# Interaction of Erdosteine with TrkA Signaling Pathways: Implications for Analgesia

## TL;DR

Erdosteine, a mucolytic drug, may act as a pain reliever by blocking the TrkA receptor, which is involved in nerve growth factor signaling.

## Contribution

Erdosteine and its metabolite Met-1 are shown to inhibit TrkA activation via binding and structural modification, suggesting a novel non-opioid analgesic mechanism.

## Key findings

- Erdosteine and Met-1 bind to key residues in the TrkA receptor and reduce a disulfide bridge between Cys300 and Cys345.
- Both compounds inhibit NGF-induced TrkA autophosphorylation in vitro, with maximal inhibition reaching 40% at 1 mM after 24 hours.
- The inhibition suggests erdosteine functions as a TrkA antagonist, potentially offering analgesic effects through NGF signaling inhibition.

## Abstract

Thiol-containing drugs may interact with a region of tropomyosin receptor kinase A (TrkA), potentially inhibiting its activation by nerve growth factor (NGF). This action has been linked to potential analgesic activities. Here, we describe the ability of erdosteine, a thiolic compound classified as a mucolytic agent, to bind to the TrkA receptor sequence in silico and its in vitro effects on TrkA activation induced by NGF in cultured human neuroblastoma cells. Our results show that erdosteine and its metabolite, Met-1, bind to the TrkA receptor pocket, involving the primary TrkA residues Glu331, Arg347, His298, and His297. Furthermore, Met-1 has the ability to reduce the disulfide bridge between Cys300 and Cys345 of TrkA. In vitro measurement of TrkA autophosphorylation following NGF activation confirmed that erdosteine and Met-1 interfere with NGF-induced TrkA activation, leading to a consequent loss of the molecular recognition and spatial reorganization necessary for the induction of the autophosphorylation process. This effect was inhibited by low millimolar concentrations of the two compounds, reaching a maximal inhibition (around 40%) after 24 h of exposure to 1 mM erdosteine, and then plateauing. These findings suggest that erdosteine can act as a TrkA antagonist, thus indicating that this drug may have potential as an analgesic via a novel non-opioid mechanism of action operating through NGF signaling inhibition at the level of TrkA.