Pain is the leading cause of disability in the developed world but remains a poorly treated condition. Specifically,
postsurgical pain continues to be a frequent and undermanaged condition. Here, we investigate the
analgesic potential of pharmacological NaV1.7 inhibition in a mouse model of acute
postsurgical pain, based on incision of the plantar skin and underlying muscle of the hind paw. We demonstrate that local and systemic treatment with the selective NaV1.7 inhibitor μ-theraphotoxin-Pn3a is effectively antiallodynic in this model and completely reverses mechanical
hypersensitivity in the absence of motor adverse effects. In addition, the selective NaV1.7 inhibitors ProTx-II and PF-04856264 as well as the clinical candidate
CNV1014802 also reduced
mechanical allodynia. Interestingly, co-administration of the
opioid receptor antagonist naloxone completely reversed
analgesic effects of Pn3a, indicating an involvement of endogenous
opioids in the
analgesic activity of Pn3a. In addition, we found superadditive antinociceptive effects of subtherapeutic Pn3a doses not only with the
opioid oxycodone but also with the GABAB receptor agonist
baclofen. Transcriptomic analysis of gene expression changes in dorsal root ganglia of mice after surgery did not reveal any changes in
mRNA expression of endogenous
opioids or
opioid receptors; however, several genes involved in
pain, including Runx1 (
Runt related transcription factor 1), Cacna1a (
CaV2.1), and Cacna1b (CaV2.2), were downregulated. In summary, these findings suggest that
pain after surgery can be successfully treated with NaV1.7 inhibitors alone or in combination with
baclofen or
opioids, which may present a novel and safe treatment strategy for this frequent and poorly managed condition.