The NaV1.7 Channel Subtype as an Antinociceptive Target for Spider Toxins in Adult Dorsal Root Ganglia Neurons

Abstract

Although necessary for human survival, pain may sometimes become pathologic if long-lasting and associated with alterations in its signaling pathway. Opioid painkillers are officially used to treat moderate to severe, and even mild, pain. However, the consequent strong and not so rare complications that occur, including addiction and overdose, combined with pain management costs, remain an important societal and economic concern. In this context, animal venom toxins represent an original source of antinociceptive peptides that mainly target ion channels (such as ASICs as well as TRP, CaV, KV and NaV channels) involved in pain transmission. The present review aims to highlight the NaV1.7 channel subtype as an antinociceptive target for spider toxins in adult dorsal root ganglia neurons. It will detail (i) the characteristics of these primary sensory neurons, the first ones in contact with pain stimulus and conveying the nociceptive message, (ii) the electrophysiological properties of the different NaV channel subtypes expressed in these neurons, with a particular attention on the NaV1.7 subtype, an antinociceptive target of choice that has been validated by human genetic evidence, and (iii) the features of spider venom toxins, shaped of inhibitory cysteine knot motif, that present high affinity for the NaV1.7 subtype associated with evidenced analgesic efficacy in animal models.

Newly Discovered Action of HpTx3 from Venom of Heteropoda venatoria on Nav1.7 and Its Pharmacological Implications in Analgesia

“…By sequence alignment, we found that the sequence of HpTx3 has high identity with those of some Nav channel peptide toxins in the NaSpTx family 3 [7,18] (see Discussion), which suggested HPLC chromatogram and the same molecular weight, the component we purified from the Heteropoda venatoria venom was identified as peptide neurotoxin HpTx3.…”

“…By sequence alignment, we found that the sequence of HpTx3 has high identity with those of some Na v channel peptide toxins in the NaSpTx family 3 [7,18] (see Discussion), which suggested that HpTx3 might have an inhibitory effect on Na v channels. In order to investigate the Na v channel-targeted activity and the subtype selectivity of HpTx3, the effects of HpTx3 on mammal Na v 1.2-1.9 expressed in HEK293T or ND7/23 cells were detected.…”

“…By sequence alignment, we found that the sequence of HpTx3 has high identity with those of some Nav channel peptide toxins in the NaSpTx family 3 [7,18] (see Discussion), which suggested…”

“…Sensory neurons in the peripheral nervous system can produce action potential when the stimulation is applied, and Na v 1.7 plays an important role in initiating such action potentials [5,6]. It has been well-established that Na v 1.7 is highly expressed in dorsal root ganglia neurons and its mutations induce genetic pain and painless disorders, which makes Na v 1.7 one of the most promising targets for pain control [7][8][9]. For example, gain-of-function mutation in the SCN9A gene that encodes the α subunit of Na v 1.7 caused severe episodic pain, whereas loss-of-function mutations in SCN9A resulted in insensitivity to pain [10].…”

“…Nevertheless, due to their intrinsic limitations, such as lack of specificity and/or pronounced side-effects, the potential of these small molecules in the therapeutic development is significantly weakened, which promotes development of the drugs with higher efficiency and less side effects from natural resources. In recent decades, the proteinaceous toxins with an analgesic effect from the venomous spiders have attracted the attention of the relevant scientific researchers [7,14]. Spider venom produced by venom glands can help spiders resist the natural enemies and capture preys.…”