Kristin Ørstavik

Abnormal Function of C-Fibers in Patients with Diabetic Neuropathy

The mechanisms underlying the development of painful and nonpainful neuropathy associated with diabetes mellitus are unclear. We have obtained microneurographic recordings from unmyelinated fibers in eight patients with diabetes mellitus, five with painful neuropathy, and three with neuropathy without pain. All eight patients had large-fiber neuropathy, and seven patients had pathological thermal thresholds in their feet, indicating the involvement of small-caliber nerve fibers. A total of 163 C-fibers were recorded at knee level from the common peroneal nerve in the patients (36–67 years old), and these were compared with 77 C-fibers from healthy controls (41–64 years old). The ratio of mechano-responsive to mechano-insensitive nociceptors was ∼2:1 in the healthy controls, whereas in the patients, it was 1:2. In patients, a fairly large percentage of characterized fibers (12.5% in nonpainful and 18.9% in painful neuropathy) resembled mechano-responsive nociceptors that had lost their mechanical and heat responsiveness. Such fibers were rarely encountered in age-matched controls (3.2%). Afferent fibers with spontaneous activity or mechanical sensitization were found in both patient groups. We conclude that small-fiber neuropathy in diabetes affects receptive properties of nociceptors that leads to an impairment of mechano-responsive nociceptors.

Active "itch fibers" in chronic pruritus.

An itch-specific neuronal pathway was recently discovered in healthy humans and animals. Here the authors report that activity in this specific pathway coincides with itch under pathophysiologic conditions in a patient with chronic pruritus. Microneurographic recordings from the symptomatic area revealed spontaneous activity in six single C-fiber afferents that had the characteristic features of “itch fibers.” Itch may be caused by activity in a specific subpopulation of C-fiber afferents.

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.

Neural Signal Processing: The Underestimated Contribution of Peripheral Human C-Fibers

The microneurography technique was used to analyze use-dependent frequency modulation of action potential (AP) trains in human nociceptive peripheral nerves. Fifty-one single C-afferent units (31 mechano-responsive, 20 mechano-insensitive) were recorded from cutaneous fascicles of the peroneal nerve in awake human subjects. Trains of two and four suprathreshold electrical stimuli at interstimulus intervals of 20 and 50 msec were applied to the receptive fields of single identified nociceptive units at varying repetition rates. The output frequency (interspike interval) recorded at knee level was compared with the input frequency (interstimulus interval) at different levels of accumulated neural accommodation. At low levels of use-dependent accommodation (measured as conduction velocity slowing of the first action potential in a train), intervals between spikes increased during conduction along the nerve. At increasing levels of neural accommodation, intervals decreased because of a relative supernormal period (SNP) and asymptotically approached the minimum “entrainment” interval of the nerve fiber (11 ± 1.4 msec) corresponding to a maximum instantaneous discharge frequency (up to 190 Hz). For neural coding, this pattern of frequency decrease at low activity levels and frequency increase at high levels serves as a mechanism of peripheral contrast enhancement. The entrainment interval is a good minimum estimate for the duration of the refractory period of human C-fibers. At a given degree of neural accommodation, all afferent C-units exhibit a uniform pattern of aftereffects, independent of fiber class. The receptive class of a fiber only determines its susceptibility to accommodate. Thus, the time course of aftereffects and existence or absence of an SNP is fully explained by the amount of preexisting accommodation.

ATP responses in human C nociceptors.

&NA; Microelectrode recordings of impulse activity in nociceptive C fibres were performed in cutaneous fascicles of the peroneal nerve at the knee level in healthy human subjects. Mechano‐heat responsive C units (CMH), mechano‐insensitive but heat‐responsive (CH) as well as mechano‐insensitive and heat‐insensitive C units (CMiHi) were identified. A subgroup of the mechano‐insensitive units was readily activated by histamine. We studied the responsiveness of these nociceptor classes to injection of 20 &mgr;l 5 mM adenosintriphosphate (ATP) using saline injections as control. Because of mechanical distension during injection, which typically activates mechano‐responsive C fibres, interest was focused on responsiveness to ATP after withdrawal of the injection needle. Post‐injection responses were observed in 17/27 (63%) mechano‐responsive units and in 14/22 (64%) mechano‐insensitive units. Excitation by ATP occurred in 9/11 CH units and in 5/11 CMiHi units. ATP responsive units were found both within the histamine‐responsive and the histamine‐insensitive group of mechano‐insensitive fibres. ATP responses appeared with a delay of 0–180 s after completion of injection; responses were most pronounced during the first 1–3 min of activation, and irregular ongoing activity was observed for up to 10 or even 20 min. ATP responses were dose‐dependent, concentrations lower than 5 mM gave weaker responses. No heat or mechanical sensitisation was observed in any of the major fibre classes. In conclusion, we have shown that ATP injections at high concentrations activate C‐nociceptors in healthy human skin, without preference for mechano‐responsive or mechano‐insensitive units. ATP did not sensitise human C fibres for mechanical or heat stimuli. We discuss how various mechanisms might contribute to the observed responses to ATP.

Microneurographic assessment of C-fibre function in aged healthy subjects

Physiological changes in the nervous system occur with ageing. Both a decline of function and a decrease in the number of C‐fibres in the skin have been reported for healthy aged subjects. With the use of microneurographic recordings from single C‐fibres in humans we have compared the sensory and axonal properties of these neurones in young and aged healthy subjects. A total of 146 C‐fibres were recorded from the common peroneal nerve in young subjects (mean age 24.7 years) and 230 C‐fibres were recorded in aged subjects (mean age 56.2 years). In aged subjects, changes were found in the composition of the C‐fibre population and in sensory and axonal properties. The relative incidence of afferent to efferent C‐fibres was relatively constant independent of the age of subjects. The ratio of mechano‐responsive to mechano‐insensitive nociceptors was approximately 8 : 2 in the young controls while in aged subjects it was 7 : 3. In aged subjects 13% of the fibres showed atypical discharge characteristics, while this was not observed in young subjects. Spontaneous activity, sensitization and loss of sensory function were found regularly. Changes in functions of the conductile membrane were also observed in fibres from aged subjects. The degree of activity‐dependent conduction velocity slowing in response to high frequency stimulation (2 Hz) was more pronounced, while the normalization of conduction velocity subsequent to high frequency stimulation was protracted. We found that both sensitization and desensitization or degeneration of afferent C‐fibres occur with age, but are still rare compared to patients with neuropathy. The changes in the axonal properties of C‐fibres in aged subjects are compatible with hypoexcitability of the fibres. These findings are important for the understanding and differential diagnoses regarding pathological processes and normal ageing.

Pain and small-fiber neuropathy in patients with hypothyroidism

Objective: To investigate large- and small-fiber function in patients with hypothyroidism and pain. Methods: The authors studied 38 women treated for hypothyroidism and with painful extremities and 38 healthy controls. All subjects underwent neurologic examination of the extremities, neurophysiologic testing of large myelinated nerves, and thresholds for warmth detection (WDT), cold detection (CDT), heat-pain detection (HPDT), and cold-pain detection (CPDT) in one upper and both lower limbs. Results: Eighteen patients had ongoing or intermittent ongoing distal pain in their limbs. Of these, 8 reported evoked and 10 reported paroxysmal pain. Fifteen patients had only diffuse musculoskeletal pain. A total of 16 patients had “hyperphenomena” (brush-evoked allodynia, punctate hyperalgesia, or cold allodynia or a combination of these, in their feet or hands or both). Eight patients were classified as having large fiber neuropathy, whereas 20 had “hypophenomena” (elevated thermal thresholds in their feet or hands or both). Thermal thresholds at the feet (WDT, CDT, and HPDT) were elevated (p = 0.001, p = 0.007, and p = 0.003, respectively) in the whole group of patients compared with the controls as well as WDT (p = 0.001) and CDT (p = 0.001) being elevated at the thenar eminence. All patients with ongoing, evoked, or paroxysmal pain had either hyperphenomena or hypophenomena or a combination of the two. Conclusions: Some patients treated for hypothyroidism have symptoms and findings compatible with small-fiber neuropathy or “hyperphenomena” indicating central sensitization.

Catecholamine-induced excitation of nociceptors in sympathetically maintained pain

Abstract Sympathetically maintained pain could either be mediated by ephaptic interactions between sympathetic efferent and afferent nociceptive fibers or by catecholamine‐induced activation of nociceptive nerve endings. We report here single fiber recordings from C nociceptors in a patient with sympathetically maintained pain, in whom sympathetic blockade had repeatedly eliminated the ongoing pain in both legs. We classified eight C‐fibers as mechano‐responsive and six as mechano‐insensitive nociceptors according to their mechanical responsiveness and activity‐dependent slowing of conduction velocity (latency increase of 0.5 ± 1.1 vs. 7.1 ± 2.0 ms for 20 pulses at 0.125 Hz). Two C‐fibers were activated with a delay of several seconds following strong endogenous sympathetic bursts; they were also excited for about 3 min following the injection of norepinephrine (10 μl, 0.05%) into their innervation territory. In these two fibers, a prolonged activation by injection of low pH solution (phosphate buffer, pH 6.0, 10 μl) and sensitization of their heat response following prostaglandin E2 injection were recorded, evidencing their afferent nature. Moreover, their activity‐dependent slowing was typical for mechano‐insensitive nociceptors. We conclude that sensitized mechano‐insensitive nociceptors can be activated by endogenously released catecholamines and thereby may contribute to sympathetically maintained pain. No evidence for ephaptic interaction between sympathetic efferent and nociceptive afferent fibers was found.

Microneurographic findings of relevance to pain in patients with erythromelalgia and patients with diabetic neuropathy

Mechanisms responsible for neuropathic pain are still unclear. By using microneurography we have been able to record from single C-nociceptive and sympathetic fibers in patients and attempted to uncover possible abnormal functional properties of these fibers of relevance for pain. In two previously published studies conducted on patients with erythromelalgia and patients with diabetic neuropathy, some of the major findings were: (1) spontaneous activity in nociceptive fibers, (2) sensitization of mechano-insensitive C-fibers, and (3) an altered distribution of C-afferent nerve fibers with a reversal of the proportion of the two main subtypes of C-nociceptive fibers, indicating a loss of function of polymodal nociceptors. Although some degree of spontaneous activity and sensitization also was found in patients without pain, these mechanisms may still be of importance for the development and maintenance of neuropathic pain. A change in the distribution of C-nociceptive fibers in the skin as shown in the patients with diabetic neuropathy may help to reveal mechanisms responsible for small-fiber dysfunction.

Endothelin1 activates and sensitizes human C-nociceptors

&NA; Microneurography was used to record action potentials from afferent C‐fibers in cutaneous fascicles of the peroneal nerve in healthy volunteers. Afferent fibers were classified according to their mechanical responsiveness to von Frey stimulation (75 g) into mechano‐responsive and mechano‐insensitive nociceptors. Various concentrations of Endothelin1 (ET1) and Histamine were injected into the receptive fields of C‐fibers. Activation and heat sensitization were monitored. Axon reflex flare and psychophysical ratings were assessed after injection of ET1 and codeine into the forearms after pre‐treatment with an H1 blocker or sodium chloride. 65% of mechanosensitive nociceptors were activated by ET1. One‐third showed long lasting responses (>15 min). In contrast, none of thirteen mechano‐insensitive fibers were activated. Sensitization to heat was observed in 62% of mechanosensitive and in 46% of mechano‐insensitive fibers. Injection of ET1 produced a widespread axon reflex flare, which was suppressed by pre‐treatment with an H1 receptor blocker. In addition, pain sensations were induced more often than itching by ET1 in contrast to codeine. No wheal was observed after injection of ET1. Both itching and pain were decreased after H1 blocker treatment. In summary: (1) In humans ET1 activates mechanosensitive, but not mechano‐insensitive, nociceptors. (2) Histamine released from mast cells is not responsible for all effects of ET1 on C‐nociceptors. (3) ET1 could have a differential role in pain compared to other chemical algogens which activate additionally or even predominantly mechano‐insensitive fibers.