As I began to write this commentary, I watched my 6-year-old granddaughter read a book about unicorns. Knowing that she recently had learned in school about “facts” and “fantasies,” I asked her “So, are unicorns real?” “Of course, they are real,” she said. “Of course, they are real,” she repeated, pointing at her head. “Unicorns are real… in here.”
As neuroscientists, we take it as axiomatic that our conscious representation of the world depends, in large part, on cerebral processes. It is becoming increasingly clear, however, that the experience of pain is shaped at many levels, both cerebral and subcerebral, within the neuraxis. In this issue of PAIN, Buch et al.2 present the results of a randomized, double-blind, placebo-controlled crossover study in which they investigated whether peripheral nerve block could temporarily eliminate phantom and stump pain after limb amputation. The results of this careful study provide strong evidence that afferent input from the peripheral nervous system, ie, from dorsal root ganglion (DRG) neurons, plays an important role in postamputation pain. This is important, because it establishes that peripheral afferents are important contributors to this form of pain, a view quite different from the idea that maladaptive cerebral plasticity drives phantom pain.9,12 The new study adds to a body of evidence14 suggesting that, in humans, phantom pain is a result of inappropriate exaggerated peripheral afferent input, generated by axotomized neurons within the DRGs that used to innervate the limb. The mechanistic underpinning for this phenomenon seems to arise from the fact that limb amputation involves, by definition, the shearing off the peripheral axons of DRG neurons. The molecular basis for the increased barrage from axotomized peripheral afferent neurons is now clear, since, for example, it has been demonstrated that after their peripheral axons are severed, they turn on the expression of NaV1.3 sodium channels that are not normally expressed within adult peripheral afferents15; this maladaptive change is triggered, in large part, by loss of access to peripheral pools of nerve growth factor.5 The aberrantly expressed NaV1.3 channels are notable in amplifying small stimuli below the action potential threshold, and these channels recover rapidly from activation, so that their expression results in “molecular mistuning” that renders the axotomized DRG neurons hyperexcitable.4
The new work of Buch et al. adds to a body of evidence that underscores a critical role of peripheral afferents in the generation of multiple types of pain. As just one example, gain-of-function mutations of the NaV1.7 sodium channel, which is preferentially expressed in DRG and sympathetic ganglion neurons, produce the painful “man-on-fire” syndrome, inherited erythromelalgia (IEM).6 Studies on transfected rodent DRG neurons and on nociceptors derived from induced pluripotent stem cells (iPSC) from patients with IEM show that these mutations produce striking hyperexcitability in DRG neurons,3,6 pinpointing NaV1.7 channels as the molecular drivers and peripheral afferents as the cellular source of pain. Painful traumatic nerve injury provides an additional example. Another sodium channel preferentially expressed in peripheral afferents, NaV1.8, has been shown to accumulate along with NaV1.7, at the distal tips of transected axons within painful human neuromas.1 NaV1.7 and NaV1.8 work together to produce high-frequency firing,13 so this is a bad combination. The abnormal accumulation of these peripheral sodium channels, which adds to the hyperexcitability produced by NaV1.3, causes the injured axon tips within the neuroma to act as ectopic impulse generators. As a third example of the link between peripheral afferents and the pain experience, polymorphisms of NaV1.8 have been linked genetically and by functional profiling to mechanical pain sensitivity in human subjects.7 Here again, the molecular pathology is played out in primary afferent neurons.
The link between peripheral afferents and the experience of pain extends beyond pain causation and has begun to enter the domain of pharmacotherapy. A study 10 years ago on a family with the unusual clinical picture of carbamazepine-responsive IEM showed that, in addition to producing pain due to excessive activity of DRG neurons, the mutation of NaV1.7 in this kindred endows the channel with heightened responsiveness to carbamazepine, pointing toward a mode of action that operates in peripheral afferents.8 Subsequent studies showed that it is possible to use atomic-level molecular modeling of NaV1.7 to identify rare gene variants that confer responsiveness to carbamazepine in additional families with IEM.10,16 In each of these instances, there was clinical responsiveness to carbamazepine, ie, an effect on the pain experience. The important point here is that the drug acts on a peripheral sodium channel, again illustrating that the activity of peripheral afferents can play a large role in determining the pain experience.
In a recent study, Mis et al.11 used patient-specific iPSC-derived sensory neurons to study a unique family containing multiple related IEM subjects with the same pathogenic NaV1.7 mutation but with clearly different pain profiles including one individually who was relatively resilient to pain. iPSC-derived nociceptors from each of the different patients with IEM were hyperexcitable, but, notably, there was markedly less hyperexcitability in nociceptors from the pain-resilient patient. Whole exome sequencing revealed a specific variant of another gene, KCNQ, which encodes the KV7.2 potassium channel, in the pain-resilient individual. Dynamic clamp analysis showed that this gene variant dampened the excitability of these peripheral sensory neurons. In addition to showing that, at least in some cases, relative sensitivity to pain can be modeled in a disease-in-a-dish model using subject-specific iPSC-derived sensory neurons, this study demonstrates that mechanisms operating within peripheral sensory neurons can contribute to interindividual differences in pain.
The study of Buch et al. and the studies described above do not negate the importance of central mechanisms or of epigenetic or environmental factors that modulate pain or the response to it. Indeed, multiple factors operating at the cerebral level undoubtedly contribute in important ways to the overall pain experience. The studies discussed here, however, underscore the importance of peripheral mechanisms that contribute, in some cases in a strong way, to shaping many forms of pain. There are undoubtedly many lessons still to be learned about the multiple neuronal populations—peripheral and central—involved in the generation of pain and its modulation. Even for investigators interested in the overall experience of pain, the periphery still has lessons to teach.
Conflict of interest statement
The author has no conflict of interest to declare.
Research in the author's laboratory has been supported in part by grants from the Rehabilitation Research and Development Service and Biomedical Laboratory Research Service, Department of Veterans Affairs, The Erythromelalgia Association, and The Nancy Taylor Foundation.
. Black JA, Nikolajsen L, Kroner K, Jensen TS, Waxman SG. Multiple sodium channel isoforms and mitogen-activated protein kinases are present in painful human neuromas. Ann Neurol 2008;64:644–53.
. Buch NS, Ahlburg P, Haroutounian S, Andersen NT, Finnerup NB, Nikolajsen N. The role of afferent input in postamputation pain: a randomized, double-blind, placebo-controlled crossover study. PAIN 2019;160:1622–33.
. Cao L, McDonnell A, Nitzsche A, Alexandrou A, Saintot PP, Loucif AJ, Brown AR, Young G, Mis M, Randall A, Waxman SG, Stanley P, Kirby S, Tarabar S, Gutteridge A, Butt R, McKernan RM, Whiting P, Ali Z, Bilsland J, Stevens EB. Pharmacological reversal of a pain phenotype in iPSC-derived sensory neurons and patients with inherited erythromelalgia. Sci Transl Med 2016;8:335ra56.
. Cummins TR, Waxman SG. Downregulation of tetrodotoxin-resistant sodium currents and upregulation of a rapidly repriming tetrodotoxin-sensitive sodium current in small spinal sensory neurons after nerve injury. J Neurosci 1997;17:3503–14.
. Dib-Hajj SD, Black JA, Cummins TR, Kenney AM, Kocsis JD, Waxman SG. Rescue of alpha-SNS sodium channel expression in small dorsal root ganglion neurons after axotomy by nerve growth factor in vivo. J Neurophysiol 1998;79:2668–76.
. Dib-Hajj SD, Yang Y, Black JA, Waxman SG. The Na(V)1.7 sodium channel: from molecule to man. Nat Rev Neurosci 2013;14:49–62.
. Duan G, Han C, Wang Q, Guo S, Zhang Y, Ying Y, Huang P, Zhang L, Macala L, Shah P, Zhang M, Li N, Dib-Hajj SD, Waxman SG, Zhang X. A SCN10A SNP biases human pain sensitivity. Mol Pain 2016;12:1–16.
. Fischer TZ, Gilmore ES, Estacion M, Eastman E, Taylor S, Melanson M, Dib-Hajj SD, Waxman SG. A novel Nav1.7 mutation producing carbamazepine-responsive erythromelalgia. Ann Neurol 2009;65:733–41.
. Flor H, Elbert T, Knecht S, Wienbruch C, Pantev C, Birbaumer N, Larbig W, Taub E. Phantom-limb pain as a perceptual correlate of cortical reorganization following arm amputation. Nature 1995;375:482–4.
. Geha P, Yang Y, Estacion M, Schulman BR, Tokuno H, Apkarian AV, Dib-Hajj SD, Waxman SG. Pharmacotherapy for pain in a family with inherited erythromelalgia guided by genomic analysis and functional profiling. JAMA Neurol 2016;73:659–67.
. Mis MA, Yang Y, Tanaka BS, Gomis-Perez C, Liu S, Dib-Hajj F, Adi T, Garcia-Milian R, Schulman BR, Dib-Hajj SD, Waxman SG. Resilience to pain: a peripheral component identified using induced pluripotent stem cells and dynamic clamp. J Neurosci 2019;39:382–92.
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. Rush AM, Dib-Hajj SD, Liu S, Cummins TR, Black JA, Waxman SG. A single sodium channel mutation produces hyper- or hypoexcitability in different types of neurons. Proc Natl Acad Sci U S A 2006;103:8245–50.
. Vaso A, Adahan HM, Gjika A, Zahaj S, Zhurda T, Vyshka G, Devor M. Peripheral nervous system origin of phantom limb pain. PAIN 2014;155:1384–91.
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