Intracerebroventricular Coadministration of Protoxin-II and Trace Elements in Rats Enhances the Analgesic Effect of the 1.7 Voltage-Gate Sodium Channel Blocker

Abstract

Pain continues to be a global unmet medical need, and the current recommendations for its management require a constant exploration of new drugs that target multiple pain mechanisms, with an improved safety profile and increased treatment adherence. Currently, the enriched distribution and localization within nociceptors of the selective channel blockers and the critical role played by sodium channels in neuronal excitability nominate isoforms as specific targets to generate innovative compounds. In the present report, we verified the hypothesis that coadministration of Protoxin-II, a selective sodium channel inhibitor, and trace elements has direct and improved antinociceptive effects. Groups of seven Wistar rats were treated intracerebroventricularly with a combination of MgCl 2 , CdCl 2 , and ZnCl 2 and Protoxin-II, respectively, and with Protoxin-II alone (positive) or saline (negative) for controls. Evaluations were performed by nociception assay. Coadministration of these drugs caused an increase in the maximum possible effect of up to 40% as compared with the control groups. Our findings indicate that selective channel blockers continue to be an important nociception target and that the use of trace elements may provide simple but effective means of control over sodium channel blockers' risks, potentially lowering the necessary analgesic doses, thus improving the efficacy and safety profile.

Evaluation of Efficient Non-reducing Enzymatic and Chemical Ligation Strategies for Complex Disulfide-Rich Peptides

“…Peptide toxins that target Na V s are hailed as promising candidates for future analgesic treatments. However, despite extensive discovery and development efforts focused on potent and selective venom-derived gating-modifier toxins targeting hNa V 1.7, this potential is yet to be realized. − Recently discovered double-knotted spider toxins − and enabling synthetic methods ,,− have paved a path for the development of an exciting new class of pharmacological tools and potential drug leads, involving conjugation of two potent Na V inhibitors with different modes of action to create synthetic bivalent constructs. However, the route to synthetically accessing this new class of bivalent peptides is not straightforward due to complications introduced by the presence of complex disulfide bond frameworks in each individual peptide domain, prohibiting the use of most standard chemical ligation techniques.…”

Unveiling the Pain Relief Potential: Harnessing Analgesic Peptides from Animal Venoms

“…Peptides from P. nigriventer exhibit a wide variety of analgesic mechanisms, which include (i) a reduction in glutamate levels in the cerebrospinal fluid [ 92 ]; (ii) an effect on peripheral opioid and cannabinoid systems [ 93 , 94 ]; (iii) the activation of the NO-cGMP pathway -KATP [ 95 ]; (iv) the inhibition of spinal AChE resulting in the activation of muscarinic and nicotinic receptors [ 96 ]; (v) the selective antagonism of TRPA1 channels [ 92 ]; (vi) the reversible inhibition of voltage-gated calcium channels (VGCC) [ 97 ]; and (vii) the antagonism of the CXCR4 receptor [ 98 ]. There is a great diversity of pharmacological mechanisms in peptides of Phoneutria nigriventer venom, but the venom of other species/genera remains underexplored and even unknown.…”

“…The intraperitoneal injection of this peptide induces analgesia by inhibiting Nav1.7 channels and exhibited synergy with opioids in a model of peripheral pain induced by the injection of α-scorpion toxin OD1. Other peptides isolated from Ceratogyrus sp., Davus sp., Haplopelma lividum , Heteropoda venatoria , Thrixopelma pruriens , and Grammostola porteni also present potent candidates for analgesic drugs through the modulation of ion channels [ 79 , 87 , 88 , 90 , 91 , 96 , 99 , 100 , 101 , 102 , 103 , 104 ].…”