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

Thermal and mechanical sensory and pain testing in healthy students

Several lines of clinical and experimental investigations of a wide variety of painful conditions have suggested ethnic and gender differences in pain perception. In this study we report some findings of cold and heat sensations, thermal pain thresholds, mechanical pressure thresholds and pressure pain thresholds in healthy student volunteers. We did not find any statistical significant differences in thermal assessment. However, we revealed gender differences on the mechanical pressure sensation threshold and the mechanical pressure pain threshold. Our study confirmed significant variability across trials and individuals, which appeared greater at lower heat and mechanical pressure intensities. Additional studies and collecting more data are needed to determine ethnic and gender differences between groups

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

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

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