatic nerve ligation (PSL). Activation of astrocytes initiated spine plasticity to reduce synapses formed shortly after PSL. The cure from allodynia persisted long after ceasing active treatment. Thus, our study represents the first report of a robust, readily translatable approach for treating chronic pain that capitalizes on the causative interplay between noxious afferents, sensitized central neuronal circuits and astrocytic-activation induced plasticity.

scholarly journals Antitumor Activity of Monoterpenes Found in Essential Oils

2014 ◽  
Vol 2014 ◽  
pp. 1-35 ◽  
Author(s):  
Marianna Vieira Sobral ◽  
Aline Lira Xavier ◽  
Tamires Cardoso Lima ◽  
Damião Pergentino de Sousa
Keyword(s):  
Public Health ◽  
Antitumor Activity ◽  
Essential Oils ◽  
Genetic Disease ◽  
Public Health Problem ◽  
Mechanisms Of Action ◽  
Experimental Models ◽  
Major Public Health Problem ◽  
Bioactive Substances ◽  
Chemical Structures

Cancer is a complex genetic disease that is a major public health problem worldwide, accounting for about 7 million deaths each year. Many anticancer drugs currently used clinically have been isolated from plant species or are based on such substances. Accumulating data has revealed anticancer activity in plant-derived monoterpenes. In this review the antitumor activity of 37 monoterpenes found in essential oils is discussed. Chemical structures, experimental models, and mechanisms of action for bioactive substances are presented.

scholarly journals Does Integrative Medicine Reduce Prescribed Opioid Use for Chronic Pain? A Systematic Literature Review

Pain Medicine ◽  
2019 ◽  
Vol 21 (4) ◽  
pp. 836-859
Author(s):  
Samah Hassan ◽  
Qingping Zheng ◽  
Erica Rizzolo ◽  
Evrim Tezcanli ◽  
Sukriti Bhardwaj ◽  
...  
Keyword(s):  
Chronic Pain ◽  
Integrative Medicine ◽  
Behavioral Therapy ◽  
Public Health Problem ◽  
Preliminary Evidence ◽  
Major Public Health Problem ◽  
Opioid Use ◽  
Cross Sectional ◽  
Opioid Crisis ◽  
Quasi Experimental

Abstract Background Chronic pain (CP) is a major public health problem. Many patients with CP are increasingly prescribed opioids, which has led to an opioid crisis. Integrative medicine (IM), which combines pharmacological and complementary and alternative medicine (CAM), has been proposed as an opioid alternative for CP treatment. Nevertheless, the role of CAM therapies in reducing opioid use remains unclear. Objectives To explore the effectiveness of the IM approach or any of the CAM therapies to reduce or cease opioid use in CP patients. Methods An online search of MEDLINE and Embase, CINAHL, PubMed supp., and Allied and Complementary Medicine Database (AMED) for studies published in English from inception until February 15, 2018, was conducted. The Mixed Methods Appraisal Tool (MMAT) was used to critically appraise selected studies. Results The electronic search yielded 5,200 citations. Twenty-three studies were selected. Eight studies were randomized controlled trials, seven were retrospective studies, four studies were prospective observational, three were cross-sectional, and one was quasi-experimental. The majority of the studies showed that opioid use was reduced significantly after using IM. Cannabinoids were among the most commonly investigated approaches in reducing opioid use, followed by multidisciplinary approaches, cognitive-behavioral therapy, and acupuncture. The majority of the studies had limitations related to sample size, duration, and study design. Conclusions There is a small but defined body of literature demonstrating positive preliminary evidence that the IM approach including CAM therapies can help in reducing opioid use. As the opioid crisis continues to grow, it is vital that clinicians and patients be adequately informed regarding the evidence and opportunities for IM/CAM therapies for CP.

Gabapentin Suppresses Cutaneous Hyperalgesia following Heat-Capsaicin Sensitization

2002 ◽  
Vol 97 (1) ◽  
pp. 102-107 ◽  
Author(s):  
Jesper Dirks ◽  
Karin L. Petersen ◽  
Michael C. Rowbotham ◽  
Jørgen B. Dahl
Keyword(s):  
Chronic Pain ◽  
Clinical Trials ◽  
Neuropathic Pain ◽  
Outcome Measures ◽  
Acute Pain ◽  
Normal Skin ◽  
Secondary Outcome ◽  
Secondary Hyperalgesia ◽  
Thermal Nociception ◽  
Pain Transmission

Background The anticonvulsant gabapentin, proven effective for neuropathic pain in two large, placebo-controlled clinical trials, is widely used for treatment of chronic pain. Preclinical studies have demonstrated analgesic and antiallodynic effects in models involving neuronal sensitization and nerve injury, without affecting acute pain transmission. The aim of the present study was to link data from animal models and clinical trials for chronic pain by investigating the effect of gabapentin on acute nociception and experimentally induced cutaneous hyperalgesia in healthy volunteers. Methods The human experimental hyperalgesia model, the heat-capsaicin sensitization model, was induced in 25 healthy male volunteers. Subjects received oral gabapentin (1,200 mg) or placebo after heat-capsaicin sensitization was established on the forearm. The primary outcome measures were the sizes of the areas of secondary hyperalgesia to von Frey hair and brush stimulation on the forearm. Secondary outcome measures were as follows: (1) size of secondary hyperalgesia area in response to brief thermal sensitization procedure on the thigh; (2) heat pain detection thresholds in normal and sensitized skin; and (3) painfulness of 1 min of 45 degrees C stimulation in normal skin. Results Oral gabapentin profoundly suppressed established cutaneous sensitization on the forearm and prevented development of cutaneous sensitization on the thigh. Thermal nociception in normal skin was unchanged. Side effects were modest. Conclusion The results link preclinical findings with results from clinical trials of neuropathic pain. The results further suggest that gabapentin may prove effective in acute pain disorders involving neuronal sensitization, such as postoperative pain and acute herpetic pain, and could prove effective in prevention of chronic pain.

Experimental pain models and clinical chronic pain: Is plasticity enough to link them?

1997 ◽  
Vol 20 (3) ◽  
pp. 458-459 ◽  
Author(s):  
Paolo Marchettini ◽  
Marco Lacerenza ◽  
Fabio Formaglio
Keyword(s):  
Chronic Pain ◽  
Neuropathic Pain ◽  
Animal Models ◽  
Experimental Pain ◽  
Experimental Models ◽  
Basic Information ◽  
Pain Models ◽  
Clinical Conditions

The central hyperexcitability observed in animal models supports a pathophysiological explanation for chronic human pain. Novel information on cholecystokinin (CCK) upregulation offers a rationale for reduced opioid response in neuropathic pain. However, the basic information provided by scientists should not lead clinicians to equate experimental models to chronic human conditions. Clinicians should provide careful reports and attempt to classify pathophysiologically clinical conditions that have so far been grouped generically. [blumberg et al.; coderre & katz; dickenson; wiesenfeld-hallin et al.]

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