Background: Post-surgical pain is an undermanaged condition with most patients experiencing acute pain after surgery. Existing analgesics suffer from poor tolerability, abuse potential and a lack of efficacy. One of the most promising targets for the treatment of pain is NaV1.7, a voltage-gated sodium channel (NaV) subtype. Human genetic studies support a key role of NaV1.7 in pain since gain-of-function and loss-of-function mutations lead to pain syndromes and insensitivity to pain, respectively. We recently isolated the novel tarantula venom peptide μ-theraphotoxin-Pn3a that potently and selectively inhibits NaV1.7. The aim of this project was to characterize the analgesic potential of NaV1.7 inhibition in a mouse model of post-surgical pain using Pn3a and other selective NaV1.7 inhibitors.
Methods: We established and characterized a mouse model of post-surgical pain to allow for testing of Pn3a and other NaV1.7 inhibitors. Briefly, an incision was made through skin and underlying muscle of the plantar foot and then closed with sutures. The mechanical and thermal pain threshold was examined by a blinded observer and analgesic efficacy of compounds was determined.
Results: Heat allodynia as well as mechanical allodynia was present up to at least 48h post-surgery. At 24h post-surgery, intraperitoneal (3mg/kg) as well as local intraplantar (3µM) injection of Pn3a was significantly analgesic compared to vehicle control. In contrast, the NaV1.7 inhibiting peptide ProTx-II as well as the small molecule PF04856264 were partially analgesic after local and systemic administrations compared to Pn3a.
Conclusions: Pn3a is an unique pharmacological tool to define the role of NaV1.7 in pain pathways and has great potential to become a lead substance toward novel treatment approaches for pain. Specifically, we demonstrate that pain after surgery can be treated with NaV1.7 inhibitors which presents a novel treatment strategy for this undermanaged condition.