Inge Petter Kleggetveit

High spontaneous activity of C-nociceptors in painful polyneuropathy

Summary Ongoing pain in peripheral neuropathy is linked to spontaneous activity in mechanoinsensitive nociceptors. The molecular mechanism differentiating painful from nonpainful neuropathy is still unclear. ABSTRACT Polyneuropathy can be linked to chronic pain but also to reduced pain sensitivity. We investigated peripheral C‐nociceptors in painful and painless polyneuropathy patients to identify pain‐specific changes. Eleven polyneuropathy patients with persistent spontaneous pain and 8 polyneuropathy patients without spontaneous pain were investigated by routine clinical methods. For a specific examination of nociceptor function, action potentials from single C‐fibres including 214 C‐nociceptors were recorded by microneurography. Patients with and without pain were distinguished by the occurrence of spontaneous activity and mechanical sensitization in C‐nociceptors. The mean percentage of C‐nociceptors being spontaneously active or mechanically sensitized was significantly higher in patients with pain (mean 40.5% and 14.6%, respectively, P = .02). The difference was mainly due to more spontaneously active mechanoinsensitive C‐nociceptors (operationally defined by their mechanical insensitivity and their axonal characteristics) in the pain patients (19 of 56 vs 6 of 43; P = .02). The percentage of sensitized mechanoinsensitive C‐nociceptors correlated to the percentage of spontaneously active mechanoinsensitive C‐nociceptors (Kendall’s tau = .55, P = .004). Moreover, spontaneous activity of mechanoinsensitive C‐nociceptors correlated to less pronounced activity‐dependent slowing of conduction (Kendall’s tau = −.48, P = .009), suggesting that axons were included in the sensitization process. Hyperexcitability in mechanoinsensitive C‐nociceptors was significantly higher in patients with polyneuropathy and pain compared to patients with polyneuropathy without pain, while the difference was much less prominent in mechanosensitive (polymodal) C‐nociceptors. This hyperexcitability may be a major underlying mechanism for the pain experienced by patients with painful peripheral neuropathy.

Role of TRPM8 and TRPA1 for cold allodynia in patients with cold injury.

Abstract Local cold injury often induces hypersensitivity to cold and cold allodynia. Sensitisation of TRPM8 or TRPA1 could be the underlying mechanisms. This was evaluated by psychophysics and axon‐reflex‐flare induction following topical menthol and cinnamaldehyde application in cold injury patients and healthy subjects. The patients had no signs of neuropathy except cold allodynia. We applied 20% cinnamaldehyde and 40% menthol solutions in the cold‐allodynic area of the patients and in a corresponding area in healthy subjects and obtained sensory ratings during application. Thermotesting and Laser Doppler Imaging were performed before and after exposure to the compounds. Menthol did not induce axon‐reflex‐erythema in patients or in controls. After menthol cold pain threshold was decreased in healthy subjects; however, no further sensitisation was observed in the patients moreover in some patients an amelioration of their cold allodynia was observed. Cinnamaldehyde‐induced pain sensation did not differ between patients and controls. Heat pain thresholds following cinnamaldehyde were lowered to a similar extent in patients and controls (43–39.8 and 44–39 °C) and also the axon‐reflex‐flare responses were comparable. No evidence for sensitisation of responses to TRPM8 or TRPA1‐stimulation was found in patients with cold injury‐induced cold allodynia. The lack of TRPM8 induced axon‐reflex indicates that also de‐novo expression of TRPM8 on mechano‐insensitive C‐nociceptors does not underlie cold allodynia in these patients. We conclude from these data that the mechanisms for the induction of cold allodynia in the patients with cold injury are independent of TRPM8 or TRPA1 and differ therefore from neuropathic pain patients.

Large and Small Fiber Dysfunction in Peripheral Nerve Injuries With or Without Spontaneous Pain

UNLABELLED Few data have been available on the functional role of small fiber damage in patients with peripheral nerve injuries with and without spontaneous pain. The aim of the present study was to investigate the function of large myelinated nerve fibers as well as small nerve fibers in a material of 60 patients with peripheral nerve injuries in upper or lower extremities, 30 patients with spontaneous pain, and 30 patients without pain. Patients were questioned about the characteristics of pain and investigated clinically with EMG/neurography and assessment of thermal thresholds in the innervation territory of the lesioned nerve as well as in the contralateral area. Sensation of touch and warmth and cold detection was significantly reduced in the injured side in both groups. There was a tendency, not significant, for heat pain thresholds to be more elevated in the affected side compared with the healthy side in the pain group only (47.8°C versus 45.1°C). There were no significant differences in thermal thresholds between the 2 groups of patients. The main finding was a high percentage of hyperphenomena (allodynia to light touch and reduced mechanical pain thresholds) in the pain group only. PERSPECTIVE Small fiber function did not significantly differ between patients with and without pain, indicating that elevated thermal thresholds alone will not reflect mechanisms responsible for the generation of pain. Hyperphenomena were present in the affected side of the pain group only.

Differential effects of low dose lidocaine on C-fiber classes in humans.

UNLABELLED The nonselective sodium channel blocker lidocaine is widely used as a local anesthetic but also systemically for treatment of postoperative and neuropathic pain. Voltage-gated sodium channels are crucial for action potential generation and conduction, and their availability controls the amount of activity-dependent conduction velocity slowing. This important axonal property, as assessed by microneurography, is used to differentiate human mechanoinsensitive (silent) nociceptors from the classical polymodal nociceptors. In the current study, microneurography was used to assess axonal properties of the 2 main nociceptor classes in humans, before and after intradermal injection of lidocaine .1% or control saline solution in the receptive field. In mechanosensitive nociceptors, lidocaine reduced baseline conduction velocity and turned activity-dependent slowing into speeding of conduction. In contrast, mechanoinsensitive fibers were not affected in their baseline conduction velocity or their activity-dependent slowing, but probability of conduction block with repetitive stimulation increased. Recovery cycles showed reduced hyperpolarization in all C-fiber classes after lidocaine injections. These results support our hypothesis that sodium channel subtypes are differentially expressed in the 2 nociceptor classes of mechanosensitive C-fibers (CMs) and mechanoinsensitive C-fibers (CMis). PERSPECTIVE This study reveals that microneurography can be used to assess pharmacological effects on single C-fibers directly in humans.

Double spikes to single electrical stimulation correlates to spontaneous activity of nociceptors in painful neuropathy patients

Summary Spontaneously active C nociceptors in painful neuropathy patients reveal multiple firing to single electrical stimuli, suggesting that axonal hyperexcitability contributes to neuropathic pain. Abstract Multiple firing of C nociceptors upon a single electrical stimulus has been suggested to be a possible mechanism contributing to neuropathic pain. Because this phenomenon maybe based on a unidirectional conduction block, it might also be related to neuropathic changes without a direct link to pain. We investigated painful neuropathy patients using microneurography and analysed nociceptors for the occurrence of multiple spiking and spontaneous activity. In 11 of 105 nociceptors, double spiking was found, with 1fibre even showing triple spikes on electrical stimulation. The interval between the main action potential and the multiple spikes ranged from 13 to 100 ms. There was a significant association between spontaneous activity and multiple spiking in C nociceptors, with spontaneous activity being present in 9 of 11 fibres with multiple spiking, but only in 21 of 94 nociceptors without multiple spiking (P < .005, Fisher exact test). Among the 75 C nociceptors without spontaneous activity, only 2 nociceptors showed multiple spiking. In 8 neuropathy patients without pain, double spiking was found only in 4 of 90 nociceptors. Multiple spiking of nociceptors coincides with spontaneous activity in nociceptors of painful neuropathy patients. We therefore conclude that rather than being a generic sign of neuropathy, multiple spiking is linked to axonal hyperexcitability and spontaneous activity of nociceptors. It is still unclear whether it also is mechanistically related to the clinical pain level.

SCN10A Mutation in a Patient with Erythromelalgia Enhances C-Fiber Activity Dependent Slowing

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.

Delayed diagnosis and worsening of pain following orthopedic surgery in patients with complex regional pain syndrome (CRPS)

Abstract Background and aims Complex regional pain syndrome (CRPS) is a serious and disabling chronic pain condition, usually occurring in a limb. There are two main types, CRPS 1 with no definite nerve lesion and CRPS 2 with an identified nerve lesion. CRPS 1 and 2 may occur following an injury (frequently following fractures), surgery or without known cause. An early diagnosis and start of adequate treatment is considered desirable for patients with CRPS. From the clinical experience of the principal investigator, it became apparent that CRPS often remained undiagnosed and that the clinical conditions of many patients seemed to be worsened following orthopedic surgery subsequent to the initial eliciting event. The aim of the present retrospective study of 55 patients, all diagnosed with either CRPS 1 or 2, was to evaluate the time from injury until diagnosis of CRPS and the effect on pain of orthopedic surgical intervention subsequent to the original injury/surgery. Methods Clinical symptoms with an emphasis on pain were assessed by going through the patients’ records and by information given during the investigation at Oslo University Hospital, where the patients also were examined clinically and with EMG/neurography. Alteration in pain was evaluated in 27 patients who underwent orthopedic surgery subsequent to the eliciting injury. Results Of a total of 55 patients, 28 women and 27 men (mean age 38.7 (SD 12.3), 38 patients were diagnosed with CRPS type 1, and 17 with CRPS type 2. Mean time before diagnosis was confirmed was 3.9 years (SD1.42, range 6 months-10 years). The eliciting injuries for both CRPS type 1 and type 2 were fractures, squeeze injuries, blunt injuries, stretch accidents and surgery. A total of 27 patients (14 men and 13 women) were operated from one to 12 times at a later stage (from 6 months to several years) following the initial injury or any primary operation because of fracture. A total of 22 patients reported a worsening of pain following secondary surgical events, while four patients found no alteration and one patient experienced an improvement of pain. None of the 22 patients reporting worsening, were diagnosed with CRPS prior to surgery, while retrospectively, a certain or probable diagnosis of CRPS had been present in 17/22 (77%) patients before their first post-injury surgical event. Conclusions and implications A mean time delay of 3.9 years before diagnosis of CRPS is unacceptable. A lack of attention to more subtle signs of autonomic dysfunction may be an important contributing factor for the missing CRPS diagnosis, in particular serious in patients reporting worsening of pain following subsequent orthopedic surgery. It is strongly recommended to consider the diagnosis of CRPS in all patients with a long-lasting pain condition. We emphasize that the present report is not meant as criticism to orthopedic surgical practice, but as a discussion for a hopefully increased awareness and understanding of this disabling pain condition.

Pathological nociceptors in two patients with erythromelalgia‐like symptoms and rare genetic Nav 1.9 variants

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.

Diagnosis of carpal tunnel syndrome

In this edition of Scandinavian Journal of Pain, Izadi and collaborators publish an interesting paper [1] showing the lack of relationship between clinical provocative tests of carpal tunnel syndrome (CTS) and results of nerve conduction studies (NCS), while they found significant associations between the results of NCS and clinical grading, Numeric Pain Rating Scale (NPRS) and the Boston carpal tunnel questionnaire (BCTQ). CTS is due to a compression of the median nerve at the level of the wrist. It is by far the most common peripheral nerve entrapment syndrome, with a prevalence around 2–3% in a general population [2]. CTS is associated with a number of risk factors, including pregnancy, hypothyroidism, diabetes, rheumatoid arthritis and obesity [3]. The role of work-related factors is somehow controversial, but occupational biomechanical factors play a substantial role in the causation of CTS [4] and some recognize it as a work-related disorder caused by strain and repeated movements [5]. The treatment of this entrapment mononeuropathy is either conservative (splinting, steroid injections) or surgical decompression of the carpal tunnel. Surgery has proved to be more efficient compared to non-surgical methods [6–8], but CTS may also improve spontaneously in some untreated patients [9, 10]. Accordingly, while surgical decompression is the advised initial therapy for patients with severe CTS, milder forms of CTS without evidence of axonal loss can initially be treated conservatively [11]. It is important to bear in mind that several differential diagnoses may mimic CTS [11], including cervical radiculopathies (especially C6/C7), different types of peripheral polyneuropathies, other mononeuropathies including proximal median and ulnar neuropathy as well as local conditions of the wrist (arthrosis, tendinitis). Although CTS-surgery is regarded as efficient and relatively safe, it represents, as all surgical procedures, a potential risk of complications [12] including postoperative pain. A correct diagnosis is therefore mandatory before a surgical intervention, in order to avoid an unnecessary operation. CTS is characterized by pain/paresthesia in the hand/ wrist, typically localized to the radial fingers within the innervation territory of the median nerve. However, sensory complaints from non-median innervated hand/ fingers [13] and pain in the arm/shoulder [14] are also common. The symptoms are typically worsened at night and may be reduced by shaking the hand. At daytime, the complaints may be provoked by repetitive activity or holding the hand/arm in sustained positions [15]. Intermittent sensory complaints often dominate in the early stage, while more fixed sensory symptoms and motor complaints may appear if the compression of the nerve is sustained. A fixed sensory deficit and thenar wasting/weakness is associated with poorer prognosis [16]. Thenar wasting is a sign of marked axonal loss and may represents a serious handicap for the patient since thumb opposition is important for the grip-function of the hand. The outcome of carpal tunnel surgery is better if the nerve is decompressed before a severe abnormality as marked axonal loss has occurred [16, 17], and it is accordingly important to identify early signs of axonal loss before the condition becomes so severe that thenar atrophy is clinically present. This is only possible via neurophysiological tests such as NCS and electromyography (EMG) (see e.g. [18] for an overview), methods with a notable impact on treatment plans both for CTS specifically and for neuromuscular disorders in general [19, 20].

Changes in Ionic Conductance Signature of Nociceptive Neurons Underlying Fabry Disease Phenotype

The first symptom arising in many Fabry patients is neuropathic pain due to changes in small myelinated and unmyelinated fibers in the periphery, which is subsequently followed by a loss of sensory perception. Here we studied changes in the peripheral nervous system of Fabry patients and a Fabry mouse model induced by deletion of α-galactosidase A (Gla−/0). The skin innervation of Gla−/0 mice resembles that of the human Fabry patients. In Fabry diseased humans and Gla−/0 mice, we observed similar sensory abnormalities, which were also observed in nerve fiber recordings in both patients and mice. Electrophysiological recordings of cultured Gla−/0 nociceptors revealed that the conductance of voltage-gated Na+ and Ca2+ currents was decreased in Gla−/0 nociceptors, whereas the activation of voltage-gated K+ currents was at more depolarized potentials. Conclusively, we have observed that reduced sensory perception due to small-fiber degeneration coincides with altered electrophysiological properties of sensory neurons.