(297) Central adenosine A3 receptor (A3AR) activation reverses neuropathic pain

Little, Joshua W.; Chen, Z.; Ford, Amanda; Janes, Kali; Doyle, Tim; Tosh, D.; Jacobson, Kenneth A.; Salvemini, Daniela

doi:10.1016/j.jpain.2014.01.207

Cited by 3 publications

(5 citation statements)

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“…On the basis of the potent in vitro A 3 AR activity of these congeners, selected compounds were tested in vivo using previously reported methods for the ability to reduce chronic neuropathic pain following oral administration in the mouse chronic constriction injury (CCI) model (Figure ). 2-Phenylethynyl analogues 12 and 15 , differing in the nature of the C6 group, were efficacious in reducing pain at the point of peak pain, day 7, although neither reached 100% reversal of the pain and the duration of action was less than that observed for the corresponding C6-NHMe analogue, i.e., 9 .…”

Section: Resultsmentioning

confidence: 99%

“…The correlation of activation of the A 3 AR with relief from chronic neuropathic pain has been established in various rodent models. , Selected compounds evaluated in functional assays and in the CCI pain model in mice had A 3 AR selectively and activity comparable to nucleosides containing an exocyclic amine. Activation of the A 1 AR is also known to reduce neuropathic pain, but except for two relatively weak analogues, 6-Me 16 and 6-MeO 22 , these derivatives have no appreciable affinity for the A 1 AR.…”

Section: Discussionmentioning

confidence: 99%

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Purine (N)-Methanocarba Nucleoside Derivatives Lacking an Exocyclic Amine as Selective A₃ Adenosine Receptor Agonists

et al. 2016

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Purine (N)-methanocarba-5′-N-alkyluronamidoriboside A3 adenosine receptor (A3AR) agonists lacking an exocyclic amine resulted from an unexpected reaction during a Sonogashira coupling and subsequent aminolysis. Because the initial C6-Me and C6-styryl derivatives had unexpectedly high A3AR affinity, other rigid nucleoside analogues lacking an exocyclic amine were prepared. Of these, the C6-Me-(2-phenylethynyl) and C2-(5-chlorothienylethynyl) analogues were particularly potent, with human A3AR Ki values of 6 and 42 nM, respectively. Additionally, the C2-(5-chlorothienyl)-6-H analogue was potent and selective at A3AR (MRS7220, Ki 60 nM) and also completely reversed mouse sciatic nerve mechanoallodynia (in vivo, 3 μmol/kg, po). The lack of a C6 H-bond donor while maintaining A3AR affinity and efficacy could be rationalized by homology modeling and docking of these hypermodified nucleosides. The modeling suggests that a suitable combination of stabilizing features can partially compensate for the lack of an exocyclic amine, an otherwise important contributor to recognition in the A3AR binding site.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Purine (N)-Methanocarba Nucleoside Derivatives Lacking an Exocyclic Amine as Selective A₃ Adenosine Receptor Agonists

et al. 2016

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“…A 3 AR agonists are potent non-narcotic analgesics able to block and reverse neuropathic pain [7] by acting at peripheral, spinal, and supraspinal sites [32]. This study, the first to examine potential signaling pathways, identifies inhibition of NADPH oxidase with subsequent modulation of two well-described glia-restricted redox-dependent signaling pathways as an important spinal mechanism of action (Fig.…”

Section: Discussionmentioning

confidence: 99%

A3 adenosine receptor agonist prevents the development of paclitaxel-induced neuropathic pain by modulating spinal glial-restricted redox-dependent signaling pathways

Janes

Esposito

Doyle

et al. 2014

Pain

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Chemotherapy-induced peripheral neuropathy (CIPN) accompanied by chronic neuropathic pain is the major dose-limiting toxicity of several anticancer agents including the taxane paclitaxel (Taxol®). A critical mechanism underlying paclitaxel-induced neuropathic pain is the increased production of peroxynitrite (PN) in spinal cord generated in response to activation of the superoxide-generating enzyme, NADPH oxidase. PN in turn contributes to the development of neuropathic pain by modulating several redox-dependent events in spinal cord. We recently reported that activation of the Gi/Gq-coupled A3 adenosine receptor (A3AR) with selective A3AR agonists (i.e., IB-MECA) blocked the development of chemotherapy induced-neuropathic pain evoked by distinct agents, including paclitaxel, without interfering with anticancer effects. The mechanism(s) of action underlying these beneficial effects has yet to be explored. We now demonstrate that IB-MECA attenuates the development of paclitaxel-induced neuropathic pain by inhibiting the activation of spinal NADPH oxidase and two downstream redox-dependent systems. The first relies on inhibition of the redox-sensitive transcription factor (NFκB) and mitogen activated protein kinases (ERK and p38) resulting in a decreased production of neuroexcitatory/pro-inflammatory cytokines (TNF-α, IL-1β) and increased formation of the neuroprotective/anti-inflammatory IL-10. The second involves inhibition of redox-mediated posttranslational tyrosine nitration and modification (inactivation) of glia-restricted proteins known to play key roles in regulating synaptic glutamate homeostasis: the glutamate transporter GLT-1 and glutamine synthetase. Our results unravel a mechanistic link into biomolecular signaling pathways employed by A3AR activation in neuropathic pain while providing the foundation to consider use of A3AR agonists as therapeutic agents in CIPN patients.

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“…These efforts have thus far proven unsuccessful in yielding a usable therapeutic option owing to several undesirable consequences, notably, cardiovascular side effects due to A 1 AR/A 2A AR activation (12, 14). We recently reported that endogenous adenosine signals via A 3 AR to inhibit chronic neuropathic pain (15) and have identified selective orally bioavailable A 3 AR agonists as potent non-narcotic analgesics across several preclinical models of chronic neuropathic pain, including CIPN (16). Contrasting A 1 AR and A 2A AR agonist’s restricted therapeutic use, A 3 AR agonists, including IB-MECA, have already advanced to phase II/III clinical trials for non-pain states and have thus far displayed good safety profiles (17, 18).…”

Section: Introductionmentioning

confidence: 99%

“…Contrasting A 1 AR and A 2A AR agonist’s restricted therapeutic use, A 3 AR agonists, including IB-MECA, have already advanced to phase II/III clinical trials for non-pain states and have thus far displayed good safety profiles (17, 18). While we have identified that A 3 AR agonists reverse mechano-hypersensitivities through the activation of A 3 ARs in regions responsible for nociceptive processing (i.e., the spinal cord and rostral ventromedial medulla (15), the signaling pathways engaged at these sites remain unknown.…”

Section: Introductionmentioning

confidence: 99%

Spinal neuroimmune activation is independent of T-cell infiltration and attenuated by A3 adenosine receptor agonists in a model of oxaliplatin-induced peripheral neuropathy

Janes

Wahlman

Little

et al. 2015

Brain, Behavior, and Immunity

118

146

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Many commonly used chemotherapeutics including oxaliplatin are associated with the development of a painful chemotherapy-induced peripheral neuropathy (CIPN). This dose-limiting complication can appear long after the completion of therapy causing a significant reduction in quality-of-life and impeding cancer treatment. We recently reported that activation of the Gi/Gq-coupled A3 adenosine receptor (A3AR) with selective A3AR agonists (i.e., IB-MECA) blocked the development of chemotherapy induced-neuropathic pain in models evoked by distinct agents including oxaliplatin without interfering with their anticancer activities. The mechanism(s) of action underlying these beneficial effects has yet to be explored. Our results demonstrate that the development of oxaliplatin-induced mechano-hypersensitivity (allodynia and hyperalgesia) in rats is associated with the hyperactivation of astrocytes, but not microglial cells, increased production of pro-inflammatory and neuroexcitatory cytokines (TNF, IL-1β), and reductions in the levels of anti-inflammatory/neuroprotective cytokines (IL-10, IL-4) in the dorsal horn of the spinal cord. These events did not require lymphocytic mobilization since oxaliplatin did not induce CD45+/CD3+ T-cell infiltration into the spinal cord. A3AR agonists blocked the development of neuropathic pain with beneficial effects strongly associated with the modulation of spinal neuroinflammatory processes: attenuation of astrocytic hyperactivation, inhibition of TNF and IL-1β production, and an increase in IL-10 and IL-4. These results suggest that inhibition of an astrocyte-associated neuroinflammatory response contributes to the protective actions of A3AR signaling and continues to support the pharmacological basis for selective A3AR agonists as adjuncts to chemotherapeutic agents for the management of chronic pain.

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(297) Central adenosine A3 receptor (A3AR) activation reverses neuropathic pain

Cited by 3 publications

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Purine (N)-Methanocarba Nucleoside Derivatives Lacking an Exocyclic Amine as Selective A₃ Adenosine Receptor Agonists

Purine (N)-Methanocarba Nucleoside Derivatives Lacking an Exocyclic Amine as Selective A₃ Adenosine Receptor Agonists

A3 adenosine receptor agonist prevents the development of paclitaxel-induced neuropathic pain by modulating spinal glial-restricted redox-dependent signaling pathways

Spinal neuroimmune activation is independent of T-cell infiltration and attenuated by A3 adenosine receptor agonists in a model of oxaliplatin-induced peripheral neuropathy

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(297) Central adenosine A3 receptor (A3AR) activation reverses neuropathic pain

Cited by 3 publications

References 0 publications

Purine (N)-Methanocarba Nucleoside Derivatives Lacking an Exocyclic Amine as Selective A3 Adenosine Receptor Agonists

Purine (N)-Methanocarba Nucleoside Derivatives Lacking an Exocyclic Amine as Selective A3 Adenosine Receptor Agonists

A3 adenosine receptor agonist prevents the development of paclitaxel-induced neuropathic pain by modulating spinal glial-restricted redox-dependent signaling pathways

Spinal neuroimmune activation is independent of T-cell infiltration and attenuated by A3 adenosine receptor agonists in a model of oxaliplatin-induced peripheral neuropathy

Contact Info

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Purine (N)-Methanocarba Nucleoside Derivatives Lacking an Exocyclic Amine as Selective A₃ Adenosine Receptor Agonists

Purine (N)-Methanocarba Nucleoside Derivatives Lacking an Exocyclic Amine as Selective A₃ Adenosine Receptor Agonists