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Papers of the Week

Papers: 23 Mar 2019 - 29 Mar 2019

Animal Studies, Pharmacology/Drug Development

2019 Mar 21


Anti-allodynic effects of the selective NaV1.7 inhibitor Pn3a in a mouse model of acute post-surgical pain: evidence for analgesic synergy with opioids and baclofen.


Mueller A, Starobova H, Morgan M, Dekan Z, Cheneval O, Schroeder CI, Alewood PF, Deuis JR, Vetter I
Pain. 2019 Mar 21.
PMID: 30908355.


Pain is the leading cause of disability in the developed world but remains a poorly treated condition. Specifically, post-surgical 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 post-surgical 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 anti-allodynic 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. Additionally, we found super-additive antinociceptive effects of sub-therapeutic 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 post-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.