Sodium channels as potential analgesics Flashcards
Nasser et al.,2004
Nasser showed that micelacking functional NaV1.7 in their nociceptors exhibited higher-than-normal pain thresholds; they were slower to withdraw a paw from painful stimuli and spent less time licking or biting it after being hurt
Cox et al., 2006
Cox et al., used a genome wide scan and identified that families which exhibited a pain-free phenotype, which is now known as Congenital Insensitivity to Pain (CIP), all had mutations within the region of SCN9A (the gene that codes for Nav1.7)
Yang et al., 2004
In 2004, Chinese researchers linked specific gain-of-function mutations in SCN9A to inherited erythromelalgia (IEM)—a condition with symptoms at the opposite end of the spectrum from those of CIP.
Why is IEM called “man on fire” syndrome?
Patients with IEM feel searing, excruciating, scalding pain in response to mild warmth. This is because the gain-of-function mutations in SCN9A result in an unusually active Nav1.7 channel which makes pain-signalling neurons respond to even mild stimuli (Cummins et al.,2004)
Why were these initial results of Nav1.7 in 2004/2006 so attractive to researchers working on treatments for neuropathic pain?
Neuropathic pain is virtually untreatable—even powerful analgesics such as opioids have mixed success in pain management and have a tendency to induce dependence. In other words, the existing drugs either don’t work, work only partially, or have unacceptable side effects. As a result, there is a desperate need for better medications.
Why was it thought that targetting Nav1.7 would work better than opioids?
It was found that Nav1.7 had almost an exclusive presence in peripheral neurons and so would allow compounds/treatments targeting the protein to steer clear of the central nervous system, and thus avoid dependence and other side effects common to opioids.
Why is specificity important when designing therapeutics to treat neuropathic pain?
Other sodium channel family members are important for diverse physiological functions. Lack of specificity will result in the inhibition of other sodium channel family members such as NaV1.5, which is present in cardiac tissue. Inhibiting this channel will result in an yarrhythmia, or worse. Similarly the inhibition of NaV1.4, which is present in muscle tissue, will result in partial paralysis.
(Focken et al.,2016).
Theouter, voltage-sensing domains tend to be less conserved between NaV subtypes. As a result, small molecules such as aryl sulfonamides which inhibit the domain IV voltage sensor on NaV1.7, and thus prevent the channel from opening in response to changes in voltage, were thought to be a promising therapeutic.
Researchers from Xenon Pharmaceuticals and Genentech recently showed that some members of this class of compounds had good specificity for NaV1.7 over cardiac NaV1.5 and produced analgesia in mouse models of acute and inflammatory pain. However they show poorer specificity for their target over two channels present predominantly in the brain, NaV1.2 and NaV1.6
What did Waxman’s group in collaboration with Pfizer show in 2016?
They showed that a synthetic aryl sulfonamide dubbed PF-05089771 could reduce neuronal hyperactivity in a “pain-in-a-dish” model—sensory neurons grown from induced pluripotent stem cells derived from patients with IEM mutations.
The drug was also well-tolerated as a single oral dose in a randomized, double-blind trial of five IEM patients, and temporarily reduced the magnitude and duration of pain attacks in most participants. However, the authors noted that there was a high degree of variability in responses among patients (Cao et al.,2016).
(Lee et al.,2014)
In 2014 it was found that monoclonal antibodies could be designed to selectively target NaV1.7, and provide analgesia in mice. However, the results have not yet been replicated.
Zeng et al., 2018
Like aryl sulfonamides, certain tarantula toxins selectively bind to one of NaV1.7’s four voltage-sensing domains, and can lock the channel in a closed or inactivated state by making it voltage-insensitive. Zeng et al., (2018) found that JZTX-34 releases pain by selectively binding to the domain II voltage sensor of Nav1.7 in a closed configuration.
Is it true that Nav1.7 plays a role in other sensory pathways apart from pain?
It was found that mice lacking NaV1.7 from all the cells in their bodiesv(not just the pain-sensing neurons) died shortly after birth. (Nasser et al., 2004). NaV1.7 knockout humans, by contrast, have no obvious phenotypic abnormalities except, of course, CIP.
Researchers have now discovered that NaV1.7 is also present in olfactory neurons, and its knockout causes anosmia. This is a mild defect in humans but a life-threatening one for lab mice, which rely on smell to find food and potential mates.
Why might only targetting Nav1.7 at periphery prevent clinical success?
Although NaV1.7’s predominant presence in peripheral neurons was initially highlighted as a therapeutic advantage, it has now been found that the sensory neurons that convey information about tissue damage have terminals which are actually inside the blood-brain barrier, in the central nervous system. It is likely that there is quite a lot of action of NaV1.7 at these central terminals, and it may be that drugs have to get there to be useful.
NaV1.7 is also expressed in the central terminals of sensory neurons, specifically in laminae I and II of the dorsal horn where co-localisation with IB4, CGRP and synaptophysin suggests that NaV1.7 is involved in regulation of neurotransmitter release and transmission of nociceptive signals to higher brain centres (Black et al., 2012)
Does Nav1.7 play another role apart from controlling the passage of sodium ions in sensory neurons?
It was found that in the Nav1.7 knockout mice, opioid peptides (enkephalins) were upregulated. As a result, it is hypothesised that the CIP phenotype in patients lacking functional NaV1.7 from birth might therefore come not only from the lack of sodium channel activity, but also from a boost in endogenous opioid signaling. Therefore this may be something that analgesic drugswould have to reproduce to be successful (Minett et al.,2015).
Evidence to support this theory comes from Wood and his colleagues. They administered an opioid blocker (naloxone) to a woman with CIP and found that she could begin to detect unpleasant stimuli.
(Deuis et al.,2017)
It was found that administering a highly selective NaV1.7-blocking spider toxin called Pn3a (which is not by itself analgesic) alongside subtherapeutic doses of opioids produced profound analgesia in mouse models of inflammatory pain, suggesting that a combinatorial drug approach might finally recapture the pain insensitivity researchers are pursuing.
Give evidence that shows that Nav1.7 is not as simple as it was initially understood to be?
It was found that a woman born with CIP developed features of neuropathic pain after sustaining pelvic fractures and an epidural haematoma that impinged on the right fifth lumbar nerve root. Her case strongly suggests that at least some of the symptoms of neuropathic pain can persist despite the absence of the NaV1.7 channel (Wheeler et al.,2014).
