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bioRxiv · 10.1101/2025.07.01.662507

The c-Src inhibitor eCF506 diminishes opioid tolerance creating bias against β-arrestin2 recruitment

Singleton, S.·Nunn, F.·Lorente-Macias, A.·Unciti-Broceta, A.·Hales, T. G.
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Abstract

Opioids reduce severe pain, but persistent use is compromised by tolerance, attenuated by either {beta}-arrestin2 depletion, prompting development of biased opioids limited by partial efficacy, or c-Src kinase inhibitors, potentially acting through off-target effects. We tested eCF506, a conformationally selective c-Src inhibitor, on morphine antinociception and examined its effect on receptor signaling and {beta}-arrestin2 recruitment. Oral eCF506 inhibited morphine tolerance in C57BL/6J mice. Exposure of PathHunter CHO cells to eCF506 did not affect inhibition of cAMP accumulation by the agonist, DAMGO, but reduced {beta}-arrestin2 recruitment. This effect, mimicked by targeted degradation of c-Src, occurred through inhibition of c-Src catalytic function as evidenced by its diminution by the catalytically inactive Src250-536(K298M) construct. This mutant also restricted the effect of c-Src inhibitors on {beta}-arrestin2 recruitment. eCF506 additionally increased surface expression of receptors and limited their internalization by endomorphin-2 but did not alter DAMGO-evoked GRK-mediated receptor phosphorylation. These findings suggest that eCF506 prolongs opioid antinociception by inducing signalling bias, diminishing {beta}-arrestin2-mediated receptor regulation.

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Singleton, S., Nunn, F., Lorente-Macias, A., Unciti-Broceta, A., Hales, T. G.. 2025-07-05. The c-Src inhibitor eCF506 diminishes opioid tolerance creating bias against β-arrestin2 recruitment. https://doi.org/10.1101/2025.07.01.662507

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