Ornithoctonus huwena, Chinese tarantula, is one of the most venomous spiders in China, and its venom can kill insects and some small vertebrates. Huwentoxin-XVI (HWTX-XVI) is a new type of neurotoxin purified from the venom of ornithoctonus huwena. It consists of 39 amino acid residues, including six cysteines involved three disulfide bonds. Its molecular weight is 4437.4 Da. HWTX-XVI is white or white like powder, odorless, easily soluble in water, and water solution is almost colorless and transparent. HWTX-XVI was found to selectively inhibit N-type calcium channels of rat dorsal root ganglion (DRG) cells (IC50~60 nM), while had no significant effect on the sodium, potassium channels and other calcium channel subtypes of rat DRG cells.
The analgesic activity of HWTX-XVI is mainly reflected in the second phase pain, while the analgesic effect on the first phase pain is not obvious, indicating that HWTX-XVI may have no analgesic effect on pain directly caused by mechanical and chemical stimulation. Intraperitoneal injection of XVI has a good analgesic effect on formalin induced acute inflammatory pain in rats. Intramuscular injection has obvious analgesic effect on both mechanical pain and hot plate pain of post-operative injury model, and no toxic side effects such as tremor and dyskinesia are observed in animal models under the high dose of XVI. The inhibition of HWTX-XVI is time dependent and the blocking is reversible. In addition, HWTX-XVI could significantly block the contraction of vas deferens smooth muscle in rats induced by low voltage stimulation. These results suggest that HWTX-XVI may have a better clinical application prospects.
HWTX-XVI is a neurotoxin selectively acting on N-type calcium channel. Since N-type calcium channel is an ideal target for treating pain, it is speculated that HWTX-XVI has good analgesic effect. Compared with morphine hydrochloride group, the analgesic effect of 500 μg /kg HWTX-XVI and 5mg/kg morphine group was comparable. HWTX-XVI blocks GVIA-sensitive N-type calcium channels in rat DRG neurons, and its analgesic effect, low side effects and reversibility make it a promising candidate for the development of a novel analgesic agent.
Jiang, L., Peng, L., Chen, J., Zhang, Y., Xiong, X., Liang, S. Molecular diversification based on analysis of expressed sequence tags from the venom glands of the Chinese bird spider Ornithoctonus huwena. Toxicon, 2008, 51, 1479-1489.
King, G.F., Escoubas, P., Nicholson, G.M. Peptide toxins that selectively target insect Na(V) and Ca(V) channels. Channels (Austin), 2008. 2, 100-116.
Adams, D.J., Callaghan, B., Berecki, G. Analgesic conotoxins: block and G protein-coupled receptor modulation of N-type (Ca(V) 2.2) calcium channels. Br. J. Pharmacol, 2012, 166, 486-500.
Adams, D.J., Berecki, G. Mechanisms of conotoxin inhibition of N-type (Ca(v) 2.2) calcium channels. Biochim. Biophys. Acta, 2013, 1828, 1619-1628.