Pain-relieving prospects for adenosine receptors and ectonucleotidases

Department of Cell and Molecular Physiology, UNC Neuroscience Center, University of North Carolina, Chapel Hill, NC 27599, USA.
Trends in Molecular Medicine (Impact Factor: 9.45). 04/2011; 17(4):188-96. DOI: 10.1016/j.molmed.2010.12.006
Source: PubMed


Adenosine receptor agonists have potent antinociceptive effects in diverse preclinical models of chronic pain. By contrast, the efficacy of adenosine and adenosine receptor agonists in treating pain in humans is unclear. Two ectonucleotidases that generate adenosine in nociceptive neurons were recently identified. When injected spinally, these enzymes have long-lasting adenosine A(1) receptor-dependent antinociceptive effects in inflammatory and neuropathic pain models. Furthermore, recent findings indicate that spinal adenosine A(2A) receptor activation can enduringly inhibit neuropathic pain symptoms. Collectively, these studies suggest the possibility of treating chronic pain in humans by targeting specific adenosine receptor subtypes in anatomically defined regions with agonists or with ectonucleotidases that generate adenosine.

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    • "This effect results from A 1 R activation as it was blocked by a selective A 1 R antagonist and was no longer seen in A 1 R knockout mice (Zylka et al., 2008; Sowa et al., 2009, 2010c). It was suggested that use of recombinant enzymes might represent a novel therapeutic strategy for chronic pain or pre-emptive analgesia (Zylka, 2011). "
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    ABSTRACT: The main focus for development of adenosine targets as analgesics to date has been A1Rs due to its antinociceptive profile in various preclinical pain models. The usefulness of systemic A1R agonists may be limited by other effects (cardiovascular, motor), but enhanced selectivity for pain might occur with partial agonists, potent and highly selective agonists, or allosteric modulators. A2AR agonists exhibit some peripheral pronociceptive effects, but also act on immune cells to suppress inflammation and on spinal glia to suppress pain signalling and may be useful for inflammatory and neuropathic pain. A2BR agonists exhibit peripheral proinflammatory effects on immune cells, but also spinal antinociceptive effects similar to A2AR agonists. A3Rs are now demonstrated to produce antinociception in several preclinical neuropathic pain models, with mechanistic actions on glial cells, and may be useful for neuropathic pain. Endogenous adenosine levels can be augmented by inhibition of metabolism (via adenosine kinase) or increased generation (via nucleotidases), and these approaches have implications for pain. Endogenous adenosine contributes to antinociception by several pharmacological agents, herbal remedies, acupuncture, transcutaneous electrical nerve stimulation, exercise, joint mobilization, and water immersion via spinal and/or peripheral effects, such that this system appears to constitute a major pain regulatory system. Finally, caffeine inhibits A1-, A2A- and A3Rs with similar potency, and dietary caffeine intake will need attention in trials of: (a) agonists and/or modulators acting at these receptors, (b) some pharmacological and herbal analgesics, and (c) manipulations that enhance endogenous adenosine levels, all of which are inhibited by caffeine and/or A1R antagonists in preclinical studies. All adenosine receptors have effects on spinal glial cells in regulating nociception, and gender differences in the involvement of such cells in chronic neuropathic pain indicate gender may also need attention in preclinical and human trials evaluating efficacy of adenosine-based analgesics.
    Neuroscience 10/2015; DOI:10.1016/j.neuroscience.2015.10.031 · 3.36 Impact Factor
    • "signaling system in neuropathic pain are poorly understood (Sawynok and Liu, 2003; Zylka, 2011). Orthosteric adenosine A1R agonists have antinociceptive effects after systemic or spinal administration (Lee and Yaksh, 1996; Sawynok, 1998; Lavand'homme and Eisenach, 1999; Gong et al., 2010) but poor selectivity across the four subtypes of adenosine GPCRs, and side effect liability have limited their therapeutic development (Zylka, 2011). For instance, A1Rs are not restricted to the spinal cord and primary afferents but are also expressed elsewhere in the central nervous system, heart, and adipose tissue and can thus mediate side effects such as bradycardia and reduced arterial pressure (Yang et al., 2002). "
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    ABSTRACT: In the spinal cord and periphery, adenosine inhibits neuronal activity through activation of the adenosine A1 receptor (A1R) resulting in antinociception and highlighting the potential of therapeutically targeting the receptor in the treatment of neuropathic pain. This study investigated the changes in adenosine tone and A1R signalling, together with the actions of a novel A1R positive allosteric modulator (PAM), VCP171, on excitatory and inhibitory neurotransmission at spinal cord superficial dorsal horn synapses in a rat partial nerve-injury model of neuropathic pain. In the absence of A1R agonists, superfusion of the A1R antagonist, DPCPX (1 μM), produced a significantly greater increase in electrically evoked AMPAR-mediated synaptic current (eEPSC) amplitude in both lamina I and II neurons from nerve-injured than in controls, suggesting that endogenous adenosine tone is increased in the dorsal horn. Inhibitory GABAergic and glycinergic synaptic currents were also significantly increased by DPCPX in controls but there was no difference following nerve-injury. The A1R agonist, N6-Cyclopentyladenosine (CPA), produced greater inhibition of eEPSC amplitude in lamina II but not lamina I of the spinal cord dorsal horn in nerve-injured versus controls, suggesting a functional increase in A1R sensitivity in lamina II neurons after nerve-injury. The A1R PAM, VCP171, produced a greater inhibition of eEPSC amplitude of nerve-injury versus control animals in both lamina I and lamina II neurons. Enhanced adenosine tone and A1R sensitivity at excitatory synapses in the dorsal horn after nerve-injury suggest that new generation PAMs of the A1R can be effective treatments for neuropathic pain. The American Society for Pharmacology and Experimental Therapeutics.
    Molecular pharmacology 06/2015; 88(3). DOI:10.1124/mol.115.099499 · 4.13 Impact Factor
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    • "Our results substantially extend our previous findings exploring A 3 AR in pain (Chen et al., 2012) by identifying an endogenous analgesic A 3 AR pathway within key regions of the CNS that is distinguished by its potent efficacy and state-dependent nature, functioning to suppress only pathological pain without altering the normal pain threshold or activating reward centres in normal rats. Cardiovascular side effects are the major limitation of therapeutic approaches that enhance adenosine signalling (Fredholm et al., 2011; Zylka, 2011; Boison, 2013); however, A 3 AR agonists in clinical trials, IB-MECA and Cl-IBMECA, have no reported serious side effects (Fishman et al., 2012). Yet, while these prototypical A 3 AR agonists were anti-nociceptive in our preclinical studies (Chen et al., 2012 "
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    ABSTRACT: Chronic pain is a global burden that promotes disability and unnecessary suffering. To date, efficacious treatment of chronic pain has not been achieved. Thus, new therapeutic targets are needed. Here, we demonstrate that increasing endogenous adenosine levels through selective adenosine kinase inhibition produces powerful analgesic effects in rodent models of experimental neuropathic pain through the A3 adenosine receptor (A3AR, now known as ADORA3) signalling pathway. Similar results were obtained by the administration of a novel and highly selective A3AR agonist. These effects were prevented by blockade of spinal and supraspinal A3AR, lost in A3AR knock-out mice, and independent of opioid and endocannabinoid mechanisms. A3AR activation also relieved non-evoked spontaneous pain behaviours without promoting analgesic tolerance or inherent reward. Further examination revealed that A3AR activation reduced spinal cord pain processing by decreasing the excitability of spinal wide dynamic range neurons and producing supraspinal inhibition of spinal nociception through activation of serotonergic and noradrenergic bulbospinal circuits. Critically, engaging the A3AR mechanism did not alter nociceptive thresholds in non-neuropathy animals and therefore produced selective alleviation of persistent neuropathic pain states. These studies reveal A3AR activation by adenosine as an endogenous anti-nociceptive pathway and support the development of A3AR agonists as novel therapeutics to treat chronic pain. Published by Oxford University Press on behalf of the Guarantors of Brain 2014. This work is written by US Government employees and is in the public domain in the US.
    Brain 11/2014; 138(1). DOI:10.1093/brain/awu330 · 9.20 Impact Factor
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