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

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

Analytical Method for Joint Optimization of Ffe and Dfe Equalizations for Multi-Level Signals

Channel equalization is the efficient method for recovering distorted signal and correspondingly reducing bit error rate (BER). Different type of equalizations, like feed forward equalization (FFE) and decision feedback equalization (DFE) are canceling channel effect and recovering channel response. Separate optimization of tap coefficients for FFE and DFE does not give optimal result. In this case FFE and DFE tap coefficients are found separately and they are not collaborating. Therefore, the final equalization result is not global optimal. In the present paper new analytical method for finding best tap coefficients for FFE and DFE joint equalization is introduced. The proposed method can be used for both NRZ and PAM4 signals. The idea of the methodology is to combine FFE and DFE tap coefficients into one optimization problem and allow them to collaborate and lead to the global optimal solution. The proposed joint optimization method is fast, easy to implement and efficient. The method has been tested for several measured channels and the analysis of the results are discussed

Parallel Type Decomposition Scheme for Quasi-Linear Abstract Hyperbolic Equation

Cauchy problem for an abstract hyperbolic equation with the Lipschitz continuous operator is considered in the Hilbert space. The operator corresponding to the elliptic part of the equation is a sum of operators $A_{1},\,A_{2},\,\ldots,\,A_{m}$. Each addend is a self-adjoint and positive definite operator. A parallel type decomposition scheme for an approximate solution of the stated problem is constructed. The main idea of the scheme is that on each local interval classic difference problems are solved in parallel (independently from each other) respectively with the operators $A_{1},\,A_{2},\,\ldots,\,A_{m}$. The weighted average of the received solutions is announced as an approximate solution at the right end of the local interval. Convergence of the proposed scheme is proved and the approximate solution error is estimated, as well as the error of the difference analogue for the first-order derivative for the case when the initial problem data satisfy the natural sufficient conditions for solution existence.Comment: 21 pages, 3 figure

A Parallel Type Decomposition Scheme for Quasi-Linear Abstract Hyperbolic Equation

The Cauchy problem for an abstract hyperbolic equation with the Lipschitz continuous operator is considered in the Hilbert space. The operator corresponding to the elliptic part of the equation is the sum of operators A 1, A 2, A m {A {1},A{2},\ldots,A{m}}. Each summand is a self-adjoint and positive definite operator. A parallel type decomposition scheme for an approximate solution of the stated problem is constructed. The main idea of the scheme is that on each local interval the classical difference problems are solved in parallel (independently from each other) with the operators A 1, A 2, A m {A{1},A{2},\ldots,A{m}}. The weighted average of the obtained solutions is announced as an approximate solution at the right end of the local interval. The convergence of the proposed scheme is proved and the approximate solution error is estimated, as well as the error of the difference analogue for the first-order derivative for the case when the initial problem data satisfy the natural sufficient conditions for solution existence

NSAIDs attenuate hyperalgesia induced by TRP channel activation

Transient receptor potential (TRP) cation channels have been extensively investigated as targets for analgesic drug discovery. Because some non-steroidal anti-inflammatory drugs (NSAIDs) are structural analogs of prostaglandins (mediators of inflammation) and NSAIDs attenuate heat nociception and mechanical allodynia in models of inflammatory and neuropathic pain, we examined three widely used NSAIDs (diclofenac, ketorolac, and xefocam) on the activation of TRPA1 and TRPV1 channels using thermal paw withdrawal (Hargreaves) test and mechanical paw withdrawal (von Frey) test in male rats. Thermal withdrawal latencies and mechanical thresholds for both hind paws were obtained with 5, 15, 30, 45, 60, and 120 min intraplantar post-injection of TRPA1 agonizts, allyl isothiocyanate (AITC) (a natural compound of mustard oil) and cinnamaldehyde (CA), and TRPV1 agonist capsaicin or vehicle. Twenty minutes prior to the start of the experiment with TRP agonizts, diclofenac, ketorolac or xefocam were pre-injected in the same hindpaw and animals were examined by these two tests. After pretreatment of all three NSAIDs in the ipsilateral (injected) hindpaw that produced strong antinociceptive effects, AITC, CA, and capsaicin caused significant decreases in latency of the thermal withdrawal reflex compared with vehicle or the contralateral hindpaw. The same findings were observed for the paw withdrawal threshold. In approximately 30 min the effects of CA, AITC, and capsaicin returned to baseline. The data are different from our previous evidence, where TRPA1 agonizts AITC and CA and TRPV1 agonist capsaicin produced hyperalgesia for nearly 2 h and resulted in facilitation of these withdrawal reflexes (Tsagareli et al., 2010, 2013). Thus, our data showing that NSAIDs suppress thermal and mechanical hyperalgesia following TRP activation could presumably due to inactivation or desensitization of TRPA1 and TRPV1 channels by NSAIDs. Keywords: Allodynia, Cold pain, Heat pain, Hyperalgesia, Signal transduction, Nociceptio

S-Parameters Quality Estimation in Physical Units

S-Parameters are the most common way to describe electrical behavior of linear electric networks. However, any available S-Parameters that is available for describing a physical system is not perfectly accurate and does not describe it comprehensively. It becomes important to be able to estimate the quality of existing data in order to achieve reliability of the results and conclusions developed based on it. A metric is created in the present work to estimate a physical system based on passivity, reciprocity and causality properties in physical units. First, based on the original S-Parameters, will be created passive, causal and reciprocal S-Parameters; then similarity metric will be defined in time domain to get estimation in physical units; finally similarity metric in time domain will be applied between original and passive, causal and reciprocal matrices to get correspondingly passivity, causality and reciprocity estimations in physical units

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

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

TRPA1 Channel is Involved in SLIGRL-Evoked Thermal and Mechanical Hyperalgesia in Mice

Persistent itch (pruritus) accompanying dermatologic and systemic diseases can significantly impair the quality of life. It is well known that itch is broadly categorized as histaminergic (sensitive to antihistamine medications) or non-histaminergic. Sensory neurons expressing Mas-related G-protein-coupled receptors (Mrgprs) mediate histamine-independent itch. These receptors have been shown to bind selective pruritogens in the periphery and mediate non-histaminergic itch. For example, mouse MrgprA3 responds to chloroquine (an anti-malarial drug), and are responsible for relaying chloroquine-induced scratching in mice. Mouse MrgprC11 responds to a different subset of pruritogens including bovine adrenal medulla peptide (BAM8–22) and the peptide Ser-Leu-Ile-Gly-Arg-Leu (SLIGRL). On the other hand, the possibility that itch mediators also influence pain is supported by recent findings that most non-histaminergic itch mediators require the transient receptor potential ankyrin 1 (TRPA1) channel. We have recently found a significant increase of thermal and mechanical hyperalgesia induced by non-histaminergic pruritogens chloroquine and BAM8–22, injected into mice hindpaw, for the first 30–45 min. Pretreatment with TRPA1 channel antagonist HC-030031 did significantly reduce the magnitude of this hyperalgesia, as well as significantly shortened the time-course of hyperalgesia induced by chloroquine and BAM8–22. Here, we report that MrgprC11-mediated itch by their agonist SLIGRL is accompanied by heat and mechanical hyperalgesia via the TRPA1 channel. We measured nociceptive thermal paw withdrawal latencies and mechanical thresholds bilaterally in mice at various time points following intra-plantar injection of SLIGRL producing hyperalgesia. When pretreated with the TRPA1 antagonist HC-030031, we found a significant reduction of thermal and mechanical hyperalgesia

Frequency-Domain Interpolation of Long Structures for System-Level Signal Integrity Analysis

System-level modeling requires cascading frequency domain characteristics of the subparts of the system. It can only be done if the data is given in the same frequency samples. Since often it is not the case, interpolation has to be done to reduce the data to the same frequency points. Incorrect interpolation might create nonsense artifacts, especially if the model includes a long structure. In the present work interpolation problems of a frequency response data are studied. The practical solution for these problems is suggested and different measured test cases are investigated

The central nucleus of amygdala is involved in tolerance to the antinociceptive effect of NSAIDs

Velike sportske manifestacije izazivaju globalnu pozornost i imaju izrazito velik utjecaj na zemlju odnosno grad domaćina. Bez obzira na velik broj dugoročnih i kratkoročnih ekonomskih koristi za zemlju domaćina, vlada kriza interesa za domaćinstvo Olimpijskih igara prije svega zbog milijunskih troškova organizacije. Zahtjevi prema gradovima domaćinima su veliki. Uz sportske kapacitete, potrebno je osigurati olimpijsko selo sportašima, smještaj organizatorima, medijima, gostima, transport i još dosta drugih popratnih stvari. Već i sam proces kandidiranja, prije nego se uopće krene s organizacijom, može biti prilično skup. U ovom diplomskom radu, na primjeru Olimpijskih igara u Sočiju koje slove za jedne od najskupljih u povijesti, analiziraju se prije svega negativni utjecaji velikih sportskih manifestacija na turizam i odnos troškova i koristi organizacije. Neiskorištena infrastruktura čije održavanje stoji milijune dolara, proračunski minusi, nezadovoljstvo lokalnog stanovništva i pad podrške istog za takvim manifestacijama rezultat su neprilagođene strategije organiziranja takve manifestacije za što je Soči odličan primjer jer je kao grad s suptropskom klimom bio domaćin Zimskim olimpijskim igrama.Mega sport events attract global attention and have a huge impact on the host country or city. Despite the large number of long-term and short-term economic benefits to the host country, there is a crisis of interest in hosting the Olympic Games, primarily due to enormous costs related to the organization of events. Requirements for host cities are high. In addition to sports facilities, it is necessary to provide the Olympic Village with athletes, accommodation for organisers, media, guests, transportation and many other related costs. The very process of applying, before moving on with the organization at all, can be quite expensive. In this master thesis, the example of the Sochi Olympics, which is considered one of the most expensive in history, will highlight the negative impacts of major sporting events on tourism in the country and the balance between cots and benefits of hosting the event. Unused infrastructure worth millions of dollars, budget holes, dissatisfaction of the local population and a decline in support for such events are the result of an unadapted strategy for organizing such a manifestation. Sochi stands as a prime example because it hosted the Winter Olympics as a subtropical climate