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Optical Control of Adenosine-Mediated Pain Modulation.

ABSTRACT: Adenosine receptors (ARs) play many important roles in physiology and have been recognized as potential targets for pain relief. Here, we introduce three photoswitchable adenosine derivatives that function as light-dependent agonists for ARs and confer optical control to these G protein-coupled receptors. One of our compounds, AzoAdenosine-3, was evaluated in the classical formalin model of pain. The molecule, active in the dark, was not metabolized by adenosine deaminase and effectively reduced pain perception in a light-dependent manner. These antinociceptive effects suggested a major role for A₁R and A₃R in peripheral-mediated pain sensitization, whereas an average adenosine-mediated antinociceptive effect will be facilitated by A_2AR and A_2BR. Our results demonstrate that a photoswitchable adenosine derivative can be used to map the contribution of ARs mediating analgesia in vivo.

SUBMITTER: Hull K

PROVIDER: S-EPMC8634359 | biostudies-literature | 2021 Sep

REPOSITORIES: biostudies-literature

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Optical Control of Adenosine-Mediated Pain Modulation.

Hüll Katharina K Fernández-Dueñas Víctor V Schönberger Matthias M López-Cano Marc M Trauner Dirk D Ciruela Francisco F

Bioconjugate chemistry 20210827 9

Adenosine receptors (ARs) play many important roles in physiology and have been recognized as potential targets for pain relief. Here, we introduce three photoswitchable adenosine derivatives that function as light-dependent agonists for ARs and confer optical control to these G protein-coupled receptors. One of our compounds, AzoAdenosine-3, was evaluated in the classical formalin model of pain. The molecule, active in the dark, was not metabolized by adenosine deaminase and effectively reduced ...[more]

PMID: 34448572

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Project description:Neuropathic pain remains poorly treated for large numbers of patients, and little progress has been made in developing novel classes of analgesics. To redress this issue, ziconotide (Prialt™) was developed and approved as a first-in-class synthetic version of ω-conotoxin MVIIA, a peptide blocker of Cav 2.2 channels. Unfortunately, the impracticalities of intrathecal delivery, low therapeutic index and severe neurological side effects associated with ziconotide have restricted its use to exceptional circumstances. Ziconotide exhibits no state or use-dependent block of Cav 2.2 channels; activation state-dependent blockers were hypothesized to circumvent the side effects of state-independent blockers by selectively targeting high-frequency firing of nociceptive neurones in chronic pain states, thus alleviating aberrant pain but not affecting normal sensory transduction. Unfortunately, numerous drugs, including state-dependent calcium channel blockers, have displayed efficacy in preclinical models but have subsequently been disappointing in clinical trials. In recent years, it has become more widely acknowledged that trans-aetiological sensory profiles exist amongst chronic pain patients and may indicate similar underlying mechanisms and drug sensitivities. Heterogeneity amongst patients, a reliance on stimulus-evoked endpoints in preclinical studies and a failure to utilize translatable endpoints, all are likely to have contributed to negative clinical trial results. We provide an overview of how electrophysiological and operant-based assays provide insight into sensory and affective aspects of pain in animal models and how these may relate to chronic pain patients in order to improve the bench-to-bedside translation of calcium channel modulators.Linked articlesThis article is part of a themed section on Recent Advances in Targeting Ion Channels to Treat Chronic Pain. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.12/issuetoc.

Dataset Information

Optical Control of Adenosine-Mediated Pain Modulation.

Publications

Optical Control of Adenosine-Mediated Pain Modulation.

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