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    • Mechanisms implicated in antinociception by A R

    2022-12-01

    Mechanisms implicated in antinociception by A3R agonists in neuropathic pain are summarized in Box 3. Cellular transduction mechanisms for A3Rs include inhibition of cyclic AMP, PKA via Gαi, interactions with PLC/IP3/DAG and signaling via Gαi and Gαq, and interactions with PI3K/MEK/ERK via βγ subunits; β-arrestin mediates receptor internalization (Chen et al., 2014). Mechanistic studies elaborate specific consequences of general signaling mechanisms.A3R agonists exhibit anticancer activity in several preclinical models, and are in exploration as potential therapeutics for certain forms of cancer (Fishman et al., 2012, Antonioli et al., 2013). A3R agonists have also been examined in a model of bone cancer pain involving injection of mammary gland carcinoma dorsomorphin into the tibia (Varani et al., 2013). Chronic treatment with Cl-IB-MECA produced a significant reduction in tumor growth and alleviated manifestations of cancer pain (i.e. reduced pressure thresholds); furthermore, Cl-IB-MECA reduced the onset and progression of bone cancer, with a greater effectiveness when given earlier following cell injection. Imaging of the bone revealed bone degradation with the tumor, and IB-MECA decreased bone degeneration. Thus, the A3R agonist exhibited both anticancer effects and anti-cancer pain effects (Varani et al., 2013). A3Rs are upregulated in synovial tissue and circulating mononuclear cells in rheumatoid arthritis (Ochaion et al., 2009, Varani et al., 2011), and exploration of the clinical effects of A3R agonists for this condition has commenced (Silverman et al., 2008, Fishman et al., 2012). A further potential approach that may be effective in conditions where there are enhanced endogenous adenosine levels is to use allosteric modulators which would have selective actions at sites where elevation of adenosine levels occurs. LUF6000 is an allosteric enhancer of adenosine binding at A3Rs, and has been demonstrated to reduce inflammation in models of adjuvant- and monoiodoacetate-induced arthritis (Cohen et al., 2014). While pain measures were not included in that study, it is likely that reduced pain would occur as a result of the reduction in inflammation.
    Adenosine regulating agents Adenosine receptors are located on the outside surface of the cell, and respond to endogenous adenosine that is generated: (a) intracellularly (from ATP or SAH) and then transported outside the cell via equilibrative nucleoside transporters, or (b) extracellularly from ATP (released from vesicles, via ion channels, or by cell damage) by the action of ecto-nucleotidases (Zylka, 2011, Sebastião et al., 2013). Inside the cell, adenosine is phosphorylated (to AMP) by adenosine kinase or deaminated (to inosine) by adenosine deaminase; outside the cell adenosine is deaminated (to inosine) by ecto-adenosine deaminase or taken up into the cell by equilibrative or concentrative transporters (Zylka, 2011, Sebastião et al., 2013). Manipulation of endogenous tissue levels of adenosine has been explored for potential pain indications.
    Adenosine as a mediator of pharmacological antinociception There are three major classes of drugs used as analgesics, non-steroidal anti-inflammatory drugs, opioids, and adjuvants; the latter includes a wide range of drugs defined primarily for indications other than pain (e.g. antidepressants, anticonvulsants) or by mechanisms of action (e.g. NMDA receptor antagonists, ion channel blockers). Adenosine receptors are widely distributed throughout the pain signaling network, and adenosine systems constitute an endogenous regulatory system that potentially can be recruited by pharmacological agents to produce antinociception. The first major example of a drug recruiting endogenous adenosine was morphine when given spinally (DeLander and Hopkins, 1986, Sweeney et al., 1987, Eisenach et al., 2004, Wu et al., 2005). Adenosine can regulate pain signaling via actions at multiple sites, and is now known to contribute to the action of various pharmacological agents and manipulations that regulate pain.