Fifteen years of Na_V1.7 channels as an analgesic target: Why has excellent in vitro pharmacology not translated into in vivo analgesic efficacy?

Abstract

In 2006, humans with a congenital insensitivity to pain (CIP) were found to lack functional Na V 1.7 channels. In the subsequent 15 years there was a rush to develop selective inhibitors of Na V 1.7 channels with the goal of producing broadly effective analgesics without the problems of addiction and tolerance associated with opioids.Pharmacologically, this mission has been highly successful, leading to a number of highly potent and selective inhibitors of Na V 1.7 channels. However, there are very few examples where these inhibitors have yielded effective analgesia in preclinical pain models or human clinical trials. In this review, we summarise the role of the Na V 1.7 channel in nociception, its history as a therapeutic target and the quest to develop potent inhibitors of this channel. Finally, we discuss possible reasons why the pain-free state seen in humans with CIP has been so difficult to replicate pharmacologically.

Spider Venom Peptide Pn3a Inhibition of Primary Afferent High Voltage-Activated Calcium Channels

“…Consistently, Pn3a treatment was ineffective in rodent models of acute nociception or inflammatory pain, also in agreement with studies where other Na v 1.7 modulators were assayed such as the VSD-peptide ProTx-II ( Schmalhofer et al, 2008 ) and small molecule PF-04856264 ( Deuis et al, 2017 ). The overall contribution of Na v 1.7 to pain in some animal behaviour-based models has been questioned ( Shields et al, 2018 ), whereas research and development of multiple potent and selective Na v 1.7 inhibitors have failed to recapitulate the pain-free state that characterized CIP in humans ( Eagles et al, 2020 ). Importantly, the genetic ablation of SCN9 A in mice and in a human CIP patient, the absence of functional Na v 1.7 leads to increases in endogenous opioid-dependent analgesia and diminished pain-induced peripheral nociceptive drive ( Minett et al, 2015 ).…”

“…These observations lead to increased interest in discovery of a highly selective and potent inhibitors of Na v 1.7 to reduce the side effects seen in pan Na v channel inhibitors. However, Na v 1.7 inhibitors have for the most part failed to reproduce the pain-free state observed in chronic insensitivity to pain (CIP) ( Eagles et al, 2020 ). Subsequently it was shown that genetic deletion of SCN9A in both mice and humans, that the absence of functional Na v 1.7 but not Na v 1.8, increases endogenous opioid receptor (OR) analgesia via upregulation of the enkephalin precursor Penk mRNA, which could be inhibited by the OR antagonist, naloxone ( Minett et al, 2015 ).…”

Na v 1.7 target modulation and efficacy can be measured in nonhuman primate assays

“…Despite a concerted effort by pharmaceutical companies to develop selective Na v 1.7 channel inhibitors, the clinical efficacy has been disappointing (28). However, it is not clear that the target has been tested comprehensively in the clinic, as no assays of target modulation were used.…”

Neuroscience and Neuroimmunology Solutions for Osteoarthritis Pain: Biological Drugs, Growth Factors, Peptides and Monoclonal Antibodies Targeting Peripheral Nerves

“…However, in the years that have elapsed since then, it has been increasingly clear that translation from in vitro studies and preclinical studies conducted with rodent models to humans is extremely challenging. Many of the excellent pharmacology studies conducted with in vitro and preclinical models do not translate into in vivo analgesic efficacy [93]. Furthermore, many of the drug pipelines do not test promising candidates in an appropriate translational large animal model and jump straight from mice to men [94].…”