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A novel peptide, \u03bc-theraphotoxin-Pn3a, isolated from venom of the tarantula <jats:italic>Pamphobeteus nigricolor,<\/jats:italic> potently inhibits Na<jats:sub>V<\/jats:sub>1.7 (IC<jats:sub>50<\/jats:sub> 0.9\u2009nM) with at least 40\u20131000-fold selectivity over all other Na<jats:sub>V<\/jats:sub> subtypes. Despite on-target activity in small-diameter dorsal root ganglia, spinal slices, and in a mouse model of pain induced by Na<jats:sub>V<\/jats:sub>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<jats:sub>V<\/jats:sub>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<jats:sub>V<\/jats:sub>1.7 inhibitors produced profound analgesia. 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