Turning off pain: research has found possible ways to target the problem of neuropathic pain.
A common problem in veterans with nerve damage, neuropathic pain can be more disabling than the loss of motor function. It can be severe and linger long after an injury. Sadly, at present, doctors can do little to help. Treatments available for neuropathic pain--opioids, antidepressants, anticonvulsants, and other CNS-active drugs--are in many people not fully effective and can cause risky side effects.
"Minutemen" of the Pain Pathway
Throughout evolution of our species, pain has been our ally, an alarm system that helps us steer away from danger. Without it, we would be full of cuts and bruises and oblivious to the damaging effects of repeat offenses to our body. Pain cautions us to be safe with fire, motivates us to nurture broken bones, and reminds us to be wary of dangerous situations. By sparing the body from physical harm, pain ensures our well-being and, thus, our survival.
In a normal painful encounter, injury awakens nociceptors--specialized pain-signaling nerve cells that serve as minutemen of the pain pathway. They respond rapidly, within milliseconds, by firing electrical signals to the brain via a gateway in the spinal cord. The brain interprets the signals and deploys a protective response that works to alert the body and alleviate its suffering. Nociceptors are present everywhere in the body, always vigilant and responsive to thermal, mechanical, and chemical provocations, ensuring proper functioning of nociception--the process of pain perception (Woolf and Ma, 2007).
However, in people with neuropathic pain, the proper functioning of nociception is disrupted. Nerve damage makes nociceptors fire spontaneously, even in the absence of provocation. Sometimes, pain is felt out of proportion to the level of stimulation. It is exaggerated. The lightest brush of clothing becomes painful, the comforting warmth of a fireplace simply unbearable. It's as if the nociceptors are on a rampage. They become "hyperexcitable"--wired up for no obvious reason.
A closer examination sheds some light on the basis for neuropathic pain. Lining the surface of all nociceptors are special molecules called "voltage-gated sodium channels" (VGSCs), whose responsibility is to help with nociception. Sodium channels are electrogenic; that is, they produce tiny electrical signals and help by contributing to nociceptor firing. How, when, and what they contribute to the firing depends on the type of VGSC that is roused within the nociceptor.
Our genome has recipes to cook up at least nine different varieties or subtypes of VGSCs, each with its unique physiological "signature," and scientists are learning that the type of VGSC cocktail roused within a nociceptor is enough to tip the balance between nociception (normal pain sensibility) and hyperexcitability (abnormal generation of pain signals). Not surprisingly, therefore, scientists in the pursuit of finding better ways to treat neuropathic pain are immersed in researching the inner workings of the VGSC family, teasing out intricate details about its different members, their behavior in nociception, and how it changes in response to nerve injury (Figure 1).
The Indictment of VGSCs
In recent years, much attention has been focused on four members of the VGSC family--Nav1.3, Nav1.7, Nav1.8, and Nav1.9--and has identified their potential as drug targets for neuropathic pain. Studies of painful neuromas (tangled masses of nerves that develop as a result of amputation or trauma) surgically removed from patients with intractable pain after nerve injury and traumatic limb amputation show accumulation of Nav1.3, Nav1.7, and Nav1.8 (Black, J.A., et al., 2008). The burning pain and tingling can be so severe that these individuals, out of desperation, choose surgery after surgery, only to find marginal success in many instances.
One recent study found that surgery relieved spontaneous pain in just two of the six patients, suggesting surgical removal of neuromas in itself does not necessarily lead to pain relief (Nikolajsen et al., 2010). Other studies of postmortem tissue from injured human nerves and chronic neurogenic pain report significant changes in the level and tissue distribution of Nav1.8 and Nav1.9 sodium channels after nerve injury (Coward et al., 2000).
The link between Nav1.7 and pain became even stronger when a series of discoveries in the United States and abroad revealed alterations in the genetic recipe for Nav1.7 in people with certain pain disorders (Waxman, S.G., 2007). The altered recipes produce dysfunctional Nav1.7 channels. The several dozen different alterations or "mutations" discovered so far are grouped roughly into three categories based on the three distinct clinical syndromes they cause.
Two types of "gain-of-function" mutations in Nav1.7 produce severe chronic pain in humans, while "loss-of-function" mutations produce inability to sense pain. One set of gain-of-function mutations produces erythromelalgia or the "man-on-fire" syndrome in which dysfunctional Nav1.7 channels cause nociceptors to fire at the merest hint of provocation and stay provoked for an abnormal length of time (Dib-Hajj, S.D., et al., 2005). Patients experience episodes of excruciating pain at the slightest increase in temperature (Figure 2).
Another set of gain-of-function mutations produces paroxysmal extreme pain disorder (PEPD), which manifests as severe pain in the mandibular, ocular, and rectal areas. Mutations in patients with PEPD affect gate controls within Nav1.7 channels such that they remain open much longer than they should, resulting in an exaggerated and relentless type of firing (Dib-Hajj, S.D., et al., 2008).
A third syndrome, inherited insensitivity to pain, is caused by loss-of-function mutations that weaken Nav1.7 channels altogether. People with such mutations do not feel pain at all. Their Nav1.7 channels simply do not work. Needless to say, they accumulate painless fractures, painless burns, and other life-threatening injuries throughout their lives. In some cases, they do not live to adulthood.
Turning Off Pain
Successful treatment of neuropathic pain requires restoring balance within nociceptors so they fire on command and only when needed. VGSCs play an important role in nociceptor firing. However, the contribution of VGSCs is not limited just to nociception; they are required for the proper functioning of other organs such as the brain, heart, skeletal muscles, and uterus.
Sodium-channel-blocking drugs currently available for treating neuropathic pain are only partially effective and poorly tolerated. This is largely because existing sodium-channel-blocking drugs recognize regions that are common to all members of the VGSC family and, as such, are not specific. They target all members of the VGSC family regardless of where they are present or how they conduct themselves. Thus, at doses sufficient to reduce pain, the available, nonspecific sodium-channel blockers can affect the brain (producing confusion or sleepiness) or the heart (interfering with normal cardiac rhythms). Drugs that are specific enough to quiet down just the malfunctioning members of the VGSC family while leaving others to carry on with their normal physiological mandates are, therefore, urgently needed.
A few decades ago the task of developing "subtype" specific VGSC-blocking drugs would have been unrealistic, given our limited understanding of the complex interplay behind nociceptor firing. Many questions had to be addressed: Of the several known VGSCs, are some involved only in nociceptor firing? With the family members looking so much alike, are there any discerning features--physical, social, or behavioral--that might help toward rational drug design? How can individual members of the VGSC family be controlled in just the preferred tissue?
That is changing now, thanks to the efforts of pain researchers around the world. Considerable progress has been made in understanding the molecular and physiological intricacies behind nociceptor firing. Identification and profiling of individual members of the VGSC family, particularly those with nociceptors as their primary residence, has opened up the exciting possibility of therapies aimed specifically at hyperexcitable nociceptors, precluding any off-target side effects.
Discoveries of molecules that assist VGSCs in nociceptor hyperexcitability are enlarging the ensemble of potential targets that can be tested (Sharkey et al., 2009; Laezza et al., 2009; Stamboulian et al., 2010). Information gleaned from pharmacogenomic studies (predictive matchmaking between a person's genome and his/her responsiveness to a particular drug) is identifying individual genetic variations, or polymorphisms, which, while not producing disease per se, may alter responsiveness to drugs or threshold for pain (Fischer et al. 2009; Choi et al. 2009). This is paving the way for customized treatments for neuropathic pain.
The growing evidence implicating Nav1.7 in people with painful disorders and in our fundamentalability to feel pain is fueling major translational efforts by pharmaceutical companies toward the development of subtype specific sodium-channel-blocking drugs for neuropathic pain. Considering the pace of technological and scientific advances, this may soon become a reality.
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Yu, F.H., Catterall, W.A. "Overview of the Voltage-gated Sodium Channel Family." Genome Biology 2003, 4:207.
Waxman, S.G. "Nav1.7, Its Mutations, and the Syndromes that They Cause" Neurology. 2007 Aug 7;69(6):505-7.
Black, J.A., Nikolajsen, L., Kroner, K., et al. "Multiple Sodium Channel Isoforms and Mitogen-activated Protein Kinases Are Present in Painful Human Neuromas." Ann Neurol. 2008 Dec; 64(6):644-53.
Nikolajsen, L., Black, J.A., Kroner, K., et al. "Neuroma Removal for Neuropathic Pain: Efficacy and Predictive Value of Lidocaine Infusion." Clin J Pain, in press, 2010.
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Drenth, J.P. & S.G. Waxman. "Mutations in Sodium-channel Gene SCN9A Cause a Spectrum of Human Genetic Pain Disorders." J. Clin. Invest. 117: 3603-3609, 2007.
Dib-Hajj, S.D., Rush, A.M., Cummins, T.R., et al. "Gain-of-function Mutation in Na(v)1.7 in Familial Erythromelalgia Induces Bursting of Sensory Neurons." Brain 128: 1847-1854, 2005.
Dib-Hajj, S.D., Estacion, M., Jarecki, B.W., et al. "Paroxysmal Extreme Pain Disorder M1627K Mutation in Human Nav1.7 Renders DRG Neurons Hyperexcitable." Mol. Pain 4: 37. 2008.
Sharkey, L., Cheng, X., Drews, V., et al. "The Ataxia3 Mutation in the N-terminal Cytoplasmic Domain of Sodium Channel Nav1.6 Disrupts Intracellular Trafficking." J. Neurosci; 29(9):2733-41, 2009.
Laezza, F., Lampert, A., Kozel, M.A., et al. "FGF 14N-Terminal Splice Variants Differentially Modulate Nav1.2 and Nav1.6 Sodium Channels." Molec. Cell. Neurosci., 42(2):90-101, 2009.
Stamboulian, S., Choi, J-S., Ahn, H.S., et al. "ERK 1/2 Mitogen-activated Protein Kinase Phosphorylates Sodium Channel Na(v)1.7 and Alters its Gating Properties" J. Neurosci., 30(5): 1637-1647, 2010.
Choi, J-S., Zhang, L., Dib-Hajj, S.D., et al. "Mexiletine-responsive Erythromelalgia Due to a New Nav1.7 Mutation Showing Use-dependent Current Fall-off." Experimental Neurology, 16(2):383-9, 2009.
Fischer, T.Z., Gilmore, E.S., Estacion, M., et al. "A Novel Nav1.7 Mutation Producing Carbamazepine-responsive Erythromelalgia." Ann Neurol. 65:733-741, 2009.
Estacion, M., Harty, T.P., Choi, J-S., et al. "A Sodium Channel Gene SCN9A Polymorphism that Increases Nociceptor Excitability." Ann Neurol. 66(6): 862-6, 2009.
by Lakshmi Bangalore, PhD
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|Publication:||PN - Paraplegia News|
|Date:||Jan 1, 2011|
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