Wednesday, October 26, 2016
The advancement of medicine has numerous accomplishments; however, one of the slower improvements involves addressing and managing pain. Significant instances of pain, both in acute and chronic form, afflict hundreds of millions of people worldwide, but most modern treatments struggle to demonstrate meaningful improvement versus past treatments. In fact it is estimated that at least half of surgical patients do not receive effective pain control after their treatments.1,2 Also addiction to pain medication has become a mounting problem in recent years making long-term pain management strategies more difficult.
One potential strategy for managing pain that has gained popularity in recent years is focusing on the activation of analgesic targets like sodium channels Nav1.7, Nav1.8 and Nav1.9. These sodium channels belong to a larger family of voltage gated sodium channels (Nav1.1-1.9) that each has specific locations and functional roles in the body. Among the aforementioned three sodium channels, Nav1.7 is viewed as the most important and its function was first identified from conditional knockout studies in mice expressing Nav1.8 after assumptions were raised from a small family appeared to have significant pain insensitivities via a loss-of-function recessive mutation in Nav1.7.3,4 The resultant study identified Nav1.7 playing a significant role relative to inflammatory pain and the conditional deletion of Nav1.7, not surprisingly, heavily reduced that level of pain to an almost non-registered symptomatic level.3,5,6
Nav1.7 and its 1.8 and 1.9 cohorts are present near the synapses of neurons that are commonly thought to be responsible for sending and receiving pain signals. Overall Nav1.7 appears to transmit action potentials via neurotransmitter release through a threshold managed by Nav1.9, which receives input from Nav1.8.7-10 However, it does not appear that Nav1.7 activation is exclusively reliant on Nav1.8 or 1.9.7
While one means to address pain in the past was the utilization of global sodium channel blockers, developing a drug that has strong specificity for Nav1.7 is thought to be a principal strategy for more effective pain management by localizing treatment to increase selectivity and reduce negative side effects, especially those involving the heart since Nav1.7 is not located near the heart. While not all forms of pain involve Nav1.7, which should surprise no one, a significant number of pain processes appear to incorporate Nav1.7, which has produced the aforementioned enthusiasm for producing a target therapy.4,7
Of course since the major discovery associated with Nav1.7 occurred in 2006,4 various drug development programs have been underway to produce an appropriate and effective treatment. Unfortunately despite the creation of numerous specific stable antagonists, the general results have been disappointing ranging from non-replicated results to unexpected negative side effects.11 One piece of information from these studies highlights an apparent contradiction where the more selective the antagonist for Nav1.7 the less effective the pain reduction versus less selective molecules like lidocaine being more effective.6
The major reason behind this result is thought to be a relationship between Nav1.7 and enhanced natural opioid signaling born from studies involving Nav1.7 null mutant CIP.4 Basically in null mutants an unknown biological relationship develops producing the dramatic change in opioid concentrations in a natural/steady-state condition that is responsible for blocking pain. This belief is supported by the ability of Naloxone, an inverse agonist for the u-opioid receptor (MOR) and antagonist for k and d-opioid receptors, to frequently reverse the pain insensitivity born from Nav1.7 null.7,12 However, oddly enough while knocking out SCN9A, a gene responsible for encoding Nav1.7, produces this enhanced opioid concentration state; simply reducing the activation efficiency of Nav1.7 after development does not seem to produce anywhere near the enhancement of opiods. Basically there is no proportional response.
One explanation for this result is look at how the null creature compensates for the loss of Nav1.7 during development. No Nav1.7 expression commonly results in transcriptional up-regulation of Penk, which is a precursor of met-enkephalin, but Penk was not up-regulated in Nav1.8 or 1.9 nulls.7,13 This result suggests that the neurotransmitter release associated with Nav1.7 is the critical step. Complete channel block of Dorsal Root Ganglion (DRG) neurons via high concentrations tetrodotoxin, this is relevant because a number of the neurons at this location have Nav1.7 channels, also creates a state of enhanced opioid expression.7 However, without a complete channel block there does not appear to be significant increase in opioid or enkephalin expression.7 Overall the increase in opioid concentration within null mice, and probably humans, target nociceptive input consistent with the expression of opioid receptors on small nociceptive afferents.7,14
This result seems to suggest that there is no middle ground in blocking Nav1.7; either the treatment has to produce a 100% channel block or there is no significant increase in pain insensitivity/pain relief.15,16 This issue is a problem for while some agents attempt to improve selectivity by binding to areas outside the pore-forming region on channels through less effective conservation producing inhibitory action independent of the channel’s functional state,6 it is highly unlikely that even these strategies will develop a molecule to create a 100% selective block without significant negative side effects. This challenge has lead researchers to focus on biologics, like venom toxins, over small molecules due to increased rates of selectivity even incorporating techniques like saturation mutagenesis;17-19 however, at this moment success appears improbable.
This result regarding full channel block produces two questions: first the interaction of Nav1.7 suggests that sodium can function as a secondary messenger with respects to the expression of enkephalin through the alteration of Penk mRNA expression levels. Such a belief is supported by the behavior of the ionophore monensin, which results in decreased expression of Penk whereas blocking the channel up-regulates Penk mRNA.13
If this is the case, then the importance of Nav1.7 over that of Nav1.8 and 1.9 may be directly attributable to the level of sodium that passes through Nav1.7, which has a greater effect on overall intracellular sodium concentrations versus other sodium channels. For example HEK293 cell lines with permanent expression of Nav1.7 establish a resting intracellular sodium concentration around double the level of control cells.7
Second, Nav1.7 could produce a form of some level of natural opioid inhibition or at least a form of negative feedback. This mindset seems to be supported by gain-of-function mutations in Nav1.7 typically producing conditions of erythromelalgia (PE), which is characterized by episodes of symmetrical burning pain of the feet, lower legs, and even hands and is tied to increased Nav1.7 channel activity.6 However, if this is the case it raises an interesting question to why null Nav1.7 seem to produce no inherent negatives born from the additional concentrations of opioids, i.e. no addiction or sensitivity. Perhaps in null cases other pathways form to provide a level of opioid feedback inhibition or “saturation” management.
Based on the above information it does not appear that producing a molecule to interfere with Nav1.7 activity can be effectively used to treat pain because full blockage is seemingly required to produce conditions associated with pain insensitivity and general pain treatment. Also blocking Nav1.7 over long and consistent periods of time may damage other important sensory processes. The reason Nav1.7 demonstrates success in knockouts, both cultured and natural, may be because the knockout mutation forces the body to focus on other pathways to manage the other systems that Nav1.7 would normally interact with if it existed. However, that does not exclude using information pertaining to Nav1.7 activity to identify a better pain management treatment.
A better strategy may be to pursue strategies to expand or mimic concentrations of met-enkephalin, which is directly influenced by Nav1.7 activity. Met-enkephalin is a strong agonist for the d-opioid receptor, has some influence on the u-opioid receptor and almost no effect on the k-opioid receptor.7 However, despite its meaningful opioid influence, met-enkephalin has low residence times in the body due to rapid levels of metabolization.20 Thus, simply injecting met-enkephalin into a person would serve little purpose in addressing pain because it would have to be done at large doses and too frequently. However, a synthetic enkephalin, [D-Ala2]-Met-enkephalinamide (DALA) has shown some positive attributes at managing pain by changing its rate of metabolism.
In the end despite the clear understanding that pain relief can be achieved by blocking a channel like Nav1.7, no compounds have been developed to effectively and easily take advantage of that reality. Due to the requirement of full channel block it is highly unlikely that a treatment involving small molecules will ever be successful, leaving the door open only for modified biologics. However, even with a successful “in lab” molecule the location of Nav1.7 in higher concentrations behind the blood brain barrier may make meaningful treatment difficult without some level of increased blood brain barrier penetration. Overall the allure of channel block pain therapy involving a specific location like Nav1.7 may need to be supplemented by further focus on the more downstream products associated with channel activation or inactivation like Met-enkephalin to complement pain relief strategies.
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