Pharmacological characterisation of the highly Nav1.7 selective spider venom peptide Pn3a

Abstract

Human genetic studies have implicated the voltage-gated sodium channel Na(V)1.7 as a therapeutic target for the treatment of pain. A novel peptide, mu-theraphotoxin-Pn3a, isolated from venom of the tarantula Pamphobeteus nigricolor, potently inhibits Na(V)1.7 (IC50 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(V)1.7 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(V)1.7 inhibitors PF-04856264 and phlotoxin 1. However, when administered with subtherapeutic doses of opioids or the enkephalinase inhibitor thiorphan, these subtype-selective Na(V)1.7 inhibitors produced profound analgesia. Our results suggest that in these inflammatory models, acute administration of peripherally restricted Na(V)1.7 inhibitors can only produce analgesia when administered in combination with an opioid