The development of painful paclitaxel-induced peripheral neuropathy (PIPN) represents a major dose-limiting side effect of paclitaxel chemotherapy. Here we report a promising effect of duvelisib (Copiktra), a novel FDA-approved PI3Kδ/γ isoform-specific inhibitor, in preventing paclitaxel-induced pain-like behavior and pronociceptive signaling in DRGs and spinal cord dorsal horn (SCDH) in rat and mouse model of PIPN. Duvelisib blocked the development of mechanical hyperalgesia in both males and females. Moreover, duvelisib prevented paclitaxel-induced sensitization of TRPV1 receptors, and increased PI3K/Akt signaling in small-diameter DRG neurons and an increase of CD68+ cells within DRGs. Specific optogenetic stimulation of inhibitory neurons combined with patch-clamp recording revealed that duvelisib inhibited paclitaxel-induced weakening of inhibitory, mainly glycinergic control on SCDH excitatory neurons. Enhanced excitatory and reduced inhibitory neurotransmission in the SCDH following PIPN was also alleviated by duvelisib application. In summary, duvelisib showed a promising ability to prevent neuropathic pain in PIPN. The potential use of our findings in human medicine may be augmented by the fact that duvelisib is an FDA-approved drug with known side effects.SIGNIFICANCE STATEMENT We show that duvelisib, a novel FDA-approved PI3Kδ/γ isoform-specific inhibitor, prevents the development of paclitaxel-induced pain-like behavior in males and females and prevents pronociceptive signaling in DRGs and spinal cord dorsal horn in rat and mouse model of paclitaxel-induced peripheral neuropathy.

• MeSH
• antitumorózní látky fytogenní * farmakologie   MeSH
• bolest MeSH
• fosfatidylinositol-3-kinasy MeSH
• hyperalgezie chemicky indukované   farmakoterapie   prevence a kontrola   MeSH
• isochinoliny MeSH
• krysa rodu rattus MeSH
• myši MeSH
• nemoci periferního nervového systému MeSH
• neuralgie * chemicky indukované   farmakoterapie   prevence a kontrola   MeSH
• paclitaxel škodlivé účinky   MeSH
• puriny MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Paclitaxel chemotherapy treatment often leads to neuropathic pain resistant to available analgesic treatments. Recently spinal Toll-like receptor 4 (TLR4) and the transient receptor potential cation channel subfamily V member 1 (TRPV1) were identified to be involved in the pro-nociceptive effect of paclitaxel. The aim of this study was to investigate the role of phosphatidylinositol 3-kinase (PI3K) and serine/threonine kinases in this process, with the use of their antagonists (wortmannin, LY-294002, and staurosporine). The single paclitaxel administration (8 mg/kg i.p.) in mice induced robust mechanical allodynia measured as a reduced threshold to von Frey filament stimulation and generated reduced tachyphylaxis of capsaicin-evoked responses, recorded as changes in mEPSC frequency in patch-clamp recordings of dorsal horn neurons activity in vitro, for up to eight days. Paclitaxel application also induced increased Akt kinase phosphorylation in rat DRG neurons. All these paclitaxel-induced changes were prevented by the wortmannin in vivo pretreatment. Acute co-application of wortmannin or LY-294002 with paclitaxel in spinal cord slices also attenuated the paclitaxel effect on capsaicin-evoked responses. Staurosporine was effective in the acute in vitro experiments and on the first day after the paclitaxel treatment in vivo, but in contrast to wortmannin, it did not have a significant impact later. Our data suggest that the inhibition of PI3K signaling may help alleviate pathological pain syndromes in the paclitaxel-induced neuropathy.

• MeSH
• buňky zadních rohů míšních účinky léků   metabolismus   MeSH
• excitační postsynaptické potenciály účinky léků   MeSH
• fosfatidylinositol-3-kinasy metabolismus   MeSH
• hyperalgezie chemicky indukované   farmakoterapie   metabolismus   MeSH
• inhibitory proteinkinas farmakologie   MeSH
• kapsaicin farmakologie   MeSH
• kationtové kanály TRP MeSH
• kationtové kanály TRPV metabolismus   MeSH
• krysa rodu rattus MeSH
• lipopolysacharidy farmakologie   MeSH
• mícha účinky léků   metabolismus   MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• neuralgie chemicky indukované   farmakoterapie   metabolismus   MeSH
• onkogenní protein v-akt metabolismus   MeSH
• paclitaxel toxicita   MeSH
• peptidové fragmenty imunologie   metabolismus   MeSH
• potkani Wistar MeSH
• protein-serin-threoninkinasy antagonisté a inhibitory   metabolismus   MeSH
• proteinkinasa C imunologie   metabolismus   MeSH
• signální transdukce účinky léků   MeSH
• toll-like receptor 4 metabolismus   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

AIMS: Neuroinflammatory changes in the central nervous system are widely involved in the initiation and maintenance of neuropathic pain after peripheral nerve injury. The present study investigated how losartan treatment may affect the development of neuropathic pain and neuroinflammation. MAIN METHODS: The effect of losartan treatment on the development of peripheral neuropathy was studied in L5 spinal nerve ligation (SNL) model in rats with systemic (100 mg/kg) or intrathecal (10 μl/ 20 μM solution) application of losartan. Electronic von Frey filament and plantar test were used to determine pain thresholds to mechanical and thermal stimulations. At the 7th post-operative day, CD68-positive cells in DRG and dorsal roots were quantified by immunohistochemistry and western blot analyses were used to compare the expression levels of neuroinflammatory markers in lumbar spinal cord (SC). KEY FINDINGS: Our data confirmed the presence of SNL-evoked heat hyperalgesia and mechanical allodynia. Losartan application blocked the SNL-induced hypersensitivity to thermal stimuli but failed to prevent mechanical allodynia. No significant difference between systemic and i.t. administration of losartan was observed. Immunohistochemistry confirmed the presence of infiltrated macrophages in the ipsilateral DRG that was significantly attenuated with the losartan treatment. Western blot SC tissue analysis revealed that systemic treatment with losartan prevented SNL-induced upregulation of CCR2, TNFα, TNFR1, and OX42 while its effect on CCL2 and AT1R expression was not significant. SIGNIFICANCE: Our results show that losartan treatment attenuates neuroinflammation and neuropathic pain after SNL. These effects of losartan represent an interesting direction for the development of novel treatments of peripheral neuropathy.

• MeSH
• hyperalgezie farmakoterapie   prevence a kontrola   MeSH
• krysa rodu rattus MeSH
• losartan metabolismus   farmakologie   MeSH
• měření bolesti metody   MeSH
• mícha účinky léků   MeSH
• míšní nervy účinky léků   MeSH
• modely nemocí na zvířatech MeSH
• neuralgie metabolismus   MeSH
• poranění periferního nervu farmakoterapie   MeSH
• potkani Wistar MeSH
• práh bolesti účinky léků   MeSH
• spinální ganglia účinky léků   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Neuropatická bolest představuje u pacientů se systémovým onemocněním závažný problém a vede k výraznému omezení v životě pacientů. V kazuistice prezentujeme případ pacienta s idiopatickou plicní fibrózou s rozvojem autoimunitní neuropatie a neuropatické bolesti včetně alodynie v návaznosti na herpetickou infekci plic. Ke zmírnění výrazných neuropatických bolestí pacient užívá vysoké dávky gabapentinu s velmi dobrou tolerancí, bez nežádoucích účinků.

Neuropathic pain is a serious problem in patients with systemic disease and leads to significant limitation of the functional status.The case presented here describes patient with idiopathic pulmonary fibrosis with the development of autoimmune neuropathyand neuropathic pain with allodynia following herpes infection of the lungs. Pacient uses high doses of gabapentin in order toachieve relief of neuropatic pain with very good tolerance and without side effects.

• MeSH
• dospělí MeSH
• gabapentin MeSH
• hormony kůry nadledvin aplikace a dávkování   terapeutické užití   MeSH
• hyperalgezie farmakoterapie   MeSH
• inhibitory zpětného vychytávání serotoninu a noradrenalinu terapeutické užití   MeSH
• karbamazepin aplikace a dávkování   terapeutické užití   MeSH
• komorbidita MeSH
• lidé MeSH
• neuralgie * diagnostické zobrazování   farmakoterapie   klasifikace   MeSH
• plicní fibróza terapie   MeSH
• polyneuropatie * komplikace   MeSH
• pregabalin škodlivé účinky   terapeutické užití   MeSH
• senioři MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• Publikační typ
• kazuistiky MeSH

Crotalphine is a structural analogue to a novel analgesic peptide that was first identified in the crude venom from the South American rattlesnake Crotalus durissus terrificus. Although crotalphine's analgesic effect is well established, its direct mechanism of action remains unresolved. The aim of the present study was to investigate the effect of crotalphine on ion channels in peripheral pain pathways. We found that picomolar concentrations of crotalphine selectively activate heterologously expressed and native TRPA1 ion channels. TRPA1 activation by crotalphine required intact N-terminal cysteine residues and was followed by strong and long-lasting desensitization of the channel. Homologous desensitization of recombinant TRPA1 and heterologous desensitization in cultured dorsal root ganglia neurons was observed. Likewise, crotalphine acted on peptidergic TRPA1-expressing nerve endings ex vivo as demonstrated by suppression of calcitonin gene-related peptide release from the trachea and in vivo by inhibition of chemically induced and inflammatory hypersensitivity in mice. The crotalphine-mediated desensitizing effect was abolished by the TRPA1 blocker HC030031 and absent in TRPA1-deficient mice. Taken together, these results suggest that crotalphine is the first peptide to mediate antinociception selectively and at subnanomolar concentrations by targeting TRPA1 ion channels.

• MeSH
• akční potenciály účinky léků   MeSH
• analgetika farmakologie   terapeutické užití   MeSH
• bradykinin toxicita   MeSH
• HEK293 buňky MeSH
• hyperalgezie chemicky indukované   farmakoterapie   etiologie   MeSH
• kationtové kanály TRP antagonisté a inhibitory   genetika   metabolismus   MeSH
• kationtový kanál TRPA1 MeSH
• kultivované buňky MeSH
• lidé MeSH
• modely nemocí na zvířatech MeSH
• mutace genetika   MeSH
• myši inbrední C57BL MeSH
• myši knockoutované MeSH
• myši MeSH
• neurony účinky léků   metabolismus   MeSH
• peptidy farmakologie   terapeutické užití   MeSH
• spinální ganglia cytologie   MeSH
• vápník metabolismus   MeSH
• zánět komplikace   MeSH
• zvířata MeSH
• zymosan toxicita   MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

BACKGROUND: Interaction of CD200 with its receptor CD200R has an immunoregulatory role and attenuates various types of neuroinflammatory diseases. METHODS: Immunofluorescence staining, western blot analysis, and RT-PCR were used to investigate the modulatory effects of CD200 fusion protein (CD200Fc) on activation of microglia and astrocytes as well as synthesis of pro- (TNF, IL-1β, IL-6) and anti-inflammatory (IL-4, IL-10) cytokines in the L4-L5 spinal cord segments in relation to behavioral signs of neuropathic pain after unilateral sterile chronic constriction injury (sCCI) of the sciatic nerve. Withdrawal thresholds for mechanical hypersensitivity and latencies for thermal hypersensitivity were measured in hind paws 1 day before operation; 1, 3, and 7 days after sCCI operation; and then 5 and 24 h after intrathecal application of artificial cerebrospinal fluid or CD200Fc. RESULTS: Seven days from sCCI operation and 5 h from intrathecal application, CD200Fc reduced mechanical and thermal hypersensitivity when compared with control animals. Simultaneously, CD200Fc attenuated activation of glial cells and decreased proinflammatory and increased anti-inflammatory cytokine messenger RNA (mRNA) levels. Administration of CD200Fc also diminished elevation of CD200 and CD200R proteins as a concomitant reaction of the modulatory system to increased neuroinflammatory reactions after nerve injury. The anti-inflammatory effect of CD200Fc dropped at 24 h after intrathecal application. CONCLUSIONS: Intrathecal administration of the CD200R1 agonist CD200Fc induces very rapid suppression of neuroinflammatory reactions associated with glial activation and neuropathic pain development. This may constitute a promising and novel therapeutic approach for the treatment of neuropathic pain.

• MeSH
• antigeny povrchové farmakologie   terapeutické užití   MeSH
• časové faktory MeSH
• CD antigeny metabolismus   MeSH
• cytokiny genetika   metabolismus   MeSH
• fyzikální stimulace škodlivé účinky   MeSH
• gliový fibrilární kyselý protein metabolismus   MeSH
• hyperalgezie farmakoterapie   etiologie   MeSH
• ischialgie komplikace   farmakoterapie   MeSH
• krysa rodu rattus MeSH
• mícha účinky léků   metabolismus   MeSH
• modely nemocí na zvířatech MeSH
• neuroglie účinky léků   metabolismus   MeSH
• potkani Wistar MeSH
• práh bolesti účinky léků   MeSH
• receptory buněčného povrchu antagonisté a inhibitory   terapeutické užití   MeSH
• regulace genové exprese účinky léků   MeSH
• spinální injekce MeSH
• zánět farmakoterapie   etiologie   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

BACKGROUND: Acute postoperative pain is one of the frequent reasons for pain treatment. However, the exact mechanisms of its development are still not completely clear. Transient receptor potential vanilloid 1 (TRPV1) receptors are involved in nociceptive signaling in various hypersensitive states. Here we have investigated the contribution of TRPV1 receptors expressed on cutaneous peripheral nociceptive fibers and in the spinal cord on the development and maintenance of hypersensitivity to thermal and mechanical stimuli following surgical incision. A rat plantar incision model was used to test paw withdrawal responses to thermal and mechanical stimuli. The effect of the TRPV1 receptor antagonist SB366791 was investigated 1) by intrathecal injection 15 min before incision and 2) intradermal injection before (30 min) and immediately after the surgery. Vehicle-injected rats and naïve animals treated identically were used as controls. RESULTS: Plantar incision induced mechanical allodynia and hyperalgesia and thermal hyperalgesia. A single intrathecal administration of SB366791 significantly reduced postincisional thermal hyperalgesia and also attenuated mechanical allodynia, while mechanical hyperalgesia remained unaffected. Local intradermal SB366791 treatment reduced thermal hyperalgesia and mechanical allodynia without affecting mechanical hyperalgesia. CONCLUSIONS: Our experiments suggest that both peripheral and spinal cord TRPV1 receptors are involved in increased cutaneous sensitivity following surgical incision. The analgesic effect of the TRPV1 receptor antagonist was especially evident in the reduction of thermal hyperalgesia. The activation of TRPV1 receptors represents an important mechanism in the development of postoperative hypersensitivity.

• MeSH
• anilidy farmakologie   terapeutické užití   MeSH
• časové faktory MeSH
• cinnamáty farmakologie   terapeutické užití   MeSH
• fyzikální stimulace škodlivé účinky   MeSH
• hmat MeSH
• hyperalgezie farmakoterapie   etiologie   MeSH
• kationtové kanály TRPV antagonisté a inhibitory   metabolismus   MeSH
• krysa rodu rattus MeSH
• měření bolesti účinky léků   MeSH
• mícha účinky léků   metabolismus   MeSH
• modely nemocí na zvířatech MeSH
• pooperační bolest komplikace   farmakoterapie   MeSH
• potkani Wistar MeSH
• práh bolesti účinky léků   MeSH
• reakční čas účinky léků   MeSH
• vysoká teplota MeSH
• způsoby aplikace léků MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Modulation of nociceptive synaptic transmission in the spinal cord is implicated in the development and maintenance of several pathological pain states. The chemokine CCL2 (C-C motif ligand 2) was shown to be an important factor in the development of neuropathic pain after peripheral nerve injury. In our experiments we have studied the effect of CCL2 application and TRPV1 (transient receptor potential vanilloid 1) receptor activation on nociceptive signaling and the modulation of synaptic transmission. Intrathecal drug application in behavioral experiments and patch-clamp recordings of spontaneous, miniature and dorsal root stimulation-evoked excitatory postsynaptic currents (sEPSCs, mEPSCs, eEPSCs) from superficial dorsal horn neurons in acute rat spinal cord slices were used. The intrathecal application of CCL2 induced thermal hyperalgesia and mechanical allodynia, while pretreatment with the TRPV1 receptor antagonist SB366791 diminished the thermal but not the mechanical hypersensitivity. Patch-clamp experiments showed an increase of sEPSC and mEPSC (124.5 ± 12.8% and 161.2 ± 17.3%, respectively) frequency in dorsal horn neurons after acute CCL2 application. This CCL2-induced increase was prevented by SB366791 pretreatment (89.4 ± 6.0%, 107.5 ± 14.2%). CCL2 application increased the amplitude of eEPSCs (188.1 ± 32.1%); this increase was significantly lower in experiments with SB366791 pretreatment (120.8 ± 17.2%). Our results demonstrate that the activation of spinal TRPV1 receptors plays an important role in the modulation of nociceptive signaling induced by CCL2 application. The mechanisms of cooperation between the CCL2 activated receptors and TRPV1 receptors on the central branches of primary afferent fibers may be especially important during different pathological pain states and need to be further investigated.

• MeSH
• anilidy terapeutické užití   MeSH
• buňky zadních rohů míšních účinky léků   fyziologie   MeSH
• časové faktory MeSH
• chemokin CCL2 toxicita   MeSH
• cinnamáty terapeutické užití   MeSH
• excitační postsynaptické potenciály účinky léků   MeSH
• hyperalgezie chemicky indukované   farmakoterapie   metabolismus   MeSH
• kapsaicin farmakologie   MeSH
• kationtové kanály TRPV antagonisté a inhibitory   metabolismus   MeSH
• krysa rodu rattus MeSH
• látky ovlivňující senzorický systém farmakologie   MeSH
• MAP kinasa-kinasa-kinasa 3 metabolismus   MeSH
• metoda terčíkového zámku MeSH
• mícha cytologie   účinky léků   metabolismus   MeSH
• modely nemocí na zvířatech MeSH
• novorozená zvířata MeSH
• potkani Wistar MeSH
• práh bolesti účinky léků   MeSH
• techniky in vitro MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

The past decade has seen a progressive unraveling of the molecular identities of receptors implicated in transduction of painful stimuli. Among the line-up of important ion channels involved in peripheral pain pathways, the family of the transient receptor potential (TRP) ion channels has attracted considerable attention and research work as a target class for drug discovery. One of these channels, the ankyrin transient receptor potential TRPA1, which expression is restricted to nociceptive neurons of peripheral ganglia, can be activated by isothiocyanates, pungent products from mustard oil and horse radish, phytocannabinoids, nicotin, environmental irritants contained in air polution, cigarette smoke and tear gas, but also by inflammatory mediators and endogenous products of oxidative stress. The purpose of this paper is to give an overview of the pharmacological, structural and functional properties of the TRPA1 channel in mammalian sensory system and to summarize recent evidence regarding its key properties that can be exploited for potential therapeutic advantage.

• Klíčová slova
• ankyrinový receptor, chlad, enzorická transdukce,
• MeSH
• ankyriny fyziologie   genetika   MeSH
• bolest MeSH
• financování organizované MeSH
• hyperalgezie etiologie   farmakoterapie   MeSH
• kationtové kanály TRP fyziologie   chemie   MeSH
• nocicepce MeSH
• nociceptory fyziologie   účinky léků   MeSH
• receptory Notch fyziologie   chemie   metabolismus   MeSH
• Publikační typ
• přehledy MeSH

• MeSH
• bolest farmakoterapie   MeSH
• delirium etiologie   farmakoterapie   MeSH
• dexamethason aplikace a dávkování   MeSH
• farmakoterapie MeSH
• haloperidol aplikace a dávkování   MeSH
• hyperalgezie farmakoterapie   psychologie   MeSH
• kombinovaná farmakoterapie MeSH
• lidé MeSH
• metoklopramid aplikace a dávkování   MeSH
• midazolam aplikace a dávkování   MeSH
• morfin aplikace a dávkování   MeSH
• opioidní analgetika aplikace a dávkování   škodlivé účinky   MeSH
• péče o umírající MeSH
• rizikové faktory MeSH
• umírající MeSH
• Check Tag
• lidé MeSH