Pharmacological characterisation of the highly Na _V1.7 selective spider venom peptide Pn3a

Abstract

Human genetic studies have implicated the voltage-gated sodium channel Na _V1.7 as a therapeutic target for the treatment of pain. A novel peptide, μ-theraphotoxin-Pn3a, isolated from venom of the tarantula Pamphobeteus nigricolor, potently inhibits Na _V1.7 (IC ₅₀ 0.9 nM) with at least 40–1000-fold selectivity over all other Na _V subtypes. Despite on-target activity in small-diameter dorsal root ganglia, spinal slices, and in a mouse model of pain induced by Na _V1.7 activation, Pn3a alone displayed no analgesic activity in formalin-, carrageenan- or FCA-induced pain in rodents when administered systemically. A broad lack of analgesic activity was also found for the selective Na _V1.7 inhibitors PF-04856264 and phlotoxin 1. However, when administered with subtherapeutic doses of opioids or the enkephalinase inhibitor thiorphan, these subtype-selective Na _V1.7 inhibitors produced profound analgesia. Our results suggest that in these inflammatory models, acute administration of peripherally restricted Na _V1.7 inhibitors can only produce analgesia when administered in combination with an opioid.