RgIA4 Accelerates Recovery from Paclitaxel-Induced Neuropathic Pain in Rats.

Peter N Huynh,J Michael Mcintosh,Kerry L Tucker,Sean Christensen,Denise Giuvelis

doi:10.3390/md18010012

Peter N Huynh, J Michael Mcintosh + Show 3 more

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https://doi.org/10.3390/md18010012

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Journal: Marine drugs	Publication Date: Dec 21, 2019
Citations: 25	License type: CC BY 4.0

Affiliation: University of Utah, University of New England

Abstract

Chemotherapeutic drugs are widely utilized in the treatment of human cancers. Painful chemotherapy-induced neuropathy is a common, debilitating, and dose-limiting side effect for which there is currently no effective treatment. Previous studies have demonstrated the potential utility of peptides from the marine snail from the genus Conus for the treatment of neuropathic pain. α-Conotoxin RgIA and a potent analog, RgIA4, have previously been shown to prevent the development of neuropathy resulting from the administration of oxaliplatin, a platinum-based antineoplastic drug. Here, we have examined its efficacy against paclitaxel, a chemotherapeutic drug that works by a mechanism of action distinct from that of oxaliplatin. Paclitaxel was administered at 2 mg/kg (intraperitoneally (IP)) every other day for a total of 8 mg/kg. Sprague Dawley rats that were co-administered RgIA4 at 80 µg/kg (subcutaneously (SC)) once daily, five times per week, for three weeks showed significant recovery from mechanical allodynia by day 31. Notably, the therapeutic effects reached significance 12 days after the last administration of RgIA4, which is suggestive of a rescue mechanism. These findings support the effects of RgIA4 in multiple chemotherapeutic models and the investigation of α9α10 nicotinic acetylcholine receptors (nAChRs) as a non-opioid target in the treatment of chronic pain.

Highlights

Neuropathic pain is a type of chronic pain that stems from the damage or disease of the sensory nervous system that affects an estimated 6.9–10% of the general population [1]
The therapeutic effects reached significance 12 days after the last administration of RgIA4, which is suggestive of a rescue mechanism. These findings support the effects of RgIA4 in multiple chemotherapeutic models and the investigation of α9α10 nicotinic acetylcholine receptors as a non-opioid target in the treatment of chronic pain
A clinical formulation of paclitaxel was chosen in order to induce a longer-lasting neuropathic pain clinical of paclitaxel chosen in order to induce a

Summary

Introduction

Neuropathic pain is a type of chronic pain that stems from the damage or disease of the sensory nervous system that affects an estimated 6.9–10% of the general population [1] This type of pathological pain has many causes, including traumatic nerve injury, metabolic disorders such as diabetes, and chemical damage from chemotherapeutics [2]. Paclitaxel (Figure 1) is an anti-cancer drug of the taxane family, initially extracted from the bark of the Pacific yew (Taxus brevifolia), and perhaps the most well-known natural-product chemotherapeutic. It is used as a first-line treatment for breast, ovarian, and non-small cell lung cancers [3]. In the context of cancer therapies, these side effects can be more than disruptive as they are often dose-limiting in treatment regimens [4]

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