Cutaneous Pain Research Articles

Use of a prostacyclin analogue in cholesterol crystal embolism

The prognosis of cholesterol embolism is often poor, and no treatment is presently available. We report the use of a stable prostacyclin analogue in treating cholesterol embolism in a diabetic patient with arteriopathy. As a sole therapy, it improved cutaneous manifestations and pain, in parallel with an increased transcutaneous oxymetry. We think that prostacyclin analogues are novel candidates for the treatment of cholesterol embolism.

Changes in Ib heteronymous inhibition to soleus motoneurones during cutaneous and muscle nociceptive stimulation in humans

The effects of selective tonic cutaneous and muscle pain stimulation on heteronymous Ib pathways from the gastrocnemius medialis to the soleus motoneurones were studied in five healthy human subjects. Tonic pain stimulation, monitored by a psychophysical method, was obtained by local injection of 60 mg levo-ascorbic acid (L-AS) in a volume of 0.3 ml. Nociceptive cutaneous and muscle stimulation of the dorsal foot produced opposite, long-lasting changes in heteronymous Ib pathways to soleus motoneurones: Ib facilitation during cutaneous stimulation was reversed by disinhibition during muscle stimulation. The time-course of these Ib changes strictly paralleled that of subjective pain sensation. On the contrary, when the same nociceptive stimuli were applied to the leg (at pretibial level), the differences between cutaneous and muscle pain disappeared and similar short-lasting phases of facilitation and inhibition of Ib activity were observed. It is concluded that tonic discharge of cutaneous and muscle nociceptive afferents arising from the foot have specific and opposite effects on Ib inhibitory pathways to ankle extensor motoneurones. These interactions between muscle and cutaneous nociceptive and Ib pathways may be used to change muscle synergies, thus contributing to the establishment of appropriate adaptive locomotor strategies during pain.

The nerve of these nerves!

O ur Focus article dealt with a possible locus of spontaneous and movement-induced pain following nerve injury, not the enhanced and spontaneous cutaneous pain remote from an injury site. Most of the evidence Sorkin et al. present is from behavioral studies that measure distal symptoms such as these. Thus, the data collected in this fashion do not detract from the notion that local nerve damage leads to local nociception , possibly amplified by known nerve regrowth mechanisms. Nonetheless, we agree that much work remains to be performed on nervi nervorum (NN), including their density, distribution, and response to specific injury. Observations of patients with radicular pain suggest that tumor necrosis factor alpha (TNF) is not always involved in neuropathic pain. Leg pain associated with back pain can be made worse by the straight-leg-raising test or other movements that stretch involved nerves. These movements are not painful in normal humans, innocuous to a normal nerve, and not sufficient to elicit discharge from normal NN [2]. The pain begins and ends at a specific angle of the test. This response pattern is not consistent with ectopic activity induced by TNF as described in the work of Sorkin et al. [13]. The response is consistent with local, abnormal nociceptor activity, and the NN are certainly likely candidates. Tests like these produce excursions of 0-5 mm of spinal nerves at 90° [4], not enough to cause the straightening

A longitudinal study of somesthetic perceptual disorders in an individual with a unilateral thalamic lesion

Several aspects of tactile, thermal and pain perception were evaluated in an individual (R.S.) with a hemorrhagic lesion centered in her left lateral thalamus. Over a 4-year period, psychophysical evaluations were undertaken every 6–8 months, and five magnetic resonance (MR) studies were conducted. Early tests (1991–1992) revealed large contralateral deficits in R.S.'s perception of touch, innocuous temperature, and mechanically evoked cutaneous pain –more so for the upper versus the lower extremity. R.S. showed a similar pattern for heat pain sensitivity, but a more modest deficit than for mechanically evoked pain. She showed a deficit for cold pain sensitivity on her foot, but not for her hand. Thresholds for all types of stimuli ipsilateral to the lesion were within a normative range. Late in 1993, R.S. demonstrated improvements in sensory capacity for touch and mechanically evoked pain contralaterally, although deficits were still evident. During the same period, heat pain sensitivity improved contralaterally, and strikingly, a permanent, ipsilateral hypersensitivity to heat pain developed in her hand. Throughout the entire testing period, R.S.'s ratings of perceived unpleasantness matched the patterns of perceived pain intensity. Thus, the discriminative and the affective dimensions of her pain would change in tandem. However, perceptible innocuous thermal stimuli evoked no affective response when applied contralaterally, despite being described as pleasant when presented ipsilaterally. Throughout the testing period, R.S. reported a persistent numbness on her right hemi-body. Only during a 3-month period in 1995 did she experience spontaneous pain, which was referred to her right foot. The only change in psychophysical performance related to her right foot was a transient but intense thermal allodynia several months prior to her spontaneous pain. The MR studies over this 4-year period showed changes in the extent of edema, gliosis and/or ischemia that could be related to perceptual changes. Thus, the conspicuous observations in this thalamic lesion case were: (i) differential effects upon the various pain modalities (mechanical, heat and cold); (ii) development of thermal allodynia without mechanical allodynia, including an ipsilateral effect; (iii) a deficit in positive affective responses to temperature; and (iv) the different time courses for changes in evoked somesthetic capacity versus spontaneous paresthesias and pathological pain.

The relationship between resting systolic blood pressure and cutaneous pain perception in cardiac patients with angina pectoris and controls

In order to determine the influence of resting systolic blood pressure and stable angina on cutaneous pain perception, we studied 19 male cardiac patients with stable angina and 16 male controls. Pain perception was measured using a suprathreshold evaluation of pain intensity and pain unpleasantness to a series of thermal stimuli. We found that men with higher resting blood pressure had a decrease in the perception of pain intensity and pain unpleasantness. Similarly, we found that patients with stable angina perceived pain as less intense and unpleasant than controls. These differences in pain perception may be associated with different pain mechanisms: in the case of blood pressure, differences in opioid activity and baroreceptor-regulated pain systems; in the case of stable angina, patients may adapt to continued experiences of pain, altering internal frames of reference.

Lack of local anaesthetic efficacy of Sarapin in the abaxial sesamoid block model.

Sarapin is a distillate of the pitcher plant that has long been used in human and veterinary medicine for 'regional analgesia'. The mechanism of the reported analgesic response is unknown; however, the agent is purported to provide more effective analgesia for slow, chronic pain than for sharp, acute pain. Reportedly, Sarapin is also widely used as an analgesic agent in the horse, generally in combination with corticosteroids and other agents. To determine its local anaesthetic efficacy in the horse, we tested Sarapin in a unilateral abaxial sesamoid block model at two dose levels, 2 mL and 10 mL per site, respectively. Cutaneous pain was induced with a light/heat lamp, and analgesia was assessed by measuring the hoof-withdrawal reflex latency period. Neither dose of Sarapin altered hoof-withdrawal reflex latency in this experimental model tested over a two-week period. Based on the demonstrated efficacy of this local anaesthetic model, it seems clear that Sarapin has no significant classical local anaesthetic actions in the horse, and probably not in other species either.

Phototoxic Reactions Caused by Sodium Fluorescein

To report three cases of phototoxic reactions to intravenous fluorescein for retinal angiography and to describe provocative testing in a volunteer. Three patients with phototoxic reactions were interviewed, and one volunteer underwent a controlled challenge test by applying a potent sunscreen and exposing skin areas to direct sunlight before and after fluorescein administration. All patients experienced marked cutaneous erythema, edema, and pain to sun-exposed areas within 1 hour of exposure. The reaction faded during a variable period of time, and one case resulted in mild epidermal desquamation and prolonged discomfort. We noted minimal skin changes in the volunteer who was exposed to the sun before fluorescein administration; however, marked blanching erythema and pain were noted after fluorescein administration and sunlight. Consistent with its in vitro properties as a photodynamic dye, fluorescein may rarely act as a phototoxic agent in humans at doses employed for fluorescein angiography.

Spatial summation of perceived pressure, sharpness and mechanically evoked cutaneous pain

Psychophysically, spatial summation can be demonstrated as a decrease in threshold accompanying an increased field of stimulation. The present study examined to what extent different mechanically evoked percepts (pressure, sharpness, and pain) show spatial summation. Various probes were used to apply prescribed forces to the dorsal surface of the digits of 19 healthy subjects. The threshold for three perceptual qualities showed differing degrees of spatial summation: sharpness showed no statistically significant spatial summation; pain demonstrated some significant summation (46% on average); pressure showed the greatest degree of spatial summation (76% on average). The lack of significant spatial summation for sharpness threshold is consistent with the theory that perceived sharpness can be evoked by near threshold activity of a single nociceptor. The modest amount of spatial summation for pain implies that distinctly suprathreshold activation of nociceptors is required for mechanically evoked pain perception, and such input summates centrally, but not completely. The greater spatial summation observed for pressure vs. pain thresholds implies a greater degree of central summation for slowly adapting mechanoreceptors vs. nociceptors.

Influence of selective nerve fiber blocks on argon laser-induced thermal pain in the human skin

Influence of selective nerve fiber blocks on cutaneous pain induced by short argon laser pulses was studied in healthy humans. The minimal energy per surface area needed to produce a pain sensation was lower with a larger stimulus surface indicating spatial summation. Both compression of the peripheral nerve innervating the stimulus site (A-fiber block) and prolonged topical treatment of the stimulus site with 1% capsaicin (a predominant block of nociceptive C-fibers) produced an elevation of the pain threshold. Prolonged capsaicin treatment produced significantly higher pain thresholds than the compression block. Magnitude of the pain threshold elevation induced by nerve blocks varied depending on the area of the stimulus surface. Especially following prolonged capsaicin treatment, pain threshold elevations tended to be smaller with the larger area of the stimulus surface suggesting an enhanced spatial summation effect. Tactile thresholds were significantly elevated only by the compression block. The results indicate that nociceptive C-fibers have a significant contribution to the threshold sensation of pain induced by argon laser. Moreover, following impairment of function in nociceptive C-fibers, the spatial summation of argon laser-induced pain tends to be enhanced.

Sympathectomy does not influence experimental itch and cutaneous temperature perception thresholds.

The effect of endoscopic thoracic sympathectomy on experimentally histamine-induced itch was studied in seven patients, all of whom were suffering from palmar hyperhidrosis; cutaneous warm, cold, and heat pain perception thresholds were also studied in five of these seven patients. Surgery was effective in abolishing palmar sweating in all patients. No significant differences were seen in itch, flare, wheal, or thermal perception thresholds following sympathectomy as compared to the preoperative period. These findings suggest that the sympathetic system may be of limited importance for somatosensory perception in healthy humans during normal conditions.

Chapter 2. Cutaneous polymodal receptors: characteristics and plasticity

The cutaneous sensory units labeled C-fiber polymodal nociceptors have a broadly coherent set of responsive characteristics. These include; (a) elevated thresholds to mechanical stimulation and to heat; (b) excitation by irritant and algesic chemicals; and (c) sensitization by injury or algesic substances. These characteristics and the match between the signals produced by C-polymodal nociceptors to pain-causing stimuli and human reports of pain indicate a probable causal connection. Nevertheless, there are indications that this population of sensory units may contain functionally-distinct subtypes. Some human C-polymodal nociceptors have been reported to be excited by histamine at low concentrations, whereas much of the population lacks such responsiveness. Further, in vitro studies of the effects of non-steroidal anti-inflammatory agents and low pH on sensitization suggest distinctions in the responsiveness of different elements whose general characteristics place them into the C-polymodal category. The enhanced responsiveness of C-polymodal nociceptors after heat stimulation or exposure to acidity has a probable relationship to the primary hyperalgesia produced after injury to hairy skin or in the presence of inflammation. Furthermore, the alterations of C-polymodal nociceptor characteristics after partial nerve injury and sympathectomy imply a change in phenotype of neurons spared by denervation and are suggestive of a possible relationship to sympathetically related pain and post-sympathetic neuralgias. These evidences of plasticity in responsiveness of a set of sense organs putatively associated with cutaneous pain represent lessons in the adaptability of biological mechanisms, and clues to the pathophysiology of pain.

Dose-dependent competitive block by topical acetylsalicylic and salicylic acid of low pH-induced cutaneous pain

In a human acid pain model, which uses continuous intradermal pressure infusion of a phosphate-buffered solution (pH 5.2) to induce localized non-adapting pain, the flow was adjusted to result in constant pain ratings of about 20% or 50% on a visual analog scale (VAS). Six volunteers in each group participated in 4 different placebo-controlled double-blind cross-over studies to measure rapidly evolving cutaneous analgesia from topically applied new ointment formulations of acetylsalicylic acid (ASA) and salicylic acid (SA) as well as of commercial ibuprofen and benzocain creams. Similar, log-linear dose-response curves were found for both ASA and SA, significant in effect at 3 g/ kg and higher drug contents and reaching saturation level at 15 or 30 g/ kg, respectively, which, 20 min after application, caused a mean pain suppression of 95% using ASA and 80% using SA. Half-maximal effects were achieved using 3 g/kg ASA or 15 g/kg SA. The SA action was also clearly slower to develop. With an increased flow of the acidic buffer, producing lower effective tissue pH and more intense pain, the effect of ASA and SA decreased to 73% pain suppression. A competitive mechanism of both drug effects was suggested by the fact that, with 15 g/kg ASA and SA, pain reduction could be reversed by increasing the buffer flow by a factor of 1.75., on average. Commercial ibuprofen (50 g/kg) and benzocain creams (100 g/kg) were comparably as effective as ASA and SA, but the local anesthetic caused a loss of all cutaneous sensations while the touch threshold (von Frey) under the specific analgesics was the same as under the placebo ointment. Thus, topical applications of non-steroidal anti-inflammatory drugs (NSAIDs) dissolved in different ointment formulations have proven dose-dependently effective and specific in suppressing experimental acidotic pain by a local and competitive mechanism.

PS-38-4 Unique characteristics in the SEP recovery function for the pudendal nerve

We recorded electrically stimulated somatosensory evoked potentials (electric SEPs) and pain-related SEPs following CO2 laser stimulation (CO2 laser SEPs) from a 17-year-old patient affected by myotonic dystrophy whose MRI disclosed a large syrinx extending from spinal level C2 to S3. Careful clinical and electromyographic examinations revealed no motor or sensory disturbances, apart from myotonia. The only abnormality noted in median and ulnar nerve short-latency electric SEPs (recorded with a non-cephalic reference electrode) was the absence of cervical component N13, the other SEP responses (N9, N10, N11, P14, N20) being normal. The cutaneous pain threshold and CO2 laser SEPs (both obtained by a CO2 laser beam applied to the back of the hand) were normal. Thus cervical component N13 appears to be highly sensitive to the effects of central cord lesions, even when these are asymptomatic.

Cutaneous localisation of laser induced pain in humans

Localisation of painful laser-induced stimuli has been compared to localisation of tactile stimuli in normal humans. Laser stimulation evoked pain of two qualities (sharp pricking pain and hot burning pain). Sharp pricking pain was found to be localised with almost equal precision to tactile stimuli (13.8 ± 3.4 versus 11.6 ± 2.3 mm) on the dorsum of the hand, (21.5 ± 7.9 versus 20.6 ± 7.5 mm) on the forearm and (15.5 ± 5.6 versus 13.8 ± 5.4 mm) on the foot, respectively. There was no significant difference between the ability to localise tactile stimuli and hot burning pain except on the dorsum of the hand. These results indicate that tactile information is not essential for the accurate localisation of cutaneous pain.

Functional changes in dorsal root ganglion cells after chronic nerve constriction in the rat

1. We studied the effects of a chronic nerve constriction on the evoked responses in dorsal root fibers in the rat to norepinephrine and to thermal stimuli applied either to the dorsal root ganglion (DRG) or the site of nerve injury. We recorded a total of 59 C fibers, 15 A delta-fibers, and 46 A beta-fibers from the L5 dorsal root of the rats 11-52 days after a loose ligation of the ipsilateral sciatic nerve. Most fibers were identified by the presence of spontaneous activity (SA) that originated partially at and/or proximal to the injury site. In addition, we recorded 20 C fibers, 1 A delta-fiber, and 28 A beta-fibers from the dorsal roots of normal, uninjured neurons. 2. In nerve-injured rats, the SA of some C fibers was generally increased by cooling and decreased by heating either site. In contrast, the SA of most A beta-fibers was increased by heating either the injury site or the DRG. Cooling the DRG decreased SA in A beta-fibers, whereas cooling the injury site typically had no effect. Excitatory responses were not evoked in any fiber group when the same thermal stimuli were applied to the nerve or DRG tested in normal, uninjured rats. 3. Norepinephrine (< 0.5 mM) applied either to the injury site or the DRG increased the SA of most C fibers and A delta-fibers but only a minority of A beta-fibers in previously injured nerves. The threshold concentration for excitation of the DRG somata of C fibers was 0.01 mM. No effects were found for fibers in uninjured nerves. 4. The effect of norepinephrine was blocked by a pretreatment with yohimbine, an alpha 2-blocker, but not with prazosin, an alpha 1-blocker. 5. Stimulation of the sympathetic trunk (L2-L3) excited most C fibers and a minority of A beta-fibers. In contrast, the SA of a minority of C fibers and A beta-fibers was depressed during sympathetic stimulation. 6. After a chronic nerve constriction the DRG becomes a source of abnormal activity modulated by sympathetically released norepinephrine acting on alpha 2 receptors in DRG somata. This neuropathic activity may contribute to cutaneous pain and hyperalgesia.

Neurologic Evaluation of the Rat during Sciatic Nerve Block with Lidocaine

Quantitative behavioral testing is necessary to establish a reproducible measure of differential functional blockade during regional anesthesia. Methods for assessment of the neurologic status (mental status, posture, gait, proprioception, motor function, autonomic function, and nociception) in veterinary neurology were adapted for the rat and used to monitor functional changes separately during a sciatic nerve block. Sprague-Dawley rats were acclimated to laboratory routine before the study so that lidocaine (0.1 ml, 1%) could be injected near the sciatic notch without any chemical restraint. The onset, duration, and magnitude of functional losses were monitored. Proprioceptive integrity was evaluated by assessing the response to tactile placing and the hopping response. Extensor postural thrust, a test for postural reactions in small animals, was assessed on a digital balance and found adequate for quantifying motor function. Analgesia was assessed by measuring withdrawal response latencies to noxious thermal stimulation (51 degrees C) and to superficial and deep noxious pinches. Autonomic function was monitored by measuring skin temperature. Contralateral limb function was used as an internal control, and injection of saline was used as an external control in separate, control animals. Onset of postural and gait abnormalities were observed as early as 40 s after injection. On each occasion proprioceptive impairment was detected first, followed by impairment of motor function and nociception. Complete absence of proprioception occurred from 10 to 30 min (n = 9) and of motor function at 30 min after injection (n = 10); both functions were fully recovered by 120 min. A unilateral increase in skin temperature on the foot was detected by 1 min; had reached its maximum change, 5.3 +/- 0.7 degrees C, at 10 min; and had returned to control levels at 60 min after injection (n = 12). Withdrawal response to cutaneous or superficial pain was absent in all ten animals from 5 to 30 min whereas the response to deep pain was absent in all ten animals at 20 min only. The response to noxious stimulation recovered at 90 min. Attention was paid to the temporal relation of the impairment of various functions. Quantitative observations of the onset, offset, and intensity of differential functional impairment or block over time will make it possible to establish the doses and conditions for local anesthetics that result in differential nerve block and will permit comparison of these changes among different drugs and "clinical" protocols.

Exposure to oscillating magnetic fields influences sensitivity to electrical stimuli. II. experiments on humans

To assess the effect of a magnetic treatment on pain perception, we compared the sensory threshold in 18 healthy volunteers. We determined the threshold by noninvasive electrical stimulation of the tooth pulp and skin before and after exposure to an altered magnetic field of low intensity and to a sham treatment. Five different parameters were recorded: the sensory and pain thresholds for the tooth and the sensory, pain, and tolerance thresholds for the skin. Two hours of exposure to a weak, oscillating magnetic fields induced a significant decrease in three parameters (dental sensory and cutaneous pain and tolerance thresholds), whereas the other two parameters showed a similar tendency. When the same subjects were exposed to a sham treatment, only marginal, nonsignificant variations in all parameters were observed. These results represent the first piece of evidence that weak alterations of the magnetic field may induce hyperalgesia in humans.

Validation of cutaneous stimulation interventions for pain management

The purpose of this study was to identify and validate specific activities considered important in the implementation of selected cutaneous stimulation pain management interventions including heat and cold application, massage and Transcutaneous Electrical Nerve Stimulation (TENS). A two-round Delphi survey was completed by nurses selected for their expertise in pain management. Data were analyzed using a modification of Fehring's diagnostic content validity method. Consistently high scores were obtained by the raters for each intervention and activity, with most activities perceived as critical to the intervention. From this process, a list of activities for each cutaneous stimulation intervention evolved that are applicable to education, clinical practice and clinical nursing research.

Convergence of deep somatic and visceral nociceptive information onto a discrete ventrolateral midbrain periaqueductal gray region

Pain arising from deep structures (muscles, joints, viscera) is the type of pain of most clinical relevance and also the type of pain about whose central representation we have the least knowledge. In contrast to cutaneous pain which evokes defensive behaviours, hypertension and tachycardia, the physiological reactions to most deep pain (especially if persistent) usually include quiescence, hypotension, bradycardia and decreased reactivity to the environment. Excitation of neurons within a discrete ventrolateral midbrain periaqueductal gray region evokes a reaction seemingly identical to that evoked by pain arising from deep structures. We report here, using the technique of the noxious stimulus-evoked expression of the immediateearly gene, c-fos, that neurons within this same ventrolateral periaqneductal gray region are selectively activated by a range of deep somatic and visceral nociceptive manipulations. Thus we have identified a specific brain region that both receives convergent, deep somatic and visceral nociceptive input, and which mediates the behavioural and physiological reactions characteristic of most deep pain.

Distribution of fos-like immunoreactivity in the medullary and upper cervical dorsal horn produced by stimulation of dural blood vessels in the rat

Neurophysiological studies have generally failed to find evidence of a specific ascending pathway for visceral nociception. However, pain that arises from deep or visceral tissues typically differs from cutaneous pain, particularly in its diffuse, poorly localized quality. In this study, the c-fos mapping technique was used in order to investigate possible differences in the distribution of central neurons activated by afferent pathways from cutaneous and deep tissues that may be related to the differing quality of the sensations they evoke. The distribution of neurons in the upper cervical and medullary dorsal horn that displayed fos-like immunoreactivity (fos-LI) was examined following mechanical stimulation of dural blood vessels (transverse and superior sagittal sinuses), and was compared to that found following mechanical, thermal, and chemical stimulation of facial sites. Dural stimulation was carried out Brevital anesthesia in rats that had received a chronic surgical exposure of the transverse and superior sagittal sinuses 2 d earlier. Localized mechanical stimulation of the dural surface of the transverse sinus produced a predominantly ipsilateral increase in the number of fos-LI neurons in the medullary and upper cervical dorsal horn (primarily laminae I and V), and in the transition region between the trigeminal nucleus caudalis and interpolaris. Stimulation of the superior sagittal sinus produced increases in fos-LI labeling that were generally smaller than those produced by transverse sinus stimulation. The distribution of fos-LI labeling in the dorsal horn induced by dural stimulation differed from that induced by facial stimulation in two ways. (1) Dural stimulation produced a more diffuse distribution of fos-LI than facial stimulation in the dorsal horn. Whereas facial stimulation produced a dense, localized zone of fos-LI labeling in the dorsal horn, dural stimulation produced fos-LI labeling that extended from the midlevel of caudalis to C2/C3, and also extended across a large portion of the ventrolateral-to-dorsomedial axis of the dorsal horn. This distribution roughly corresponds to the representation of most of the dorsal half of the head and face. (2) Dural stimulation produced a more restricted laminar distribution of fos-LI labeling than facial stimulation, in that the dural-induced labeling in the superficial dorsal horn was primarily restricted to lamina I, whereas facial stimulation typically induced substantial labeling in both lamina I and the outer part of lamina II. These differences in the central organization of the afferent pathways from dural and facial sites may contribute to the differences in the quality of sensations evoked by these pathways.