Predicting the Antinociceptive Efficacy of σ₁ Receptor Ligands by a Novel Receptor Fluorescence Resonance Energy Transfer (FRET) Based Biosensor

We have developed a novel methodology for monitoring the σ₁ receptor activation switch in living cells. Our assay uncovered the intrinsic nature of σ₁ receptor ligands by recording the ligand-mediated conformational changes of this chaperone protein. The change triggered by each ligand correlated well with its ability to attenuate formalin induced nociception in an animal model of pain. This tool may assist in predicting the antinociceptive efficacy of σ₁ receptor ligands

Uncovering Caffeine’s Adenosine A_2A Receptor Inverse Agonism in Experimental Parkinsonism

Caffeine, the most consumed psychoactive substance worldwide, may have beneficial effects on Parkinson’s disease (PD) therapy. The mechanism by which caffeine contributes to its antiparkinsonian effects by acting as either an adenosine A_2A receptor (A_2AR) neutral antagonist or an inverse agonist is unresolved. Here we show that caffeine is an A_2AR inverse agonist in cell-based functional studies and in experimental parkinsonism. Thus, we observed that caffeine triggers a distinct mode, opposite to A_2AR agonist, of the receptor’s activation switch leading to suppression of its spontaneous activity. These inverse agonist-related effects were also determined in the striatum of a mouse model of PD, correlating well with increased caffeine-mediated motor effects. Overall, caffeine A_2AR inverse agonism may be behind some of the well-known physiological effects of this substance both in health and disease. This information might have a critical mechanistic impact for PD pharmacotherapeutic design