Endothelin 1 activates and sensitizes human C-nociceptors.

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 (75g) 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 (>15min). 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.

Catecholamine-induced excitation of nociceptors in sympathetically maintained pain.

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 microl, 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 microl) 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.

Functional ability in female leg ulcer patients--a challenge for physiotherapy.

BACKGROUND AND PURPOSE: Venous leg ulceration represents a global health problem affecting predominantly elderly women. Traditionally, functional problems in this group of patients have attracted modest attention from wound care providers and physiotherapists. The aim of the present study was to describe and quantify disease consequences in female leg ulcer patients as a background for future physiotherapy interventions, using the nomenclature of the WHO International Classification of Functioning, Disability and Health (ICF). METHOD: A prospective study was conducted in 34 women aged 60-85 years with current or previous venous leg ulcer as compared to 27 age-matched non-ulcer subjects. The outcome variables were pain, ankle range of motion, walking speed, walking endurance, self-perceived exertion, mobility, activities of daily living (ADL), physical activity, general health, life satisfaction and use of walking aids and community services. Established instruments were utilized and categorized within ICF domains to provide a conceptual framework and basis for physiotherapeutic research. RESULTS: Leg ulcer patients showed significantly reduced values of ankle range of motion, walking speed and endurance, self-perceived exertion, mobility, ADL and physical activity level as compared to control subjects. Patients suffering from active ulceration were more negatively affected, and more of them had pain than post-ulcer fellows. By contrast, general health and life satisfaction were similarly rated by the two study groups. CONCLUSIONS: Elderly females in our study with chronic leg ulcer of venous aetiology had significant mobility impairments, but the reasons and consequences of these impairments remain to be elucidated. The potential of preventive measures and physical rehabilitation to aid functioning and prospects of leg ulcer repair need to be investigated in future studies.

Decreased mechanical pain threshold in the vestibular mucosa of women using oral contraceptives: a contributing factor in vulvar vestibulitis?

OBJECTIVE: To analyze possible differences in somatosensory perception in the vestibular mucosa in healthy women associated with the use of oral contraceptives. STUDY DESIGN: Quantitative sensory tests were performed on the vestibular mucosa in 39 healthy women. Twenty women were using oral contraceptives containing 30-40 microg ethinyl estradiol combined with various progestins; 19 women with regular menstrual periods not using oral contraceptives served as controls. The testing included mechanical and heat pain thresholds and detection thresholds of warmth and cold in the anterior and posterior part of the vestibule. RESULTS: Significant lower mechanical pain thresholds were observed in both areas tested in women using oral contraceptives. The most sensitive area was the posterior vestibule in the group using oral contraceptives with a mechanical pain threshold of 72 +/- 10 ( +/-SEM) mN as compared to 161 +/- 3 mN (p < 0.01), in the controls. The result of the thermotest showed no significant differences between the groups. CONCLUSION: Oral contraceptives may induce increased sensitivity in the vestibular mucosa in healthy women and might be one contributingfactor in the development of vulvar vestibulitis.

Pathological C-fibres in patients with a chronic painful condition.

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.

ATP responses in human C nociceptors.

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 (CM(i)H(i)) 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 microl 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 CM(i)H(i) 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.

Parameter estimation of human nerve C-fibers using matched filtering and multiple hypothesis tracking.

We describe how multiple-target tracking may be used to estimate conduction velocity changes and recovery constants of human nerve C-fibers. These parameters discriminate different types of C-fibers and pursuing this may promote new insights into differential properties of nerve fiber membranes. Action potentials (APs) were recorded from C-fibers in the peroneal nerve of awake human subjects. The APs were detected by a matched filter constituting a maximum-likelihood constant false-alarm rate detector. Using the multiple-hypothesis tracking method and Kalman filtering, the detected APs (targets) in each trace (scan) were associated to individual nerve fibers (tracks) by their typical conduction latencies in response to electrical stimulation. The measurements were one-dimensional (range only) and the APs were spaced in time with intersecting trajectories. In general, the AP amplitude of each C-fiber differed for different fibers. Amplitude estimation was therefore incorporated into the tracking algorithm to improve the performance. The target trajectory was modeled as an exponential decay with three unknowns. These parameters were estimated iteratively by applying the simplex method on the parameters that enter nonlinearly and the least squares method on the parameters that enter linearly.

Psychophysical evidence of nociceptor sensitization in vulvar vestibulitis syndrome.

Vulvar vestibulitis syndrome (VVS) is a long lasting disorder of superficial dyspareunia in young women. Quantitative sensory testing, including mechanical and temperature pain thresholds and warm/cold difference limen (WCL), was performed in the vestibular mucosa in 22 women (mean age 25.0 years) with vestibulitis and 20 control subjects (mean age 25.6 years). The tests were carried out on days 7-11 of the menstrual cycle. Patients had allodynia to mechanical testing with von Frey filaments, 14.3+/-3.1mN in the symptomatic posterior area as compared with 158+/-33.5mN in healthy subjects, P<0.0001. The pain threshold to heat was 38.6+/-0.6 degrees C in patients and 43.8+/-0.8 degrees C in controls, P<0.0001. In addition, pain threshold to cold was 21.6+/-1.2 degrees C in patients whereas cooling down to 6 degrees C was usually not painful in controls. WCL was 4.9+/-0.5 degrees C in patients and 9.6+/-1.5 degrees C in healthy subjects, P<0.01. The results are compatible with the hypothesis that patients with VVS have an increased innervation and/or sensitization of thermoreceptors and nociceptors in their vestibular mucosa.

Dynamic adjustments of walking behavior dependent on noxious input in experimental low back pain.

The aim of this study was to explore whether accelerations of the lower back during walking are temporarily attenuated by experimentally-induced low back pain, as compared with normal walking. Transient low back pain was induced by injection of 1 ml 6% hypertonic saline in the longissimus dorsi muscle in 20 healthy subjects. Acceleration was measured during walking at self-selected speeds before and repeatedly after the injection by a portable, triaxial accelerometer positioned over the L3 region. Data were subsequently adjusted for differences in walking speeds between trials and subjects. Pain was reported on a 0-10 point scale during walking until pain was no longer present. Lumbar acceleration sample mean was attenuated for the anteroposterior (P=0.002) and mediolateral (P=0.002) sensing axes as well as for the vector sum (P=0.005) at maximal pain compared to pretest values. The vertical axis showed no significant changes. Values returned to pretest level when pain was no longer present. Regardless of the initial increase and subsequent decrease in pain after injection, there was a linear relationship between pain and acceleration in 15 of the 20 subjects (0.89>/=R(2)>/=0.36, P

Noradrenaline-evoked pain in neuralgia.

We have tested the effects of cutaneous application of noradrenaline in 35 patients presenting with neuropathic pain. Depending on the outcome of sympatholytic interventions the patients were considered to have sympathetically maintained pain (SMP; n = 25) or sympathetically independent pain (SIP; n = 10). Iontophoretic application or cutaneous injection of noradrenaline into symptomatic skin aggravated pain and mechanical or thermal hyperalgesia in 7/25 SMP patients. Results from differential nerve blocks suggested that noradrenaline-induced ongoing pain and heat hyperalgesia were signalled by unmyelinated afferents, while touch-evoked pain and cold hyperalgesia were signalled by myelinated afferents. In none of the remaining 18/25 SMP patients, 10 SIP patients or 18 normal subjects did application of noradrenaline result in any appreciable increase of pain. A follow-up of 12 patients (initially 9 SMP, 3 SIP) after 12-16 years showed that one individual (previously SMP) was healthy, while 3 patients still suffered from SMP and 8 from SIP. Of the 5 SMP patients who had noradrenaline-induced pain at the initial examination, only 1 SMP patient still responded to noradrenaline with pain and hyperalgesia. Three other patients had changed to SIP and 1 individual was healthy. None of these 4 and none of the 7 initially noradrenaline-unresponsive patients experienced pain to the noradrenaline challenge at follow-up. Thus, cutaneous noradrenaline application can aggravate the pain in some, but not all SMP patients. THe abnormal noradrenaline reaction can change over time as can the pain relieving effects of sympatholytic therapy.

Effects of regional intravenous guanethidine in patients with neuralgia in the hand; a follow-up study over a decade.

A study on the effect of regional intravenous (i.v.) guanethidine blockade (RGB) was done over a 10 years period in patients with post-traumatic neuralgia. Seven patients, investigated with quantitative sensory testing (QST) before and after RGB between 1979 and 1982, were reinvestigated in the period 1990-1992. In addition to the RGB, 6 patients were subjected to a placebo procedure with tourniquet inflation and i.v. injection of saline at follow-up. All patients had ongoing pain and stimulus-induced pain (hyperalgesia) in one hand. The QST was done by an independent observer who was blind with regard to the different treatments. Three patients with long-lasting relief of ongoing pain and significant reduction of stimulus-induced pain after RGB, were classified as having sympathetically maintained pain (SMP) both at 1st examination and at follow-up 10 years later. In 2 patients, classified as having sympathetically independent pain (SIP), neither the ongoing pain nor the hyperalgesia improved at any occasion. Two patients, classified as SMP in 1979-1982, changed to SIP at follow-up. Placebo had no significant effect on the hyperalgesia to heat, cold or vibration in the 6 SMP/SIP patients tested. In conclusion, some patients with neuralgia, diagnosed 17-26 years ago, still had long-lasting pain relief from an i.v. RGB, whereas others consistently had no such effect. None obtained long-lasting pain relief from placebo. This supports the notion that different pathophysiological mechanisms are involved in post-traumatic neuralgia.

Dynamic and static components of mechanical hyperalgesia in human hairy skin.

The principle finding of the present study is that there are two types of mechanical hyperalgesia developing in human hairy skin following injurious stimuli. Mechanical hyperalgesia comprises a dynamic component (brush-evoked pain, allodynia) signalled by large myelinated afferents and a static component (hyperalgesia to pressure stimuli) signalled by unmyelinated afferents. While the static component is only found in the injured area, the dynamic component also extends into a halo of undamaged tissue surrounding the injury. The irritant chemicals, mustard oil or capsaicin, were applied transdermally in 20 subjects to a patch (2 x 2 cm) of hairy skin. Both substances evoked burning pain and hyperalgesia to mechanical stimuli. While stroking normal skin with a cotton bud was perceived only as touch prior to chemical stimulation, there was a distinctly unpleasant sensation afterwards. This component of mechanical hyperalgesia persisted for at least 30 min and was present in the skin exposed to the irritants (primary hyperalgesia) as well as in a zone of untreated skin surrounding the injury (secondary hyperalgesia) measuring 38 +/- 4 cm2 after capsaicin. Pressure pain thresholds dropped to 55 +/- 8% of baseline level after mustard oil and to 46 +/- 9% after capsaicin. However, this drop of thresholds was short-lived, lasting 5 min following mustard oil but persisting more than 30 min following capsaicin treatment. The reduction of pressure pain thresholds was only observed for treated skin areas, but not in the surrounding undamaged tissue from where brush-evoked pain could be evoked. When pressure pain thresholds were lowered, the pain had a burning quality which differed distinctly from the quality of brush-evoked pain. On-going burning pain and both types of mechanical hyperalgesia were critically temperature dependent. Mildly cooling the skin provided instant relief from on-going pain, abolished brush-evoked pain and normalized pressure pain thresholds. Rewarming resulted in a reappearance of on-going pain and hyperalgesia. The effect of a nerve compression block of the superficial radial nerve on these sensations was tested in 14 experiments. When the ability to perceive light touch had been abolished, there was also no touch-evoked pain, indicating that this component of mechanical hyperalgesia is mediated by large-diameter primary afferents. At a later stage of the block when the subjects' ability to perceive cold stimuli had also been lost, application of cool stimuli still eliminated on-going burning pain, suggesting that pain relief afforded by cooling the skin acts at the peripheral receptor level and not by central masking.(ABSTRACT TRUNCATED AT 400 WORDS)

Quantitative sensory tests in patients with neuralgia 11 to 25 years after injury.

In a previous study quantitative sensory tests were used to characterize the symptoms in patients with post-traumatic neuralgia in the hand. Two types of pain syndromes were identified, sympathetically maintained pain (SMP), and sympathetically independent pain (SIP). These two syndromes had different sensory profiles with regard to temperature discrimination and cold and heat pain thresholds. The aim of the present study was to investigate the development of symptoms 10 years later. Eighteen previously investigated patients were contacted and all answered questions concerning their symptoms. Of these, two SIP and eight SMP patients agreed to undergo quantitative sensory testing. The outcome of these tests and the patients' own reports indicated that patients with SMP, who were not repeatedly treated with sympathetic blocks, did not show any remarkable spontaneous improvement of symptoms over a decade. The SMP patients still exhibited their characteristic sensory profile with moderate impairment of temperature discrimination and allodynia to cold, heat and vibratory stimuli. However, some changes with time were observed with respect to warm-cold difference limen and vibration allodynia. Comparison with data obtained from an age-matched group of healthy individuals indicated that these changes were due to age-related factors.

Quantitative sensory testing before and after regional guanethidine block in patients with neuralgia in the hand.

Using reference values from healthy volunteers, thermal and vibration-induced pain thresholds and the sensibility for warm and cold were studied in 18 patients with neuralgia in one hand following a traumatic injury or surgery. All patients had spontaneous pain and allodynia to vibration. They were treated with intravenous regional guanethidine block (RGB). Quantitative sensory testing was performed on both hands before and 1-3 days after treatment. Eleven patients benefitted considerably from the block, with pain relief for 2 weeks or more. Ten of these 11 patients had mild nerve injuries caused by compressive trauma to the nerve. Before RGB they showed a moderate loss in temperature discrimination capacity; their heat pain thresholds were reduced and they exhibited allodynia to cold and vibration on the injured side. After RGB, the pain thresholds were normalised both to thermal and vibratory stimuli. These patients were classified as having sympathetically maintained pain (SMP). Seven patients reported no or only minor pain-relieving effect of RGB lasting 1-5 days. Severe nerve injuries were most frequent in this group of patients. On the injured side, before RGB, their ability to discriminate between warm and cold was markedly impaired, thermal pain thresholds were normal, and they showed allodynia to vibration. After RGB, there was no change in thermal pain thresholds and the allodynia to vibration persisted. These patients were classified as having sympathetically independent pain (SIP). The results indicate that quantitative thermal sensory tests, together with clinical evaluation of the nerve trauma, can help to predict which patients will have long-lasting pain alleviation after RGB treatment.

Central suppression of cold-induced C fibre pain by myelinated fibre input.

Changes in thermal sensibility for warmth, cold, heat pain and cold pain during nerve compression block of impulse conduction in myelinated fibres were studied in 20 healthy subjects. When mainly unmyelinated fibres were conducting, after 30-36 min of nerve compression, the pain threshold, induced by cold stimulation, was shifted towards higher temperatures (from 19.1 degrees C to 22.8 degrees C, mean values). Furthermore, the sensation of cold pain became more unpleasant and had a hot burning rather than a cold quality. These results indicate that a change in central decoding of the afferent input has occurred, possibly due to lack of inhibition normally exerted by concomitant activation of myelinated fibres. Whereas dramatic changes in the sensation of cold pain were observed during the course of nerve compression, no alteration in heat pain threshold was seen. This implies that heat pain threshold in hairy skin is due to activation of C nociceptor fibres without any significant contribution from myelinated nociceptor fibres. Furthermore, no gating from heat-sensitive myelinated fibre input was evident on heat pain threshold.

Analgesic effect of vibration and cooling on pain induced by intraneural electrical stimulation.

Psychophysical experiments were carried out on 16 human subjects to determine how low intensity mechanical and thermal skin stimuli interfere with the sensation of pain. Moderate or intense pain was induced by low frequency (2 Hz) electrical stimulation within cutaneous fascicles of the median nerve at wrist level, and vibration, pressure, cooling or warming were applied for short periods (usually 20-60 sec) within or outside the skin area to which the pain was projected. Vibration within the area of projected pain reduced the sensation of pain more efficiently than vibration outside that area. Moderate pain was sometimes completely inhibited but intense pain was only moderately reduced. Pressure and cooling produced some pain relief whereas mild warming had an ambiguous effect. Since the painful input derived from stimulation of fibres in the nerve trunk, and not from peripheral nociceptors, the pain suppressing effects of vibration and cooling are not explicable in terms of lowered excitability of the nociceptive nerve endings in the skin. Instead, the results indicate that activity in low threshold mechanoreceptive and cold sensitive units suppresses pain at central (probably segmental) levels.