GpTx‐1 and [Ala⁵, Phe⁶, Leu²⁶, Arg²⁸]GpTx‐1, two peptide Na_V1.7 inhibitors: analgesic and tolerance properties at the spinal level

Abstract

Our data indicate that the Na 1.7 peptide inhibitors GpTx-1 and GpTx-1-71 produce powerful, nontolerance-forming analgesia in preclinical pain models, which might be dependent on the endogenous opioid system. In addition, at the spinal level, the limited side effects imply that these Na 1.7 peptide inhibitors could be potentially developed as GpTx-1-based drugs for pain relief.

A central mechanism of analgesia in mice and humans lacking the sodium channel NaV1.7

“…Enhanced opioid receptor signaling is therefore a crucial component of analgesia in Na V 1.7 KO mice. This is consistent with recent observations that peptide antagonists of Na V 1.7 that elicit analgesia in mice can be inhibited by naloxone (Chen et al, 2018;Mueller et al, 2019). Profound analgesic synergy between Na V 1.7 blockers and low-dose opioids has also been reported (Deuis et al, 2017;Emery et al, 2016a).…”

Selective Targeting of Nav1.7 with Engineered Spider Venom-Based Peptides

“…GpTX-1, however, has been shown to be efficacious in reducing pain behaviors evoked by intraplantar injection of OD-1 [ 65 ]. In addition, spinal administration of GpTX-1 and [F5A, M6F, T26L, K28R]-GpTX-1 provided dose-dependent analgesia in mechanical, thermal, visceral, and neuropathic pain models which was undiminished with 8 days of repeated administration [ 66 ]. GpTX-1, however, had no effect on OD-1-induced pain behaviors when delivered intraperitoneally at the maximum tolerated dose [ 65 ], and no evidence to date has been presented demonstrating efficacy of an engineered peptide in a relevant pain model with systemic GpTX-1 administration.…”

Central and peripheral modulation of gastrointestinal transit in mice by DN‐9, a multifunctional opioid/NPFF receptor agonist

“…The procedure of ICV cannula implantation was conducted as previously described. 24 Briefly, mice were anesthetized with 80 mg kg −1 bodyweight pentobarbital sodium (IP) and placed in a stereotactic device (68001, RWD Life Science). A stainless-steel cannula (ID: 0.25 mm, OD: 0.50 mm) was implanted 3 mm into the right lateral ventricle using the following coordinates: 3 mm posterior and 1 mm lateral to bregma.…”