Pain Mechanisms and Treatments (228)
Dermatology and Skin Diseases (112)
Botulinum Toxin and Related Neurological Disorders (49)
Advancements in Transdermal Drug Delivery (45)
Urticaria and Related Conditions (39)
Erythromelalgia is a rare disease that is associated with hemato-oncological diseases or after taking certain drugs and toxins, but it can also occur as an independent clinical picture, for example, due to mutations in the sodium channel Na1.7. Clinically, there is a characteristic triad of attack-like burning pain and skin redness in the area of the distal extremities, which can be alleviated by excessive cooling. The attacks are triggered by heat, exertion, and stress. The diagnosis is primarily made clinically and can be confirmed by genetic testing if a sodium channel Na1.7 mutation is present. Important differential diagnoses are complex regional pain syndrome, the non-freezing cold injury, and small fiber neuropathies. Therapy is multidisciplinary and has to be planned individually and include physical therapy and psychotherapy as well as drug therapy as integral components.
Meents JE, Bressan E, Sontag S, Foerster A, Hautvast P , et al.
Pain •
The chronic pain syndrome inherited erythromelalgia (IEM) is attributed to mutations in the voltage-gated sodium channel (NaV) 1.7. Still, recent studies targeting NaV1.7 in clinical trials have provided conflicting results. Here, we differentiated induced pluripotent stem cells from IEM patients with the NaV1.7/I848T mutation into sensory nociceptors. Action potentials in these IEM nociceptors displayed a decreased firing threshold, an enhanced upstroke, and afterhyperpolarization, all of which may explain the increased pain experienced by patients. Subsequently, we investigated the voltage dependence of the tetrodotoxin-sensitive NaV activation in these human sensory neurons using a specific prepulse voltage protocol. The IEM mutation induced a hyperpolarizing shift of NaV activation, which leads to activation of NaV1.7 at more negative potentials. Our results indicate that NaV1.7 is not active during subthreshold depolarizations, but that its activity defines the action potential threshold and contributes significantly to the action potential upstroke. Thus, our model system with induced pluripotent stem cell-derived sensory neurons provides a new rationale for NaV1.7 function and promises to be valuable as a translational tool to profile and develop more efficacious clinical analgesics.
Helås T, Sagafos D, Kleggetveit IP, Quiding H, Jönsson B , et al.
European journal of pain (London, England) •
Nociceptive thresholds and supra-threshold pain ratings as well as their reduction upon local injection with lidocaine were compared between healthy subjects and patients with erythromelalgia (EM). Lidocaine (0.25, 0.50, 1.0 or 10 mg/mL) or placebo (saline) was injected intradermally in non-painful areas of the lower arm, in a randomized, double-blind manner, to test the effect on dynamic and static mechanical sensitivity, mechanical pain sensitivity, thermal thresholds and supra-threshold heat pain sensitivity. Heat pain thresholds and pain ratings to supra-threshold heat stimulation did not differ between EM-patients (n = 27) and controls (n = 25), neither did the dose-response curves for lidocaine. Only the subgroup of EM-patients with mutations in sodium channel subunits Na 1.7, 1.8 or 1.9 (n = 8) had increased lidocaine sensitivity for supra-threshold heat stimuli, contrasting lower sensitivity to strong mechanical stimuli. This pattern was particularly clear in the two patients carrying the Na 1.7 I848T mutations in whom lidocaine's hyperalgesic effect on mechanical pain sensitivity contrasted more effective heat analgesia. Heat pain thresholds are not sensitized in EM patients, even in those with gain-of-function mutations in Na 1.7. Differential lidocaine sensitivity was overt only for noxious stimuli in the supra-threshold range suggesting that sensitized supra-threshold encoding is important for the clinical pain phenotype in EM in addition to lower activation threshold. Intracutaneous lidocaine dose-dependently blocked nociceptive sensations, but we did not identify EM patients with particular high lidocaine sensitivity that could have provided valuable therapeutic guidance. Acute pain thresholds and supra-threshold heat pain in controls and patients with erythromelalgia do not differ and have the same lidocaine sensitivity. Acute heat pain thresholds even in EM patients with the Na 1.7 I848T mutation are normal and only nociceptor sensitivity to intradermal lidocaine is changed. Only in EM patients with mutations in Na 1.7, 1.8 or 1.9 supra-threshold heat and mechanical pain shows differential lidocaine sensitivity as compared to controls.
Kleggetveit IP, Schmidt R, Namer B, Salter H, Helås T , et al.
Brain and behavior •
The sodium channel Nav 1.9 is expressed in peripheral nociceptors and has recently been linked to human pain conditions, but the exact role of Nav 1.9 for human nociceptor excitability is still unclear. C-nociceptors from two patients with late onset of erythromelalgia-like pain, signs of small fiber neuropathy, and rare genetic variants of Nav 1.9 (N1169S, I1293V) were assessed by microneurography. Compared with patients with comparable pain phenotypes (erythromelalgia-like pain without Nav-mutations and painful polyneuropathy), there was a tendency toward more activity-dependent slowing of conduction velocity in mechanoinsensitive C-nociceptors. Hyperexcitability to heating and electrical stimulation were seen in some nociceptors, and other unspecific signs of increased excitability, including spontaneous activity and mechanical sensitization, were also observed. Although the functional roles of these genetic variants are still unknown, the microneurography findings may be compatible with increased C-nociceptor excitability based on increased Nav 1.9 function.
Kist AM, Sagafos D, Rush AM, Neacsu C, Eberhardt E , et al.
PloS one •
Gain-of-function mutations in the tetrodotoxin (TTX) sensitive voltage-gated sodium channel (Nav) Nav1.7 have been identified as a key mechanism underlying chronic pain in inherited erythromelalgia. Mutations in TTX resistant channels, such as Nav1.8 or Nav1.9, were recently connected with inherited chronic pain syndromes. Here, we investigated the effects of the p.M650K mutation in Nav1.8 in a 53 year old patient with erythromelalgia by microneurography and patch-clamp techniques. Recordings of the patient's peripheral nerve fibers showed increased activity dependent slowing (ADS) in CMi and less spontaneous firing compared to a control group of erythromelalgia patients without Nav mutations. To evaluate the impact of the p.M650K mutation on neuronal firing and channel gating, we performed current and voltage-clamp recordings on transfected sensory neurons (DRGs) and neuroblastoma cells. The p.M650K mutation shifted steady-state fast inactivation of Nav1.8 to more hyperpolarized potentials and did not significantly alter any other tested gating behaviors. The AP half-width was significantly broader and the stimulated action potential firing rate was reduced for M650K transfected DRGs compared to WT. We discuss the potential link between enhanced steady state fast inactivation, broader action potential width and the potential physiological consequences.
Namer B, Ørstavik K, Schmidt R, Kleggetveit IP, Weidner C , et al.
Pain •
Seven patients diagnosed with erythromelalgia (EM) were investigated by microneurography to record from unmyelinated nerve fibers in the peroneal nerve. Two patients had characterized variants of sodium channel Nav1.7 (I848T, I228M), whereas no mutations of coding regions of Navs were found in 5 patients with EM. Irrespective of Nav1.7 mutations, more than 50% of the silent nociceptors in the patients with EM showed spontaneous activity. In the patient with mutation I848T, all nociceptors, but not sympathetic efferents, displayed enhanced early subnormal conduction in the velocity recovery cycles and the expected late subnormality was reversed to supranormal conduction. The larger hyperpolarizing shift of activation might explain the difference to the I228M mutation. Sympathetic fibers that lack Nav1.8 did not show supranormal conduction in the patient carrying the I848T mutation, confirming in human subjects that the presence of Nav1.8 crucially modulates conduction in cells expressing EM mutant channels. The characteristic pattern of changes in conduction velocity observed in the patient with the I848T gain-of function mutation in Nav1.7 could be explained by axonal depolarization and concomitant inactivation of Nav1.7. If this were true, activity-dependent hyperpolarization would reverse inactivation of Nav1.7 and account for the supranormal CV. This mechanism might explain normal pain thresholds under resting conditions.
Zhang Z, Schmelz M, Segerdahl M, Quiding H, Centerholt C , et al.
Scandinavian journal of pain •
Background and aim "Gain-of-function" mutations in voltage-gated sodium channel NaV1.7 have been linked to erythromelalgia (EM), characterized by painful hot and red hands and feet. We investigated the proportion of patients with EM that carry a mutation in NaV1.7 or in other pain-related genes and studied possible clinical differences. Methods In this study, 48 patients with EM were screened for mutations in a total of 29 candidate genes, including all sodium channel subunits, transient receptor potential channels (TRPA1, TRPV1, TRPM8), neurotrophic factors (NGF, NGFR, BDNF, GDNF, NTRK1 and WNK1) and other known pain-related genes (CACNG2, KCNS1, COMT, P2RX3, TAC1, TACR1), using a combination of next generation sequencing and classical Sanger sequencing. Results In 7/48 patients protein-modifying mutations of NaV1.7 (P187L, I228M, I848T (n = 4) and N1245S) were identified. Patients with the I848T mutation could be identified clinically based on early onset and severity of the disease. In contrast, there were no clinical characteristics that differentiated the other patients with NaV1.7 mutation from those patients without. We also found more than twenty rare protein-modifying genetic variants in the genes coding for sodium channels (NaV1.8, NaV1.9, NaV1.6, NaV1.5, NaV2.1, SCN1B, SCN3B), transient receptor potential channel (TRPA1, TRPV1), and other pain-related targets (WNK1 and NGFR). Conclusion We conclude that functionally characterized mutations of NaV1.7 (I848T) are present only in a minority of patient with EM. Albeit the majority of patients (27/48) carried rare protein-modifying mutations the vast majority of those will most probably not be causally linked to their disease. Implications The key question remaining to be solved is the possible role of rare variants of NaV1.8, NaV1.9, or beta-subunits in provoking chronic pain conditions or even EM.
Petersson ME, Obreja O, Lampert A, Carr RW, Schmelz M , et al.
PloS one •
Cutaneous pain sensations are mediated largely by C-nociceptors consisting of both mechano-sensitive (CM) and mechano-insensitive (CMi) fibres that can be distinguished from one another according to their characteristic axonal properties. In healthy skin and relative to CMi fibres, CM fibres show a higher initial conduction velocity, less activity-dependent conduction velocity slowing, and less prominent post-spike supernormality. However, after sensitization with nerve growth factor, the electrical signature of CMi fibres changes towards a profile similar to that of CM fibres. Here we take a combined experimental and modelling approach to examine the molecular basis of such alterations to the excitation thresholds. Changes in electrical activation thresholds and activity-dependent slowing were examined in vivo using single-fibre recordings of CM and CMi fibres in domestic pigs following NGF application. Using computational modelling, we investigated which axonal mechanisms contribute most to the electrophysiological differences between the fibre classes. Simulations of axonal conduction suggest that the differences between CMi and CM fibres are strongly influenced by the densities of the delayed rectifier potassium channel (Kdr), the voltage-gated sodium channels NaV1.7 and NaV1.8, and the Na+/K+-ATPase. Specifically, the CM fibre profile required less Kdr and NaV1.8 in combination with more NaV1.7 and Na+/K+-ATPase. The difference between CM and CMi fibres is thus likely to reflect a relative rather than an absolute difference in protein expression. In support of this, it was possible to replicate the experimental reduction of the ADS pattern of CMi nociceptors towards a CM-like pattern following intradermal injection of nerve growth factor by decreasing the contribution of Kdr (by 50%), increasing the Na+/K+-ATPase (by 10%), and reducing the branch length from 2 cm to 1 cm. The findings highlight key molecules that potentially contribute to the NGF-induced switch in nociceptors phenotype, in particular NaV1.7 which has already been identified clinically as a principal contributor to chronic pain states such as inherited erythromelalgia.
Ørstavik K, Weidner C, Schmidt R, Schmelz M, Hilliges M , et al.
Brain : a journal of neurology •
Little is known about the contribution of C-afferent fibres to chronic painful conditions in humans. We sought to investigate the role of C-fibres in the pathophysiology of pain and hyperalgesia in erythromelalgia as a model disease for chronic pain. Erythromelalgia is a condition characterized by painful, red and hot extremities, and patients often report tenderness on walking. We made microneurographic recordings from single C-fibres in cutaneous fascicles of the peroneal nerve in patients suffering from this disease. All patients had had a pain attack recently and psychophysical signs of allodynia and punctate hyperalgesia were found. We obtained recordings from a total of 103 C-fibres and found significantly lower conduction velocities and increased activity-dependent slowing of the conduction velocity of afferent C-fibres in the patients compared with healthy controls. Furthermore, several units with biophysical properties of mechano-insensitive fibres were pathological, being spontaneously active or sensitized to mechanical stimuli. Since these fibres also mediate the axon reflex flare, their hyperexcitability might account not only for ongoing pain and tenderness but also for redness and warming in this pain syndrome. The changes in conductive properties found in the C-fibres of these patients could be the first signs of a small-fibre neuropathy. This is the first systematic study of single C-fibres in patients and it shows an active contribution of mechano-insensitive fibres to chronic pain.