Antinociceptive Effects of AGAP, a Recombinant Neurotoxic Polypeptide: Possible Involvement of the Tetrodotoxin-Resistant Sodium Channels in Small Dorsal Root Ganglia Neurons

Abstract

Antitumor-analgesic peptide (AGAP) is a novel recombinant polypeptide. The primary study showed that AGAP 1.0 mg/kg exhibited strong analgesic and antitumor effects. The tail vein administration of AGAP potently reduced pain behaviors in mice induced by intraplantar injection of formalin or intraperitoneal injection of acetic acid, without affecting basal pain perception. To further assess the mechanisms of AGAP, the effects of AGAP on sodium channels were assessed using the whole-cell patch clamp recordings in dorsal root ganglia (DRG) neurons. The results showed that AGAP (3–1000 nM) inhibited the sodium currents in small-diameter DRG neurons in a dose-dependent manner. 1000 nM AGAP could inhibit the current density-voltage relationship curve of sodium channels in a voltage-dependent manner and negatively shift the activation curves. 1000 nM AGAP could reduce the tetrodotoxin-resistant (TTX-R) sodium currents by 42.8% in small-diameter DRG neurons. Further analysis revealed that AGAP potently inhibited NaV1.8 currents by 59.4%, and negatively shifted the activation and inactivation kinetics. 1000 nM AGAP also reduced the NaV1.9 currents by 33.7%, but had no significant effect on activation and inactivation kinetics. Thus, our results demonstrated that submicromolar concentrations of AGAP inhibited TTX-R sodium channel in rat small-diameter DRG neurons. It is concluded that these new results may better explain, at least in part, the analgesic properties of this polypeptide.

Scorpion venom peptide, BmK AGAP as an adjuvant to lidocaine in sciatic nerve block causes dose-dependent increase intensity of sensory block and prolog duration of analgesia in rat.

“…Animal studies have demonstrated that the scorpion venom peptide BmK AGAP exhibit strong analgesic activity with minimum advert effects compared with morphine [4,5,6]. However, it is not clear the mechanisms of the BmK AGAP analgesic activities, as well as the structure-function relationship of voltage-gated sodium channels.…”

“…Evidence shows that it is a sodium channel-specific neurotoxin. It blocks neuron transmission by binding to voltage-independently at site-3 of sodium channels and inactivate the activated sodium channels to elicit potent analgesic activity [4,5]. Local anesthetics such as lidocaine is indicated to mediate the analgesic activities of Nav 1.3, Nav 1.7, Nav 1.8, and Nav 1.9 subunits by non-selectively blocking the voltage-gated sodium channels [16].…”

“…Three independent researchers specialized in pain assessment and were blinded to drugs administration were assigned to assess sensory block, motor block, and mechanical allodynia after drugs administration. The doses of the drugs were determined based on previous studies [4,5,10]…”

“…Li et al in 2014 demonstrated the antinociceptive effect of BmK AGAP through the tail vein injection and realized a similar strong analgesic activity compared with morphine [5]. Ruan et al, in 2018 reported that intrathecal injection of the Chinese scorpion venom peptide BmK AGAP inhibits neuropathic and inflammation-associated pain through a MARK-mediated mechanism [6].…”

The Pivotal Potentials of Scorpion Buthus Martensii Karsch-Analgesic‐Antitumor Peptide in Pain Management and Cancer

“…Voltage-gated sodium channels (VGSCs) facilitate the internal sodium current in the brain and peripheral nerves [ 16 ]. VGSCs are thus crucial in triggering as well as propagation of action potentials in excitable tissues such as the brain and peripheral nerves [ 17 ].…”