The characteristics of chronic central pain after traumatic brain injury

Central pain following traumatic brain injury (TBI) has not been studied in depth. Our purpose was to conduct a systematic study of patients with TBI suffering from chronic central pain, and to describe the characteristics of the central pain. Groups were TBI patients with (TBIP) and without central pain (TBINP) and healthy controls. TBI patients with other pain mechanisms were excluded from the study. Participants underwent quantitative somatosensory testing in the painful and pain-free body regions. Thresholds for warmth, cold, heat-pain, touch and graphesthesia were measured and pathologically evoked pain (allodynia, hyperpathia and wind-up pain) evaluated. Chronic pain was mapped and characterized. Chronic pain developed at a relatively late onset (6.6+/-9 months) was almost exclusively unilateral and reported as pricking, throbbing and burning. Although both TBIP and TBINP exhibited a significant reduction in thermal and tactile sensations compared to controls, thermal sensations in the painful regions of TBIP were significantly more impaired than pain-free regions in the same patients (p<0.01) and in TBINP (p<0.01). Painful regions also exhibited very high rates of allodynia, hyperpathia and exaggerated wind-up. The characteristics of the chronic pain resembled those of other central pain patients although TBIP displayed several unique features. The sensory profile indicated that damage to the pain and temperature systems is a necessary but not sufficient condition for the development of chronic central pain following TBI. Neuronal hyperexcitability may be a contributing factor to the chronic pain.     

Referred sensations and neuropathic pain following spinal cord injury

It has been proposed that painful and non-painful referred sensations (RSs) are associated with reorganization of sensory pathways in patients with complete spinal cord injury (SCI). In order to investigate the referred sensation (RS) phenomenon and its correlation with neuropathic pain (NP) 48 patients with complete SCI, 24 with chronic NP and 24 without pain or paraesthesias were studied using clinical examination and neurophysiological tests. Patients reporting RSs were re-examined at 2 and 10 weeks after the first examination. We defined the presence of RS as sensations perceived below the injury level in response to touch and pinprick stimuli in various body points above the injury level. The examination was carried out by one researcher applying the stimuli to the patient under two visual conditions (open and closed eyes), and then asking the patient to make tactile self-stimulation. Seven patients with SCI and NP (29%) reported RS below the injury level. RS were well located and consistently evoked at repeated examinations. Touch and pinprick stimulation elicited similar RS that were non-painful in six patients and painful in one. Visual feedback did not change RS perception and characteristics. None of the patients in the SCI group without NP presented RS. In conclusion, our results indicate that RS is relatively frequent in patients with complete SCI and NP. The common occurrence of RS in patients with NP and the location of the sensations in the same area as NP suggest that pain and RS share common pathophysiological mechanisms.     

Abnormal sensitization and temporal summation of second pain (wind-up) in patients with fibromyalgia syndrome

Although individuals with fibromyalgia syndrome (FMS) consistently report wide-spread pain, clear evidence of structural abnormalities or other sources of chronic stimulation of pain afferents in the involved body areas is lacking. Without convincing evidence for peripheral tissue abnormalities in FMS patients, it seems likely that a central pathophysiological process is at least partly responsible for FMS, as is the case for many chronic pain conditions. Therefore, the present study sought to obtain psychophysical evidence for the possibility that input to central nociceptive pathways is abnormally processed in individuals with long standing FMS. In particular, temporal summation of pain (wind-up) was assessed, using series of repetitive thermal stimulation of the glabrous skin of the hands. Although wind-up was evoked both in control and FMS subjects, clear differences were observed. The perceived magnitude of the sensory response to the first stimulus within a series was greater for FMS subjects compared to controls, as was the amount of temporal summation within a series. Within series of stimuli, FMS subjects reported increases in sensory magnitude to painful levels for interstimulus intervals of 2-5 s, but pain was evoked infrequently at intervals greater than 2 s for control subjects. Following the last stimulus in a series, after-sensations were greater in magnitude, lasted longer and were more frequently painful in FMS subjects. These results have multiple implications for the general characterization of pain in FMS and for an understanding of the underlying pathophysiological basis.     

Altered C-tactile processing in human dynamic tactile allodynia

Human unmyelinated (C) tactile afferents signal the pleasantness of gentle skin stroking on hairy (nonglabrous) skin. After neuronal injury, that same type of touch can elicit unpleasant sensations: tactile allodynia. The prevailing pathophysiological explanation is a spinal cord sensitization, triggered by nerve injury, which enables Aβ afferents to access pain pathways. However, a recent mouse knockout study demonstrates that C-tactile afferents are necessary for allodynia to develop, suggesting a role for not only Aβ but also C-tactile afferent signaling. To examine the contribution of C-tactile afferents to the allodynic condition in humans, we applied the heat/capsaicin model of tactile allodynia in 43 healthy subjects and in 2 sensory neuronopathy patients lacking Aβ afferents. Healthy subjects reported tactile-evoked pain, whereas the patients did not. Instead, patients reported their C-touch percept (faint sensation of pleasant touch) to be significantly weaker in the allodynic zone compared to untreated skin. Functional magnetic resonance imaging in 18 healthy subjects and in 1 scanned patient indicated that stroking in the allodynic and control zones evoked different responses in the primary cortical receiving area for thin fiber signaling, the posterior insular cortex. In addition, reduced activation in the medial prefrontal cortices, key areas for C-tactile hedonic processing, was identified. These findings suggest that dynamic tactile allodynia is associated with reduced C-tactile mediated hedonic touch processing. Nevertheless, because the patients did not develop allodynic pain, this seems dependent on Aβ signaling, at least under these experimental conditions.     

Quantitative sensory testing: a comprehensive protocol for clinical trials.

We have compiled a comprehensive QST protocol as part of the German Research Network on Neuropathic Pain (DFNS) using well established tests for nearly all aspects of somatosensation. This protocol encompasses thermal as well as mechanical testing procedures. Our rationale was to test for patterns of sensory loss (small and large nerve fiber functions) or gain (hyperalgesia, allodynia, hyperpathia), and to assess both cutaneous and deep pain sensitivity. The practicality of the QST protocol was tested in 18 healthy subjects, 21-58 years, half of them female. All subjects were tested bilaterally over face, hand and foot. We determined thermal detection and pain thresholds including a test for the presence of paradoxical heat sensations, mechanical detection thresholds to von Frey filaments and a 64-Hz tuning fork, mechanical pain thresholds to pinprick stimuli and blunt pressure, stimulus-response-functions for pinprick and dynamic mechanical allodynia (pain to light touch), and pain summation (wind-up ratio) using repetitive pinprick stimulation. The full protocol took 27+/-2.3 min per test area. The majority of QST parameters were normally distributed only after logarithmic transformation (secondary normalization) except for the frequency of paradoxical heat sensations, cold and heat pain thresholds, and for vibration detection thresholds. Thresholds were usually lowest over face, followed by hand, and then foot. Only thermal pain thresholds, wind-up ratio and vibration detection thresholds were not significantly dependent on the body region. There was no significant right-to-left difference for any of the QST parameters; left-to-right correlation coefficients ranged between 0.78 and 0.97, thus explaining between 61% and 94% of the variance. This study has shown that a complete somatosensory profile of one affected area and one unaffected control area, which will be necessary to characterize patients with a variety of diseases, can be obtained within 1 h. Case examples of selected patients illustrate the value of z-transformed QST data for an easy survey of individual symptom profiles.     

The Acquisition and Extinction of Fear of Painful Touch: A Novel Tactile Fear Conditioning Paradigm

Fear of touch, due to allodynia and spontaneous pain, is not well understood. Experimental methods to advance this topic are lacking, and therefore we propose a novel tactile conditioning paradigm. Seventy-six pain-free participants underwent acquisition in a predictable as well as an unpredictable pain context. In the predictable context, vibrotactile stimulation was paired with painful electrocutaneous stimulation (simulating allodynia). In the unpredictable context, vibrotactile stimulation was unpaired with pain (simulating spontaneous pain). During an extinction phase, a cue exposure and context exposure group continued in the predictable and unpredictable context, respectively, without pain. A control group received continued acquisition in both contexts. Self-reported fear and skin conductance responses, but not startle responses, showed fear of touch was acquired in the predictable context. Context-related startle responses showed contextual fear emerged in the unpredictable context, together with elevated self-reported fear and skin conductance responses evoked by the unpaired vibrotactile stimulations. Cue exposure reduced fear of touch, whereas context exposure reduced contextual fear. Thus, painful touch leads to increased fear, as does touch in the same context as unpredictable pain, and extinction protocols can reduce this fear. We conclude that tactile conditioning is valuable for investigating fear of touch and can advance our understanding of chronic pain.

A Better Touch: C-tactile Fibers Related Activity is Associated to Pain Reduction During Temporal Summation of Second Pain

C-tactile (CT) fibers, responsible for the so-called “affective” touch (AT), have drawn a fair amount of attention within the scientific community for their marked social dimension. However, while the pain-relieving potential of discriminative touch (DT) has been documented, proofs of the analgesic properties of AT are still scarce. Additionally, no study has so far tested its possible pain-relieving effects on a clinically-relevant model. Temporal summation of second pain (TSSP), otherwise referred to as “wind-up,” relies on repetitive stimulation of C-nociceptors and it is thought to reflect central sensitization, a process linked to many chronic pain conditions. In the present experimental, within participants, design we induced TSSP through trains of ascending and descending repetitive heat stimulation. Forty-two healthy participants’ pain was measured during 2 different tactile stimulations (stroking velocities AT: 10 cm/s; DT: 0.3 cm/s) or without concomitant tactile input. Since measures of pleasantness of the tactile stimulation have been found to strongly correlate with C-tactile fibers’ firing rate, these, together with participants’ body awareness, were also taken into account.Our results show that AT brought about a decrease of our participants’ pain as opposed to both DT and no touch, while DT did not produce any significant pain reduction. Thus, only AT successfully modulated wind-up. As expected, AT was perceived as more pleasant than DT, while a clear relationship between body awareness and pain was found only during DT.Targeting CT fibers could pave the way to new treatments for chronic pain conditions whose aetiology depend on abnormal C-nociceptors’ physiology.PerspectiveThis study extends previous findings on the analgesic potential of affective touch, documenting a clear pain reduction during temporal summation of second pain (TSSP). Since TSSP is thought to reflect central sensitization, the psychophysiological mechanisms of affective touch could be exploited for new chronic pain treatments.     

Secondary hyperalgesia and presynaptic inhibition: an update.

One of the most prominent features of secondary hyperalgesia is touch-evoked pain, i.e., pain evoked by dynamic tactile stimuli applied to areas adjacent or remote from the originating injury. It is generally accepted that the neurobiological mechanism of this sensory alteration involves the central nervous system (CNS) so that incoming impulses in low-threshold mechanoreceptors from the area of secondary hyperalgesia can evoke painful sensations instead of touch. Some years ago we proposed a mechanistic model for this form of pain based on presynaptic interactions in the spinal dorsal horn between the terminals of low-threshold mechanoreceptors and of nociceptors. Here we review the evidence gathered in support of this model in the intervening years with special reference to experimental studies of antidromic activity (Dorsal Root Reflexes--DRRs) in nociceptive afferents and on the acquisition of low-threshold inputs by nociceptor-specific neurons in the spinal dorsal horn. We also discuss and identify potential molecular mechanisms that may underlie the presynaptic interaction model and therefore that could be responsible for the development of secondary hyperalgesia.     

Thermal and tactile sensory deficits and allodynia in a nerve-injured patient: a multimodal psychophysical and functional magnetic resonance imaging study

OBJECTIVE: A case study was conducted to examine a patient with chronic neuropathic pain of the right foot following peripheral nerve injury and characterize associated sensory abnormalities. METHODS: Multimodal psychophysical examination of the patient's affected and nonaffected foot included thermal sensibility, dynamic touch, and directional sensibility. In addition, we used functional magnetic resonance imaging to study cortical representation of brush-evoked allodynia. RESULTS: Detailed psychophysical examination revealed substantial deficits in warm, cool, and tactile perception on the injured foot. These findings indicated severe dysfunction of perceptual processes mediated by A beta, A delta, and C fibers. Despite reduced tactile perception, light touch evoked a deep burning pain in the foot. Functional magnetic resonance imaging during brushing of the patient's injured foot showed that tactile allodynia led to activation of several cortical regions including secondary somatosensory cortex, anterior and posterior insular cortex, and anterior cingulate cortex. Brushing of the patient's nonaffected foot led to fewer activated regions. DISCUSSION: The profound sensory disturbances suggest a possible deafferentation type of tactile allodynia mediated by changes within the central nervous system, such as a disruption of normal tactile or thermal inhibition of nociception. The functional magnetic resonance imaging data suggest that tactile allodynia is represented in similar brain regions as experimental pain.     

Spatial discrimination thresholds for pain and touch in human hairy skin

The traditional concept that pain is poorly localized has been challenged by recent studies, where subjects were able to point to the stimulated spot on the skin with an accuracy of 10-20 mm. Pointing movements themselves, however, have errors of about 15 mm. To determine the limits of sensory performance of the nociceptive system independent of motor performance, point localization of heat pain (540 mJ punctate laser stimuli, 5 mm diameter), mechanical pain (256 mN punctate probe, 200 microm diameter), and touch (16 mN von Frey probe, 1.1 mm diameter) were tested in a two-alternative forced-choice paradigm in 12 healthy subjects. Stimuli were applied in randomized order to two parallel lines on the back of the hand (4-32 mm distance). The cumulative distribution functions for correct localization were of similar sigmoid shape for all test stimuli, indicating logarithmic normal distributions. The 75% correct localization threshold for painful heat was 8.6 mm (3.1 +/- 0.1 log2 units) and did not differ significantly from that of non-painful touch (9.0 mm, 3.2+/-0.2 log2 units). Localization of mechanically-induced pain (5.1 mm, 2.4 +/- 0.2 log2 units) was significantly more accurate than both heat pain and touch, possibly due to a synergism of two different sensory channels, the tactile channel and the nociceptive channel, which were activated simultaneously. For all three stimuli, discrimination was significantly better in radial-ulnar compared to proximal-distal direction, which might be related to oval receptive field shapes. Sequential spatial discrimination for touch was significantly better than simultaneous spatial discrimination tested with a grating orientation task (18.9 mm), but both were one order of magnitude worse than at the finger tip (1.3 mm, 0.4 +/- 0.1 log2 units). In conclusion, pain evoked by radiant heat pulses and touch evoked by von Frey probes were localized with similar precision on the back of the hand. These findings indicate that outside the tactile fovea at finger tips or lips the spatial discrimination capacities of the nociceptive and tactile systems are about equal.     

Variation in quantitative sensory testing and epidermal nerve fiber density in repeated measurements

Quantitative sensory testing (QST) is commonly used to evaluate peripheral sensory function in neuropathic conditions. QST measures vary in repeated measurements of normal subjects but it is not known whether QST can reflect small changes in epidermal nerve fiber density (ENFd). This study evaluated QST measures (touch, mechanical pain, heat pain and innocuous cold sensations) for differences between genders and over time using ENFd as an objective-independent measure. QST was performed on the thighs of 36 healthy volunteers on four occasions between December and May. ENFd in skin biopsies was determined on three of those visits. Compared to men, women had a higher ENFd, a difference of 12.2 ENFs/mm. They also had lower tactile and innocuous cold thresholds, and detected mechanical pain (pinprick) at a higher frequency. Heat pain thresholds did not differ between genders. By the end of the 24-week study, men and women showed a small reduction (p < 0.05) in the frequency of sharp mechanical pain evoked by pinprick whereas tactile and thermal thresholds showed no change. This coincided with a small decrease in ENFd, 4.18 ENFs/mm. Variation in measurements over time was large in a fraction of normal subjects. We conclude that most QST measures detect relatively large differences in epidermal innervation (12.2 ENFs/mm), but response to mechanical pain was the only sensory modality tested with the sensitivity to detect small changes in innervation (4.18 ENFs/mm). Since some individuals had large unsystematic variations, unexpected test results should therefore alert clinicians to test additional locations.     

Topical capsaicin in humans: parallel loss of epidermal nerve fibers and pain sensation.

Capsaicin applied topically to human skin produces itching, pricking and burning sensations due to excitation of nociceptors. With repeated application, these positive sensory responses are followed by a prolonged period of hypalgesia that is usually referred to as desensitization, or nociceptor inactivation. Consequently, capsaicin has been recommended as a treatment for a variety of painful syndromes. The precise mechanisms that account for nociceptor desensitization and hypalgesia are unclear. The present study was performed to determine if morphological changes of intracutaneous nerve fibers contribute to desensitization and hypalgesia. Capsaicin (0.075%) was applied topically to the volar forearm four times daily for 3 weeks. At various time intervals tactile, cold, mechanical and heat pain sensations were assessed in the treated and in contralateral untreated areas. Skin blisters and skin biopsies were collected and immunostained for protein gene product (PGP) 9.5 to assess the morphology of cutaneous nerves and to quantify the number of epidermal nerve fibers (ENFs). Capsaicin resulted in reduced sensitivity to all cutaneous stimuli, particularly to noxious heat and mechanical stimuli. This hypalgesia was accompanied by degeneration of epidermal nerve fibers as evidenced by loss of PGP 9.5 immunoreactivity. As early as 3 days following capsaicin application, there was a 74% decrease in the number of nerve fibers in blister specimens. After 3 weeks of capsaicin treatment, the reduction was 79% in blisters and 82% in biopsies. Discontinuation of capsaicin was followed by reinnervation of the epidermis over a 6-week period with a return of all sensations, except cold, to normal levels. We conclude that degeneration of epidermal nerve fibers contributes to the analgesia accredited to capsaicin. Furthermore, our data demonstrate that ENFs contribute to the painful sensations evoked by noxious thermal and mechanical stimuli.     

Functional Characterization of At-Level Hypersensitivity in Patients With Spinal Cord Injury

At-level and above-level hypersensitivity was assessed in patients with chronic complete thoracic spinal cord injury (SCI). Patients were classified using somatosensory mapping (brush, cold, pinprick) and assigned into 2 groups (ie, patients with at-level hypersensitivity [SCIHs, n = 8] and without at-level hypersensitivity [SCINHs, n = 7]). Gender and age-matched healthy subjects served as controls. Quantitative sensory testing (QST), electrically- and histamine-induced pain and itch, laser Doppler imaging, and laser-evoked potentials (LEP) were recorded at-level and above-level in SCI-patients. Six of 8 SCIHs, but 0 of 7 SCINHs patients suffered from neuropathic below-level pain. Clinical sensory mapping revealed spreading of hypersensitivity to more cranial areas (above-level) in 3 SCIHs. Cold pain threshold measures confirmed clinical hypersensitivity at-level in SCIHs. At-level and above-level hypersensitivity to electrical stimulation did not differ significantly between SCIHs and SCINHs. Mechanical allodynia, cold, and pin-prick hypersensitivity did not relate to impaired sensory function (QST), axon reflex flare, or LEPs. Clinically assessed at-level hypersensitivity was linked to below-level neuropathic pain, suggesting neuronal hyperexcitability contributes to the development of neuropathic pain. However, electrically evoked pain was not significantly different between SCI patients. Thus, SCI-induced enhanced excitability of nociceptive processing does not necessarily lead to neuropathic pain. QST and LEP revealed no crucial role of deafferentation for hypersensitivity development after SCI.

The Osteoarthritis Knee Model: Psychophysical Characteristics and Putative Outcomes

The knee osteoarthritis (KOA) model is a convenient and coherent archetype that is frequently used in pharmaceutical trials of drugs with analgesic and/or anti-inflammatory properties; yet, little is known about its specific pathophysiology. The presumed chronic inflammatory etiology of osteoarthritis suggests that nociceptive processes and neurogenic inflammation predominate in this condition. However, most chronic pain conditions are associated with changes in peripheral and central processing. Recent data corroborate this as an important mechanism in KOA. We compared psychophysical characteristics (including thermal Quantitative Sensory Testing); thermal, mechanical, and functional wind-up; thermal and mechanical aftersensations; and pressure algometry of 37 subjects with KOA with 35 age- and sex-matched controls. A third of the KOA subjects demonstrated hypoesthesia to vibration and the 4.56 von Frey fiber, yet few showed allodynia in their worse knee. The majority of subjects had abnormalities to pinprick (41% were hyperalgesic and 27% were hypoesthetic). Compared to controls, the more painful knee was hypoesthetic to cold detection and had greater thermal wind-up, lower pressure-pain thresholds, thermal and mechanical aftersensations, and twice the pain ratings of controls after stair climb. Substantial intraindividual differences were found in KOA subjects and controls for mechanical wind-up and algometric thresholds.PerspectiveThese results develop the KOA model and suggest mechanistic hypotheses. Certain of these tests may ultimately prove to be responsive, quasi-objective, and quantitative outcomes for research and lend empirical support to the notion of measurable sensitization in osteoarthritis.     

Selective reduction of second pain sensations by systemic morphine in humans

A variety of forms of painful stimulation were delivered to human subjects in order to determine whether therapeutic dosages of systemic morphine might produce significant attenuation of some forms of phasic pain that are tolerable for experimental usage. Consistent with previous reports, simple application of thermal or electrical energy to the skin (for 3 sec) produced sensations of pain that were not significantly reduced by prior administration of morphine. Similarly, subjects that were trained to focus their attention on the magnitude of the immediate (first) pain sensation evoked by brief electrical or mechanical stimulation did not report reduction by morphine of pain attributed to conduction in myelinated peripheral nociceptors. In contrast, the magnitude of late (second) pain sensations produced by brief pulses of electrical, thermal or mechanical stimuli to the same subjects was consistently reduced significantly by doses of 5 or 10 mg of morphine. The simplest interpretation of the effect on second pain intensity is that morphine preferentially attenuates input from unmyelinated nociceptors. This conclusion was reinforced by an experiment in which chemicals were applied to the skin. Morphine reduced pain produced by capsaicin (presumed to selectively excite unmyelinated peripheral afferents) but did not diminish pain elicited by bradykinin (presumed to excite A delta and C nociceptors). Comparing long duration pains from chemical stimulation (lasting in excess of 5 min) with briefer pains elicited by 50 msec to 3 sec of stimulation did not support the notion that morphine acts selectively on tonic pain. Also, after-sensations that could be discerned following second pain were not eliminated by morphine, and paired pulse facilitation of first pain sensations remained after administration of morphine, indicating that temporal summation is not preferentially reduced. Regardless of duration, frequency or latency, pain arising exclusively from unmyelinated nociceptors was attenuated substantially, but other elicited sensations were not reliably affected. For example, detection thresholds for warmth were unaffected by morphine, demonstrating that input from all unmyelinated afferents is not reduced.     

Cortical representation of pain: functional characterization of nociceptive areas near the lateral sulcus

Many lines of evidence implicate the somatosensory areas near the lateral sulcus (Sylvian fissure) in the cortical representation of pain. Anatomical tracing studies in the monkey show nociceptive projection pathways to the vicinity of the secondary somatosensory cortex in the parietal operculum, and to anterior parts of insular cortex deep inside the Sylvian fissure. Clinical observations demonstrate alterations in pain sensation following lesions in these two areas in human parasylvian cortex. Imaging studies in humans reveal increased blood flow in parasylvian cortex, both contralaterally and ipsilaterally, in response to painful stimuli. Painful stimuli (such as laser radiant heat) evoke potentials with a scalp maximum at anterior temporal positions (T3 and T4). Several dipole source analyses as well as subdural recordings have confirmed that the earliest evoked potential following painful laser stimulation of the skin derives from sources in the parietal operculum. Thus, imaging and electrophysiological studies in humans suggest that parasylvian cortex is activated by painful stimuli, and is one of the first cortical relay stations in the central processing of these stimuli. There is mounting evidence for closely located but separate representations of pain (deep parietal operculum and anterior insula) and touch (secondary somatosensory cortex and posterior insula) in parasylvian cortex. This anatomical separation may be one of the reasons why single unit recordings of nociceptive neurons are scarce within regions comprising low-threshold mechanoreceptive neurons. The functional significance (sensory-discriminative, affective-motivational, cognitive-evaluative) of the closely spaced parasylvian cortical areas in acute and chronic pain is only poorly understood. It is likely that some of these areas are involved in sensory-limbic projection pathways that may subserve the recognition of potentially tissue damaging stimuli as well as pain memory.     

Dynamic mechanical allodynia following finger amputation: Unexpected skin hyperinnervation

The development of chronic pain after amputations is not an uncommon event. In some cases the most disabling problem is represented by the symptom called dynamic mechanical allodynia, characterized by the painful sensation evoked by gently stroking the skin. Despite the growing interest in understanding pain mechanisms, little is known about the mechanism sustaining this peculiar type of pain. We present here the case of a 53-year-old female patient who complained of severe tactile allodynia in the hand after amputation of her left second finger, resistant to several medical and surgical treatments. In order to gain information about the pain mechanism, two neurodiagnostic skin biopsies were obtained from the area of tactile allodynia and from the contralateral, normal skin area. Skin biopsies showed an unexpected increased innervation of the allodynic skin compared to the contralateral, normal skin area (+ 80.1%). Hyperinnervation has been proposed as a mechanism of pain following nerve lesions, but the increased innervation described here could be also attributed to neuronal plasticity occurring in chronic inflammatory conditions. Independently from the uncertain cause of the epidermal hyperinnervation, in this patient we tried to reduce the elevated number of epidermal nerve fibres by treating the skin with topical capsaicin (0.075%) three times a day, and obtained a persistent pain relief. In conclusion, neurodiagnostic skin biopsy might represent an useful tool for detecting derangements of epidermal innervation in patients with dynamic mechanical allodynia and can help to select an individually tailored therapeutic strategy in such difficult clinical conditions. Further studies are needed to clarify this issue and try to gain better understanding of chronic pain mechanisms in patients who underwent finger amputation.     

Neuronal Hyperexcitability: A Substrate for Central Neuropathic Pain After Spinal Cord Injury

Neuronal hyperexcitability produces enhanced pain transmission in the spinal dorsal horn after spinal cord injury (SCI). Spontaneous and evoked neuronal excitability normally are well controlled by neural circuits. However, SCI produces maladaptive synaptic circuits in the spinal dorsal horn that result in neuronal hyperexcitability. After SCI, activated primary afferent neurons produce enhanced release of glutamate, neuropeptides, adenosine triphosphate, and proinflammatory cytokines, which are known to be major components for pain transmission in the spinal dorsal horn. Enhanced neurochemical events contribute to neuronal hyperexcitability, and neuroanatomical changes also contribute to maladaptive synaptic circuits and neuronal hyperexcitability. These neurochemical and neuroanatomical changes produce enhanced cellular signaling cascades that ensure persistently enhanced pain transmission. This review describes altered neurochemical and neuroanatomical contributions on neuronal hyperexcitability in the spinal dorsal horn, which serve as substrates for central neuropathic pain after SCI.     

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)     

Low intensity vagal nerve stimulation lowers human thermal pain thresholds

The effect of vagal nerve stimulation (VNS) on thermal pain sensation was studied in eight subjects who had vagal nerve stimulators surgically implanted for purposes of seizure control. Prior to their involvement in the study, all subjects had the intensity of their VNS (30 Hz, 0.5 ms, 1.0-2.75 mA) adjusted upwards until achieving their desired clinical effect of reduced seizures. Thermal pain thresholds were determined using a Medoc TSA-2001 with a thermode applied to the skin of the forearm. During VNS at settings 100% of those used clinically to control their seizures, subjects showed a statistically significant decrease in their thermal pain threshold of 1.1+/-0.4 degrees C. Acute effects of graded VNS on thermal pain thresholds were determined in seven of the subjects after cessation of chronic VNS. Two thermal threshold measurements were obtained while the subject received sham stimulation (0 mA intensity), during tactile control stimulation and during 30 s of VNS at intensities approximately 33, 66 and 100% of the settings utilized to control their seizures. Tactile control stimulation was provided by electrical stimulation of the skin of the ankle with the intensity adjusted by the patient to match the intensity of any sensations felt in the neck during VNS. Subjects were not aware of the settings employed. Their stimulator was adjusted with each trial and an ascending/descending ordering of intensity was utilized with an inter-trial interval of 2 min. Thermal pain thresholds were significantly decreased in relation to tactile control stimulation at all intensities of VNS tested with the greatest effect occurring at the 66% level. Subjects were also monitored non-invasively and hemodynamic responses to VNS were determined. No significant alterations in hemodynamic variables were observed. The findings of this human study are consistent with experiments in non-human animals which demonstrate a pro-nociceptive effect of low intensity VNS.