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Investigating the association between P2X7 receptors, microglia and the actions of morphineMedhurst, Stephen John January 2011 (has links)
P2X7 receptors belong to a family of membrane bound ion channels which are activated by extracellular ATP, resulting in the opening of a non-selective cation channel. After prolonged or repeated exposure to agonist, functional and cellular changes can occur, including the formation of a large pore, cell lysis and the release of mature, biologically active interleukin-1β. It is this diversity of functions that underlies the significance of this receptor in pain processing. P2X7 receptors are expressed on microglia, which when activated, release a host of mediators which contribute to central sensitisation, a phenomenon associated with neuropathic pain. The role of P2X7 receptors in the activation of microglia is less well established and is the main subject of this thesis. Before considering the interaction between P2X7 receptors and microglia, the first aim was to establish whether P2X7 receptors played a role in a pathological process known to be associated with microglial activation. An additional aim was to establish whether the site of action was in the central nervous system (CNS), where microglia are located. These aims were accomplished using a surgery-based rat model of neuropathic pain, the chronic constriction injury (CCI) model, and by comparing the effects of different P2X7 receptor antagonists when dosed peripherally or directly into the spinal cord. The results indicated that P2X7 receptor antagonists produced efficacy in the CCI model via a mechanism located in the CNS. To further investigate the association between P2X7 receptors and microglia, a different experimental paradigm was explored. Chronically dosed morphine is known to activate microglia, the consequence of which is thought to underlie morphine tolerance and reduced morphine analgesia. By administering a P2X7 receptor antagonist to CCI-operated rats treated with chronic morphine, the interaction between the P2X7 receptor and morphine tolerance and analgesia was explored. The results showed that P2X7 receptor antagonism delayed morphine tolerance and increased the efficacy of low doses of morphine, suggesting an association between P2X7 receptors and microglia. It was intended to confirm the interaction between a P2X7 receptor antagonist and morphine in another neuropathic pain model, namely varicella zoster virus-induced neuropathy. However due to a lack of reproducibility, this model was not used for pharmacological studies. Having demonstrated an association between P2X7 receptor antagonist and morphine in a chronic pain setting, studies were initiated to explore whether this interaction occurred in other morphine-related behaviours. The effect on body weight, motor coordination and single dosed morphine-induced analgesia was assessed in rats co-administered with P2X7 receptor antagonist and morphine. Results demonstrated that the blockade of P2X7 receptors enhanced morphine acute dose-induced analgesia, but had no influence on motor-impairment and body weight. The final part of the thesis used immunohistochemical and molecular techniques to confirm that microglia played a role in established allodynia induced by CCI-surgery and that P2X7 receptors directly influenced microglia-activation. In conclusion, the data in this thesis has illustrated an association between centrally activated P2X7 receptors and microglia, as well as an association between the P2X7 receptor and morphine-induced tolerance and analgesia. It is possible that co-administration of a P2X7 receptor antagonist with morphine could reduce the effective dose of morphine clinically, thereby reducing the side effects of this commonly used analgesic.
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Biophysical and pharmacological characterisations of Pannexin 1Ma, Weihong January 2010 (has links)
The ATP-gated P2X7 receptors (P2X7Rs) play a key role in the release of pro-inflammatory cytokines in response to immunological challenges. Pannexin 1 (Panx1), conventionally described as a hemichannel forming protein, was suggested to be involved in the formation of the P2X7 large pore, which provides a conduit for large molecules such as fluorescent dyes. Firstly, this thesis demonstrated that the P2X7R-mediated dye uptake, a phenomenon attributed to the activation of Panx1, was suppressed by acidic pH and this inhibition was abolished in a P2X7 mutant (aspartic acid 197 to alanine) that was insensitive to extracellular pH. Then, the functional properties of human or mouse Panx1 in HEK293 cells were analysed in the absence of P2X7. The Panx1 currents were not affected by extracellular/intracellular calcium, but were reversibly inhibited by adenosine triphosphate (ATP) and non-specific anion channel blockers. Ion substitution experiments showed that Panx1 was permeable only to monovalent anions and single channel studies revealed a medium sized unitary conductance of Panx1 (~65 pS). Based on the evidence, this thesis concluded that Panx1 is an anion channel but not a hemichannel as originally proposed.
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Inflammatory Cytokines Facilitate the Sensitivity of P2X7 Receptors Toward Extracellular ATP at Neural Progenitor Cells of the Rodent Hippocampal Subgranular ZoneLiu, Juan, Tahir Khan, Muhammad, Tang, Yong, Franke, Heike, Illes, Peter 06 April 2023 (has links)
Organotypic hippocampal slice cultures were used to model the effects of
neuroinflammatory conditions following an epileptic state on functional P2X7 receptors (Rs) of
subgranular zone (SGZ) neural progenitor cells (NPCs). The compound, 4-aminopyridine (4-AP),
is known to cause pathological firing of neurons, consequently facilitating the release of various
transmitter substances including ATP. Lipopolysaccharide (LPS) and interleukin-1(IL-1) both
potentiated the dibenzoyl-ATP (Bz-ATP)-induced current amplitudes in NPCs, although via different
mechanisms. Whereas LPS acted via promoting ATP release, IL-1 acted via its own receptor
to directly influence P2X7Rs. Thus, the effect of LPS was inhibited by the ecto-ATPase inhibitor,
apyrase, but not by the IL-1 antagonist, interleukin-1RA (IL-1RA); by contrast, the effect of IL-1
was inhibited by IL-1RA, but not by apyrase. Eventually, incubation with 4-AP upregulated the
number of nestin/glial fibrillary acidic protein/P2X7R immunoreactive cells and their appropriate
staining intensity, suggesting increased synthesis of P2X7Rs at NPCs. In conclusion, inflammatory
cytokines accumulating after epilepsy-like neuronal firing may facilitate the effect of endogenous
ATP at P2X7Rs of NPCs, thereby probably promoting necrosis/apoptosis and subsequent cell death.
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Astrocytic and Oligodendrocytic P2X7 Receptors Determine Neuronal Functions in the CNSZhao, Ya-Fei, Tang, Yong, Illes, Peter 28 March 2023 (has links)
P2X7 receptors are members of the ATP-gated cationic channel family with a preferential
localization at the microglial cells, the resident macrophages of the brain. However,
these receptors are also present at neuroglia (astrocytes, oligodendrocytes) although
at a considerably lower density. They mediate necrosis/apoptosis by the release of
pro-inflammatory cytokines/chemokines, reactive oxygen species (ROS) as well as
the excitotoxic (glio)transmitters glutamate and ATP. Besides mediating cell damage
i.e., superimposed upon chronic neurodegenerative processes in Alzheimer’s Disease,
Parkinson’s Disease, multiple sclerosis, and amyotrophic lateral sclerosis, they may also
participate in neuroglial signaling to neurons under conditions of high ATP concentrations
during any other form of neuroinflammation/neurodegeneration. It is a pertinent open
question whether P2X7Rs are localized on neurons, or whether only neuroglia/microglia
possess this receptor-type causing indirect effects by releasing the above-mentioned
signaling molecules. We suggest as based on molecular biology and functional evidence
that neurons are devoid of P2X7Rs although the existence of neuronal P2X7Rs cannot
be excluded with absolute certainty.
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Implication des récepteurs P2X7 dans l'invasivité des cellules cancéreuses humaines / Involvement of P2X7 receptors in human cancer cell invasivenessJelassi, Bilel 20 December 2013 (has links)
Le récepteur-canal P2X7 est fortement exprimé et est fonctionnel dans la lignée de cellules cancéreuses mammaires humaines hautement invasives MDA-MB-435s. L’activation de P2X7 par l’ATP extracellulaire est responsable de l'émission des prolongements cellulaires et l'augmentation de la migration cellulaire. En outre, l’activation de P2X7 augmente l’invasion cellulaire à travers la matrice extracellulaire et fait intervenir la libération de forme mature de cathepsines à cystéine dans le milieu extracellulaire. L’inhibition pharmacologique de P2X7 diminue l’invasivité des cellules cancéreuses dans un modèle de micrométastases chez le poisson zèbre. Nous avons également montré que l’émodine (1,3,8-trihydroxy-6-méthylanthraquinone) une anthraquinone isolée de Rheum officinale Baill (Rhubarbe chinoise) inhibe l’invasivité des cellules cancéreuses humaines via l’antagonisme de P2X7 et n’as pas d’effet sur les autres récepteurs P2X. Nos résultats démontrent un nouveau mécanisme entre la fonctionnalité de P2X7 dans les cellules cancéreuses et l’invasivité cellulaire, un paramètre clé dans la croissance tumorale et le développement des métastases. Ceci suggère également un rôle thérapeutique potentiel pour les antagonistes des P2X7. / P2X7 receptor channel is highly expressed and fully functional in the highly invasive human breast cancer cell line MDA-MB-435s. Its activation by extracellular ATP is responsible for the extension of neurite-like cellular prolongations, and the increase in cell migration. Furthermore, P2X7 activation enhanced invasion through the extracellular matrix and was related to the increase of mature forms of cysteine cathepsins in the extracellular medium. Pharmacological targeting of P2X7 decreases cancer cell invasiveness in a zebrafish model of micrometastases. We also showed that emodin (1,3,8-trihydroxy-6-methylanthraquinone) an anthraquinone derivative originally isolated from Rheum officinale Baill (Chinese Rhubarb) inhibits human cancer cell invasiveness by specifically antagonizing the P2X7 and not the other members of the P2X family. Our results demonstrate a novel mechanistic link between P2X7 functionality in cancer cells and invasiveness, a key parameter in tumour growth and in the development of metastases. These results also suggest a potential therapeutic role for the newly developed P2X7 antagonists.
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Increasing Efficiency of Repetitive Electroacupuncture on Purine- and Acid-Induced Pain During a Three-Week Treatment ScheduleLi, Jie, Zhang, Ying, Illes, Peter, Tang, Yong, Rubini, Patrizia 30 March 2023 (has links)
Acupuncture (AP) is an important constituent of the therapeutic repertoire of traditional
Chinese medicine and has been widely used to alleviate chronic painful conditions all over
the world. We studied in rats the efficiency of electroacupuncture (EAP) applied to the
Zusanli acupoint (ST36) as an analgesic treatment over a 3-week period of time on purine
(α,β-methylene ATP, dibenzoyl-ATP)- and acid (pH 6.0 medium)-induced pain in the rat
paw. The two ATP derivatives stimulated P2X3 and P2X7 receptors, respectively, while the
slightly acidic medium stimulated the “acid-sensitive ion channel 3” (ASIC3). It was found
that the P2X7 receptor and ASIC-mediated pain was counteracted by EAP with greater
efficiency at the end than at the beginning of the treatment schedule, while the P2X3
receptor–mediated pain was not. Our findings have important clinical and theoretical
consequences, among others, because they are difficult to reconcile with the assumption
that AP is primarily due to the release of peripheral and central opioid peptides causing the
well-known tolerance to their effects. In consequence, AP is a convenient therapeutic
instrument to treat subacute and chronic pain.
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Role of P2X7 Receptors in Immune Responses During NeurodegenerationOliveira-Giacomelli, Ágatha, Petiz, Lyvia Lintzmaier, Andrejew, Roberta, Turrini, Natalia, Silva, Jean Bezerra, Sack, Ulrich, Ulrich, Henning 27 March 2023 (has links)
P2X7 receptors are ion-gated channels activated by ATP. Under pathological conditions,
the extensive release of ATP induces sustained P2X7 receptor activation, culminating
in induction of proinflammatory pathways with inflammasome assembly and cytokine
release. These inflammatory conditions, whether occurring peripherally or in the central
nervous system (CNS), increase blood-brain-barrier (BBB) permeability. Besides its well-known involvement in neurodegeneration and neuroinflammation, the P2X7 receptor
may induce BBB disruption and chemotaxis of peripheral immune cells to the CNS,
resulting in brain parenchyma infiltration. For instance, despite common effects on
cytokine release, P2X7 receptor signaling is also associated with metalloproteinase
secretion and activation, as well as migration and differentiation of T lymphocytes,
monocytes and dendritic cells. Here we highlight that peripheral immune cells mediate
the pathogenesis of Multiple Sclerosis and Parkinson’s and Alzheimer’s disease, mainly
through T lymphocyte, neutrophil and monocyte infiltration. We propose that P2X7
receptor activation contributes to neurodegenerative disease progression beyond its
known effects on the CNS. This review discusses how P2X7 receptor activation
mediates responses of peripheral immune cells within the inflamed CNS, as occurring
in the aforementioned diseases.
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Participação dos receptores P2X7 presentes em células da glia do gânglio da raiz dorsal na nocicepçãoLemes, Júlia Borges Paes 13 February 2017 (has links)
CAPES - Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / Nos gânglios sensitivos, os corpos celulares dos neurônios encontram-se circundados
por células gliais denominadas células satélites. Estudos recentes apontam para uma possível
comunicação entre neurônios e células satélites através da liberação de ATP e ativação de
receptores P2X7 presentes nas células gliais. Além disto, células satélites adjacentes podem
estar conectadas através de junções comunicantes (“gap junctions”). Até o presente, a
comunicação entre células satélites e neurônios tem sido implicada na cronificação da dor e em
processos inflamatórios. Nesse estudo buscamos avaliar o papel da comunicação entre
neurônios e células satélites através da ativação dos receptores P2X7 assim como das junções
comunicantes em modelos de dor aguda. Em culturas primárias de gânglios da raiz dorsal,
verificamos que a administração de capsaicina leva a um aumento de cálcio em neurônios e em
seguida em células satélites sendo que a resposta das células satélites foi bloqueada por
A740003, um antagonista seletivo para receptores P2X7, indicando que os nociceptores quando
ativados liberam ATP que, por sua vez, ativa receptores P2X7 nas células gliais. Para avaliar
o papel desta comunicação celular in vivo, o antagonista P2X7 ou o bloqueador de junções
comunicantes, carbenoxolona, foram administrados por via intraganglionar (L5) e foram
avaliados os efeitos das injeções intraplantares de capsaicina, mentol e formalina em ratos.
Tanto o A740003 quanto a carbenoxolona reduziram a nocicepção induzida por capsaicina e
mentol. No teste da formalina, ambas as substâncias afetaram apenas a segunda fase do teste,
considerada a fase inflamatória. Capsaicina ativa seletivamente receptores TRPV1 e mentol
ativa receptores TRPM8, e possivelmente receptores TRPA1, que são expressos
majoritariamente em neurônios nociceptivos associados a fibras C. Além disto, estudos de
outros autores indicam a primeira fase do teste da formalina envolve principalmente a ativação
de fibras do tipo Aδ enquanto que a segunda fase envolve a ativação de fibras Aδ e C.
Considerando estes dados juntamente como os presentes resultados, podemos sugerir que a
comunicação entre células satélites e neurônios ocorre também na dor aguda, mas apenas
quando esta depende da ativação de fibras C. Deste modo, a comunicação entre neurônios e
células satélites, via liberação de ATP e ativação de receptores P2X7, assim como uma
comunicação entre células satélites adjacentes através de junções comunicantes parecem estar
envolvidos em um processamento rápido do sinal doloroso no gânglio da raiz dorsal. / In sensory ganglia, the cellular bodies of neurons are surrounded by glial cells called
satellite cells. Recent studies point to a possible communication between neurons and satellite
cells through the release of ATP and activation of P2X7 receptors present in glial cells. In
addition, adjacent satellite cells may be connected through gap junctions. Still today, the
communication between satellite cells and neurons has been implicated in chronic pain and in
inflammatory processes. In this study we sought to evaluate the role of communication between
neurons and satellite cells through the activation of the P2X7 receptors as well as of the
communicating junctions in acute pain models. In primary cultures of dorsal root ganglia, we
found that the administration of capsaicin leads to an increase of calcium in neurons and then
in satellite cells. The response of satellite cells was blocked by A740003, a selective antagonist
for P2X7 receptors, indicating that nociceptors when activated release ATP, which in turn
activates P2X7 receptors in the glial cells. To assess the role of this in vivo cellular
communication, the P2X7 antagonist or the gap junction blocker, carbenoxolone, were
administered by intraganglionar injection (L5) and the effects of intraplantar injections of
capsaicin, menthol or formalin in rats were evaluated. Both A740003 and carbenoxolone
reduced nociception induced by capsaicin and menthol. In the formalin test, both substances
affected only the second phase of the test, considered the inflammatory phase. Capsaicin
selectively activates TRPV1 receptors while menthol activates TRPM8 receptors, and possibly
TRPA1 receptors, which are expressed mainly in nociceptive neurons associated with C fibers.
In addition, studies by other authors indicate that the first phase of the formalin test involves
primarily the activation of Aδ fibers whereas the second phase involves the activation of Aδ
and C fibers. Considering these data together with the present results, we can suggest that the
communication between satellite cells and neurons also occurs in acute pain, but only, when it
depends on the activation of C fibers. Thus, communication between neurons and satellite cells,
via release of ATP and activation of P2X7 receptors, as well as communication between
adjacent satellite cells through gap junctions seems to be involved in a rapid processing of the
pain signal in the dorsal root ganglion. / Dissertação (Mestrado)
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