Dib-Hajj, S. | bioRxiv Science

bioRxiv2026

Nav1.5 expressed in TrkB+ sensory neurons mediates paclitaxel-induced mechanical pain hypersensitivity

Chemotherapy-induced neuropathic pain (CINP) is a frequent and debilitating adverse effect of anti-tumor therapies, for which current treatments are largely non-specific and offer limited efficacy. Identifying molecular mechanisms that drive CINP may enable the development of targeted therapeutic strategies. Here, we demonstrate that paclitaxel-induced mechanical pain hypersensitivity in mice occurs independently of classical Nav1.8+ nociceptors but critically depends on TrkB+ sensory neurons. Transcriptomic analysis of TrkB+ sensory neurons revealed selective expression of Scn5a, which encodes the voltage-gated sodium channel Nav1.5, a channel classically associated with cardiac excitability. Importantly, SCN5A expression was also detected in human primary sensory neurons, indicating potential translational relevance. Functional studies further showed that Scn5a knockdown, using small interfering RNA, significantly attenuates paclitaxel-induced mechanical pain hypersensitivity. Together, these findings identify TrkB+ sensory neurons as key drivers of CINP and reveal Nav1.5 as a previously unrecognized contributor to chemotherapy-induced neuropathic pain. Targeting Nav1.5 in TrkB+ sensory neurons may therefore represent a novel therapeutic strategy for the treatment of CINP.

neuroscience↗

bioRxiv2021

Inhibition of sodium conductance by cannabigerol contributes to a reduction of neuronal dorsal root ganglion excitability

Cannabigerol (CBG), a non-psychotropic phytocannabinoid, is a precursor for cannabis derivatives, {Delta}9-tetrahydrocannabinol and cannabidiol (CBD). Like CBD, CBG has been suggested as an analgesic. A previous study reported CBG (10 M) blocks voltage-gated sodium (Nav) currents in CNS neurons. However, the manner in which CBG inhibits Nav channels, and whether this effect contributes to CBGs potential analgesic behavior remain unknown. Genetic and functional studies have validated Nav1.7 as an opportune target for analgesic drug development. The efforts to develop therapeutic selective Nav1.7 blockers have been unsuccessful thus far, possibly due to issues in occupancy; drugs have been administered at concentrations many folds above IC50, resulting in loss of isoform-selectivity, and increasing off-target effects. We reasoned that an alternative approach could use compounds possessing 2 important properties: ultra-hydrophobicity and functional selectivity. Hydrophobicity could enhance absorption into neuronal cells especially with local administration. Functional selectivity could reduce likelihood of side-effects. As CBG is ultra-hydrophobic (cLogD=7.04), we sought to determine whether it also possesses functional selectivity against Nav channels that are expressed in dorsal root ganglion (DRG). We found that CBG is a ~10-fold state-dependent Nav inhibitor (KI-KR: ~2-20 M) with an average Hill-slope of ~2. We determined that at lower concentrations, CBG predominantly blocks sodium Gmax and slows recovery from inactivation; however, as concentration is increased, CBG also hyperpolarizes Nav inactivation curves. Our modeling and multielectrode array recordings suggest that CBG attenuates DRG excitability, which is likely linked with Nav inhibition. As most Nav1.7 channels are inactivated at DRG resting membrane potential, they are more likely to be inhibited by lower CBG concentrations, suggesting functional selectivity against Nav1.7 compared to other Navs (via Gmax block).

pharmacology and toxicology↗