Subcutaneous ω-Conotoxins Alleviate Mechanical Pain in Rodent Models of Acute Peripheral Neuropathy

Abstract

The peripheral effects of ω-conotoxins, selective blockers of N-type voltage-gated calcium channels (CaV2.2), have not been characterised across different clinically relevant pain models. This study examines the effects of locally administered ω-conotoxin MVIIA, GVIA, and CVIF on mechanical and thermal paw withdrawal threshold (PWT) in postsurgical pain (PSP), cisplatin-induced neuropathy (CisIPN), and oxaliplatin-induced neuropathy (OIPN) rodent models. Intraplantar injection of 300, 100 and 30 nM MVIIA significantly (p < 0.0001, p < 0.0001, and p < 0.05, respectively) alleviated mechanical allodynia of mice in PSP model compared to vehicle control group. Similarly, intraplantar injection of 300, 100, and 30 nM MVIIA (p < 0.0001, p < 0.01, and p < 0.05, respectively), and 300 nM and 100 nM GVIA (p < 0.0001 and p < 0.05, respectively) significantly increased mechanical thresholds of mice in OIPN model. The ED50 of GVIA and MVIIA in OIPN was found to be 1.8 pmol/paw and 0.8 pmol/paw, respectively. However, none of the ω-conotoxins were effective in a mouse model of CisIPN. The intraplantar administration of 300 nM GVIA, MVIIA, and CVIF did not cause any locomotor side effects. The intraplantar administration of MVIIA can alleviate incision-induced mechanical allodynia, and GVIA and MVIIA effectively reduce OIPN associated mechanical pain, without locomotor side effects, in rodent models. In contrast, CVIF was inactive in these pain models, suggesting it is unable to block a subset of N-type voltage-gated calcium channels associated with nociceptors in the skin.

A kinase-dead Csf1r mutation associated with adult-onset leukoencephalopathy has a dominant inhibitory impact on CSF1R signalling

“…Mice were habituated in individual mouse runs for 30 min prior to commencing measurement. As described previously ( Hasan et al, 2021 ), a soft-tipped von Frey filament was placed against the foot pad of the right hind paw. Pressure was slowly increased at a rate of 1 g/s, through rotation of the device handle, and the force ( g ) causing paw withdrawal displayed on the device was recorded.…”

“…Pressure was slowly increased at a rate of 1 g/s, through rotation of the device handle, and the force ( g ) causing paw withdrawal displayed on the device was recorded. A single biological replicate was determined by averaging three repeated measurements (minimum of 5-min intervals) for each mouse ( Hasan et al, 2021 ).…”

Cyclovirobuxine D, a cardiovascular drug from traditional Chinese medicine, alleviates inflammatory and neuropathic pain mainly via inhibition of voltage-gated Cav3.2 channels

“…We next examined the effect of CVB-D on native Ca v 3.2 and Ca v 2.2 channels, which have been shown to be the dominant nociceptive LVA and HVA calcium channels in small to medium-sized DRG neurons (diameter in 10–30 μm) ( Talley et al, 1999 ; Rose et al, 2013 ; Kitano et al, 2019 ; Li et al, 2019 ; Hasan et al, 2021 ; Hoppanova and Lacinova, 2022 ). Whole-cell currents mediated by endogenous Ca v 3.2 and Ca v 2.2 channels were recorded from freshly dissociated mice DRG neurons using distinct depolarization voltages ( Bourinet et al, 2005 ).…”

A kinase-dead Csf1r mutation associated with adult-onset leukoencephalopathy has a dominant-negative impact on CSF1R signaling

“…Mice were habituated in individual mouse runs for 30 minutes prior to commencing measurement. As described previously (Hasan et al, 2021) a soft-tipped von Frey filament, was placed against the foot pad of the right hind paw. Pressure was slowly increased at a rate of 1 g/s, through rotation of the device handle and the force (g) causing paw withdrawal displayed on the device was recorded.…”