Area Of Hyperalgesia Research Articles

The Effects of Intradermal Fentanyl and Ketamine on Capsaicin-Induced Secondary Hyperalgesia and Flare Reaction

In this study, we evaluated the effects of intradermal fentanyl and ketamine on capsaicin-induced hyperalgesia and axon-reflex flare. In addition, we obtained dose-response curves for possible local anesthetic effects. Saline (200 μL) and either fentanyl (1 μg or 10 μg in 200 μL) or ketamine (100 μg or 1000 μg in 200 μL) were injected simultaneously into the central volar forearm of 12 healthy volunteers. Nine minutes later, capsaicin (10 μg in 20 μL) was injected intracutaneously exactly between the two injection sites. Areas of touch-evoked allodynia and pinprick hyperalgesia, as well as intensity of pinprick hyperalgesia at the injection sites and axon-reflex flare, were evaluated. Fentanyl did not affect the area or intensity of secondary hyperalgesia. Only the larger concentration of fentanyl locally diminished axon-reflex flare without affecting mechanical detection thresholds. Inhibitory effects of ketamine on intensity of secondary hyperalgesia and axon reflex flare were observed only in the larger concentration. However, this concentration also clearly elevated mechanical detection thresholds. No inhibitory effects of ketamine in the smaller concentrations were observed. We conclude that fentanyl inhibits neuropeptide release on peripheral application without modulating secondary hyperalgesia. Ketamine failed to inhibit both secondary hyperalgesia and axon reflex flare as long as nonlocal anesthetic concentrations were applied. Implications We investigated the peripheral effects of fentanyl and ketamine on capsaicin-induced hyperalgesia and axon-reflex flare. In large concentrations, the opioid diminished axon-reflex flare without effects on secondary hyperalgesia. We found no evidence for the involvement of endogenous glutamate in secondary hyperalgesia or axon reflex flare.

Effect of sympathetic activity on capsaicin-evoked pain, hyperalgesia, and vasodilatation.

Painful nerve and tissue injuries can be exacerbated by activity in sympathetic neurons. The mechanisms of sympathetically maintained pain (SMP) are unclear. To determine the effect of cutaneous sympathetic activity on pain induced by primary afferent C-nociceptor sensitization with capsaicin in humans. In healthy volunteers capsaicin was applied topically (n = 12) or injected into the forearm skin (n = 10) to induce spontaneous pain, dynamic and punctate mechanical hyperalgesia, and antidromic (axon reflex) vasodilatation (flare). Intensity of pain and hyperalgesia, axon reflex vasodilatation (laser Doppler), and flare size and area of hyperalgesia (planimetry) were assessed. The local skin temperature at the application and measurement sites was kept constant at 35 degrees C. In each individual the analyses were performed during the presence of high and low sympathetic skin activity induced by whole-body cooling and warming with a thermal suit. By this method sympathetic vasoconstrictor activity is modulated in the widest range that can be achieved physiologically. The degree of vasoconstrictor discharge was monitored by measuring skin blood flow (laser Doppler) and temperature (infrared thermometry) at the index finger. The intensity and spatial distribution of capsaicin-evoked spontaneous pain and dynamic and punctate mechanical hyperalgesia were identical during the presence of high and low sympathetic discharge. Antidromic vasodilatation and flare size were significantly diminished when sympathetic vasoconstrictor neurons were excited. Cutaneous sympathetic vasoconstrictor activity does not influence spontaneous pain and mechanical hyperalgesia after capsaicin-induced C-nociceptor sensitization. When using physiologic stimulation of sympathetic activity, the capsaicin model is not useful for elucidating mechanisms of SMP. In neuropathic pain states with SMP, different mechanisms may be present.

Dynamic mechanical allodynia in humans is not mediated by a central presynaptic interaction of A β-mechanoreceptive and nociceptive C-afferents

Recently, Cervero and Laird (NeuroReport, 7 (1996) 526–528; Pain, 68 (1996) 13–23) proposed a new pathophysiological mechanism of dynamic mechanical allodynia in skin. Using the capsaicin pain model in humans, they showed that light mechanical stimulation within an area of secondary mechanical allodynia induces vasodilatation measured by laser-Doppler flowmetry. They suggested that the low-threshold A β-mechanoreceptive fibres depolarize the central terminals of nociceptive primary afferent neurons via interneurons. Consequently, the vasodilatation is produced by impulses conducted antidromically in nociceptive C-axons. The allodynia was proposed to result from depolarization of central terminals of primary afferent neurons with C-fibres with activation of nociceptive dorsal horn neurons. In order to extend these findings, we used the same experimental approach but additionally stimulated the A β-fibres electrically to evoke secondary allodynia during simultaneous monitoring skin blood flow. Twenty microlitres of a 0.5% capsaicin solution was injected intradermally into the dorsal forearm. Skin sites that demonstrated dynamic mechanical allodynia but were not located within the area of primary hyperalgesia and flare were investigated. Ten mm away from a laser-Doppler probe, dynamic mechanical allodynia was induced for 1 min (1) by moving a cotton swab and (2) by electrically stimulating the afferent nerve endings transdermally. Increasing stimulus intensities were applied (0.3–4 mA, 40 Hz, pulse duration 0.2 ms). After intracutaneous injection of capsaicin, light mechanical stimulation elicited a burning painful sensation (numeric analogue scale (NAS) 1.5–3) and concomitant movement artefacts at the laser signal. Antidromic vasodilatation was never observed. In this area of dynamic allodynia, electrical stimulation at stimulus intensities that were not painful before capsaicin injection (A β-stimulation) was now able to elicit a burning painful sensation (NAS 1.5–3). No change in blood flow was detected. When the stimulus intensities were increased reaching levels that were also painful before capsaicin treatment (C-fibre stimulation), an increase in blood flow could be induced showing the time course of an axon reflex vasodilatation. In conclusion, electrical stimulation of A β-fibres in allodynic skin does not induce antidromic vasodilatation. Consequently, interaction of A β-mechanoreceptive fibres and nociceptive C-fibres at a presynaptic level is unlikely to produce antidromically conducted impulses and therefore cannot explain the pathophysiology of mechanical allodynia. Alternatively, it is much more likely that under pathophysiological conditions, activity in A β-fibres may activate nociceptive second-order neurons, i.e. in the spinal cord.

Efecto de la gabapentina en la alodinia buco-facial. Correlación experimental de neuralgia trigeminal

Trigeminal neuralgia is an unilateral alteration of the trigeminal nerve, characterized by recurrent paroxysms of pain in one or more of the nerve's branches. Trigger areas are described in points of the facial skin (allodynia). To evaluate the effects of gabapentin (monotherapy) and associated with carbamazepine in allodynia of trigeminal neuralgia. The effects of these drugs were studied in 14 patients with trigeminal allodynia and with 12 experimental cats, with microelectrodes of multiple connections in the central nervous system and in dental pulp to precipitate pain in injured zones, area of primary hyperalgesia, secondary hyperalgesia and allodynia zone. Unitary registrations and evoked potentials were evaluated in neuronal trigeminal organizations, encephalon, limic system and neocortex. The pairing of innocuous stimulus (allodynia) plus painful stimulus precipitate classic conditioned reflex. Unitary alteration and evoked potentials correlated with learning and memory were evaluated, involving the hippocampus in the results. The allodynia treatment obtains better results with the combined treatment than with the monotherapy. Allodynia can be the result of a neuronal sensitization due to the increment on intracellular calcium facilitating the exocytosis. Changes in the mechano-receptors of low threshold establish communication with nociceptive neurons by a presynaptic mechanism, considering new synaptic and morphologic contacts associated with learning and memory. The major effectiveness in the combined treatment is the base of an association of the gabaergic mechanism of gabapentin and the blockade of sodium and potassium ionic channels by the carbamazepine.

Attenuation of experimental pruritus and mechanically evoked dysesthesiae in an area of cutaneous allodynia

We investigated the effects of tactile allodynia on the itch and mechanically evoked dysesthesiae produced by an intradermal injection of histamine in human volunteers. After an intradermal injection of capsaicin into the volar surface of one forearm, there developed an area of tactile allodynia to stroking and hyperalgesia to pricking the skin. Histamine was then injected simultaneously into the area of allodynia (experimental arm) and into the opposite forearm (control arm). Magnitude estimates of itch were obtained every 15 s for 5 min, and the areas of cutaneous hyperalgesia (pricking-evoked pain), alloknesis (stroking-evoked itch), hyperknesis (pricking-evoked itch) and wheal and flare were measured. The areas of wheal and flare were not significantly different on the two arms. The magnitude of itch and the areas of hyperknesis and alloknesis developed normally on the control arm but were absent or greatly reduced on the experimental arm. Thus, both the itch and the alloknesis and hyperknesis normally induced by histamine were absent or greatly reduced when histamine was injected in an area of capsaicin-induced allodynia. These results are compatible with the hypothesis that activity in capsaicin-sensitive, nociceptive primary afferent neurons evokes a central neuronal inhibitory process that prevents or reduces the itch and mechanically evoked dysesthesiae normally produced by an intradermal injection of histamine.

Intrathecal, but Not Intravenous, Clonidine Reduces Experimental Thermal or Capsaicin-Induced Pain and Hyperalgesia in Normal Volunteers

Clonidine is approved for intraspinal administration in the treatment of neuropathic cancer pain.Some studies have suggested an analgesic effect after systemic clonidine administration. The purpose of this study was to compare the analgesic effects of intrathecal and IV clonidine with acute noxious stimulation and with hyperalgesia from intradermal capsaicin injection in volunteers. Sixteen healthy volunteers received intradermal injections of capsaicin (100 [micro sign]g) before and after the IV or intrathecal injection of clonidine 50 or 150 [micro sign]g in a randomized, double-blind manner. Pain and areas of mechanical hyperalgesia and allodynia were determined at specified intervals. In addition, pain to noxious heat stimulation was determined. The capsaicin injection produced pain, followed by hyperalgesia and allodynia. The intrathecal, but not IV, injection of 150 [micro sign]g of clonidine reduced capsaicin-induced pain and area of hyperalgesia. Intrathecal clonidine (150 [micro sign]g) reduced pain to heat stimulation, whereas IV clonidine did not. The groups did not differ in hemodynamic or sedative effects from clonidine. These data support the value of intraspinal administration of clonidine for the treatment of acute pain and of pain states associated with hyperalgesia. Similarly, they suggest that analgesia from the systemic administration of this [alpha]2-adrenergic agonist, if any, is weak in doses that produce sedation and reduce blood pressure. Implications: To the extent that the experimental pain conditions used in this study reflect those in patients with acute and chronic pain, these data support the spinal rather than IV injection of clonidine for analgesia. (Anesth Analg 1998;87:591-6)

Differential effect of painful heterotopic stimulation on capsaicin-induced pain and allodynia

Painful heterotopic stimulation (HTS) may inhibit experimental and clinical pain, an effect known as diffuse noxious inhibitory control (DNIC). This study examined the effect of painful HTS on capsaicin-induced pain intensity, brush-evoked pain intensity and area of brush-evoked pain in humans. Immersion of the foot into painful cold water significantly reduced capsaicin-induced pain intensity and brush-evoked pain intensity in the contralateral forearm, but did not change area of brush-evoked pain. The observed differential effect on the magnitude of pain and hyperalgesia on the one hand and area of hyperalgesia on the other suggests that the DNIC effect on spinal activity is selective and not general.

Increased capsaicin-induced secondary hyperalgesia as a marker of abnormal sensory activity in patients with fibromyalgia

In this study, capsaicin-induced secondary hyperalgesia was assessed as a marker of abnormal nociceptive processing in patients with fibromyalgia (FM). The area of mechanical secondary hyperalgesia induced by a standard solution of capsaicin placed on the volar forearm was measured in ten patients with FM and the results compared to those obtained in ten patients with rheumatoid arthritis (RA) and ten normal subjects. The area of secondary hyperalgesia was found to be substantially increased in both the FM and RA groups compared with controls. In the FM group the area of hyperalgesia correlated with the overall pain score and with the joint tenderness score. The results suggest that in FM there is enhanced sensitivity of nociceptive neurones at a spinal level, thereby supporting the concept of a generalised disturbance of pain modulation in this disorder.

Capsaicin-induced impairment of tactile spatial discrimination ability in man: indirect evidence for increased receptive fields in human nervous system

The effects of capsaicin was investigated on vibration detection thresholds, touch detection thresholds, mechanically-evoked pain thresholds, two-point discrimination ability, and ability to detect roughness of different stimulation surfaces in the left hands of human volunteers in a double-blind controlled study. Capsaicin cream induced allodynia to mechanical stimulation in both primary and secondary area of hyperalgesia. Capsaicin impaired two-point discrimination ability, and reduced the ability to detect differences of the roughness of various stimulation surfaces only within the capsaicin treated area (area of primary hyperalgesia). These changes were not seen after placebo cream. We conclude that experimental inflammation and related pain impairs spatial discrimination ability which could be due to increases in the receptive fields of neurons in the peripheral and central nervous system (CNS).

Ketamine, an NMDA receptor antagonist, suppresses spatial and temporal properties of burn-induced secondary hyperalgesia in man: a double-blind, cross-over comparison with morphine and placebo

Effects of morphine and ketamine (NMDA receptor antagonist) on temporally summated pain (`wind-up-like pain') and spatial aspects of secondary hyperalgesia were investigated in 12 healthy volunteers. Hyperalgesia was produced by a local 1° burn injury covering 12.5 cm 2 on the medial surface of the calf. Primary hyperalgesia was determined by measuring heat pain detection threshold (HPDT) within the site of injury. Spatial aspects of secondary hyperalgesia present outside the site of injury were quantitated by determination of the areas in which a mechanical punctate (von Frey hair, 50.6 mN), or brush stimuli elicited pain sensation. Temporal aspects of secondary hyperalgesia were determined by repetitively pricking the skin with a standard von Frey hair (834 mN) inducing a `wind-up-like pain'. Morphine 0.15 mg/kg, ketamine 0.15 mg/kg or placebo (NaCl 0.9%) were administrated i.v. on 3 separate days 50 min after the burn injury in a double-blind, placebo controlled, randomised and cross-over design. In all subjects HPDT was significantly reduced within the injured area compared to the pre-injury threshold (primary hyperalgesia). All subjects developed areas of allodynia and hyperalgesia to punctate stimuli and brush stimuli outside the injured area (secondary hyperalgesia). HPDT was not reduced in the area of secondary hyperalgesia. In 95% of the measurements we found a sudden appearance of pain to repeated pricking with a von Frey hair (834 mN) in the area of secondary hyperalgesia (`wind-up-like pain'). Ketamine significantly reduced the area of secondary hyperalgesia both for punctate and brush stimuli in the first measurement 15 min after injection and eight of the 11 subjects reported that the `wind-up-like pain' disappeared. On the measurements 45 and 75 min after ketamine injection, secondary hyperalgesia and `wind-up-like pain' reappeared. Morphine did not significantly change the size of the area of secondary hyperalgesia and did not affect `wind-up-like pain'. Ketamine or morphine did not change thermal detection thresholds. We conclude that spatial and temporal mechanisms, underlying secondary hyperalgesia, are mediated by glutamatergic transmission via NMDA receptors.

Characterisation of capsaicin-induced mechanical hyperalgesia as a marker for altered nociceptive processing in patients with rheumatoid arthritis

Rheumatoid arthritis (RA) is characterised by pain and tenderness not only over inflamed or damaged joints, but also over apparently normal tissues. Experimental models suggest that these features result from changes of sensitivity within both peripheral and central neurones, but direct evidence from human disease is lacking. At present, most clinical studies have evaluated overall pain experience rather than activity within components of the nociceptive pathway. Therefore, the aim of this study was to assess the use of a capsaicin-based technique to quantify changes of neuronal sensitivity in patients with RA. First 20 μl of capsaicin in solution (0.03 mg/ml) was applied topically for 30 min to apparently normal skin on the forearm of control subjects and patients with RA. The subsequent development of mechanical hyperalgesia to pinprick stimuli was then measured at various time points using a 74.4-mN von Frey hair. The relationship between the area of hyperalgesia and a number of clinical measures was determined. Capsaicin-induced mechanical hyperalgesia was found to decline with age in normal subjects ( r=0.47, P<0.01). The development of hyperalgesia had a similar time course in normal subjects and patients with RA. The maximum area of hyperalgesia, however, was substantially larger in 35 RA patients; 254.3±20.7 cm 2, compared with 35 normal controls; 109±7.5 cm 2 ( P<0.001). An association was apparent between hyperalgesic area and a composite score of joint tenderness ( r=0.47, P<0.01), but not with overall pain score or a systemic marker of inflammation. These results provide evidence for enhanced sensitisation of a population of sensory fibres in RA. Peripheral sensory activity over the forearms of rheumatoid patients has previously been shown to be normal and the results suggest the presence of enhanced central mechanisms in this disorder. The correlation between capsaicin-induced hyperalgesia and joint tenderness in the RA patients implies that joint symptoms arise partially as a result of central, and not exclusively peripheral, factors. The study supports the use of capsaicin-based techniques to explore nociceptive mechanisms in clinical disorders characterised by chronic pain.

Elevated tissue levels of interleukin-1β and tumor necrosis factor-α in vulvar vestibulitis

To compare levels of two inflammatory cytokines, interleukin-1 beta(IL-1 beta) and tumor necrosis factor-alpha(TNF-alpha), in selected regions of the vulva, vestibule, and vagina in women with vulvar vestibulitis and in asymptomatic controls. Selective samplings of surgical specimens from 12 women undergoing perineoplasty for vulvar vestibulitis and ten pain-free subjects undergoing posterior vaginal repair were prepared into tissue homogenates and analyzed for concentrations of IL-1 beta and TNF-alpha. Interleukin-1 beta and TNF-alpha concentrations were measured by sandwich enzyme-linked immunosorbent assay. The results were reported after adjustment for total tissue protein concentration. Median tissue levels of IL-1 beta and TNF-alpha were elevated 2.3-fold and 1.8-fold, respectively, in women with vulvar vestibulitis relative to pain-free women. Median IL-1 beta tissue levels were increased significantly from 1.3 pg/mg to 3.0 pg/mg total protein in women with vulvar vestibulitis compared to pain-free women. Median TNF-alpha tissue levels were increased from 83 pg/mg to 148 pg/mg total protein in women with vulvar vestibulitis compared to pain-free women. Analysis by selected anatomic site of women with vulvar vestibulitis revealed a significant 2.2-fold higher median level of TNF alpha at the vulvar site compared to the vestibule. Concentrations of IL-1 beta and TNF-alpha were elevated in women with vulvar vestibulitis relative to those in asymptomatic controls. This elevation in inflammatory cytokines with vulvar vestibulitis varied according to anatomic site and was, paradoxically, lowest in the area of highest hyperalgesia, the vulvar vestibule. Inflammatory cytokine elevation may contribute to the pathophysiology of mucocutaneous hyperalgesia.

Submodality-selective hyperalgesia adjacent to partially injured sciatic nerve in the rat is dependent on capsaicin-sensitive afferent fibers and independent of collateral sprouting or a dorsal root reflex.

We studied submodality dependence of sensory changes produced by unilateral ligation of the sciatic or the saphenous nerve in the rat. We focused especially on sensory changes in the skin area adjacent to the innervation area of the injured nerve. Moreover, we examined the roles of capsaicin-sensitive nociceptive fibers, collateral sprouting and a dorsal root reflex in sensory changes observed behaviorally. Assessment of sensory changes was performed by a pattern of behavioral tests: hot-plate test and hindlimb withdrawal responses induced by radiant heat, hot-water bath, innocuous mechanical stimuli, and noxious mechanical stimuli. In one group, the saphenous nerve ipsilateral to the sciatic ligation was topically treated with capsaicin (1%) at the time of the surgery. A proximal stump of a saphenous nerve strand was orthodromically stimulated to induce a dorsal root reflex (an antidromic volley) in nociceptive fibers of the saphenous nerve trunk. For visualization of plasma extravasation induced by a dorsal root reflex, a dye-labeling (Evans blue) technique was used. A collateral sprouting of nociceptive fibers of the uninjured saphenous nerve was evaluated by determining the plasma extravasation response induced by antidromic stimulation of the saphenous nerve. Three and 10 days following the sciatic constriction injury, the hindlimb withdrawal threshold evoked by noxious mechanical stimulation of the medial side of the paw (the innervation are of the intact saphenous nerve) was significantly decreased. There was no corresponding thermal hyperalgesia adjacent to the injured sciatic nerve. Chronic constriction of the saphenous nerve did not produce any significant hyper- or hypoalgesia to mechanical or thermal stimulation of the uninjured sciatic nerve area. Topical treatment of the ipsilateral (intact) saphenous nerve at the time of the sciatic nerve ligation completely prevented the development of mechanical hyperalgesia in the medial side of the paw (the innervation area of the saphenous nerve). No dorsal root reflex in nociceptive fibers mediating the adjacent hyperalgesia could be evoked. No collateral sprouting of the uninjured nociceptive fibers of the saphenous nerve was observed. The results indicate that the constriction injury of the sciatic nerve produced a selective hyperalgesia to mechanical stimulation in the innervation area of the neighboring saphenous nerve. At the peripheral level, the mechanical hyperalgesia adjacent to the innervation area of the injured nerve was mediated by capsaicin-sensitive nociceptive fibers. Collateral sprouting of nociceptive fibers from the uninjured to the injured innervation area did not contribute to the present sensory findings. The sciatic nerve injury did not induce a dorsal root reflex in nociceptive fibers innervating the hyperalgesic saphenous nerve area.

Innervation of hyperalgesic skin in patients with complex regional pain syndrome.

To look for anatomical and histochemical signs of interaction between sensory and sympathetic nerves in the hyperalgesic skin of patients with complex regional pain syndrome. Skin samples were obtained from eight patients whose condition developed after a suspected or confirmed peripheral nerve injury, and from nine patients with features of reflex sympathetic dystrophy (RSD) following a soft-tissue injury. A skin sample was also obtained from 18 control subjects of similar age and sex distribution to patients. In patients, skin samples were taken from an area of static mechanical hyperalgesia and from an equivalent site in the contralateral limb. In controls, skin samples were obtained from the dorsum of one hand or foot. HISTOCHEMICAL MARKERS: We used neuron-specific enolase for all classes of nerve fiber; tyrosine hydroxylase for noradrenergic fibers; vasoactive intestinal peptide for sympathetic sudomotor fibers; tyrosine hydroxylase co-existing with neuropeptide Y for sympathetic vasoconstrictor fibers; and calcitonin gene-related peptide with substance P or somatostatin for peptide-containing unmyelinated sensory fibers. In patients, the distribution of markers was similar in skin taken from an area of mechanical hyperalgesia and skin taken from an equivalent site contralaterally, and was unrelated to clinical features of RSD. The distribution of markers did not differ between patients and controls. Nerve tangles immunoreactive to neuron-specific enolase, but not to other markers, were detected in samples taken from four patients and two controls. The nerve tangles were present bilaterally in two patients, and only on the affected side in two other patients. The clinical condition was more fully developed in the four patients whose skin samples contained nerve tangles than in most other patients. A major difference in distribution or change in histochemical content of cutaneous autonomic or nociceptor fibers is unlikely to underly static mechanical hyperalgesia following a soft-tissue or peripheral nerve injury. The relevance of cutaneous nerve tangles for the pathophysiology of RSD is uncertain.

Enhanced withdrawal responses to heat and mechanical stimuli following intraplantar injection of capsaicin in rats

Withdrawal responses to heat and mechanical stimuli applied to the plantar surface of the rat hindpaw were measured before and after an intraplantar injection of capsaicin. In separate groups of rats, capsaicin doses of 1, 10 and 30 μg, and the vehicle were given into the center of the plantar surface in a volume of 10 μl. Withdrawal latency evoked by radiant heat and the frequency of withdrawal evoked by mechanical stimuli (von Frey monofilaments) were obtained from both hindpaws before and after injection. Hyperalgesia to heat was defined as a decrease in withdrawal latency and mechanical hyperalgesia was indicated by an increase in withdrawal response frequency. Intraplantar injection of capsaicin evoked nocifensive behavior characterized by lifting and guarding the injected paw which typically lasted up to 3 min following injection. Capsaicin produced a decrease in withdrawal latency to heat and increased the frequency of withdrawal to mechanical stimuli in a dose-dependent manner. These effects were observed on the injected paw only. The duration of hyperalgesia produced by capsaicin was also dose-dependent. Withdrawal latencies to heat were decreased up to 45 min following capsaicin while withdrawal responses to mechanical stimuli remained elevated up to 4 h. The area of mechanical hyperalgesia included most of the plantar surface and extended approximately 9 mm proximal and distal to the injection. Injection of the vehicle did not significantly alter withdrawal responses to heat or mechanical stimuli. These studies demonstrate that intraplantar injection of capsaicin in rats produces hyperalgesia to heat and mechanical stimuli. This model should be useful for correlative behavioral, physiological and pharmacological studies of underlying mechanisms of capsaicin-evoked hyperalgesia.

Capsaicin-evoked mechanical allodynia and hyperalgesia cross nerve territories. Evidence for a central mechanism.

The finding in some patients with neuropathic pain that mechanical allodynia (pain evoked by light touch) and hyperalgesia (supranormal pain evoked by painful stimuli) extend beyond the territory of a single nerve or spinal sensory root (extraterritorial pain) often prompts a diagnosis of psychiatric illness. The hypothesis that focal nociceptive input in a single nerve territory can result in allodynia and hyperalgesia in a nerve territory adjacent to the input was investigated in normal human subjects. On separate days, 13 healthy volunteers each received left radial and ulnar nerve blocks. After block of either nerve, sensation remaining for three classes of afferents (A beta low-threshold mechanoreceptors, A delta nociceptors, and C polymodal nociceptors) allowed inference of the nerve territory of the adjacent nerve, and the area of overlapping innervation. On a third day, 1,000 micrograms intradermal capsaicin was administered into a site such that C-nociceptor input was confined to the ulnar nerve territory. Areas of brush allodynia and pinprick hyperalgesia were determined. Spread of brush allodynia beyond all three borders of the ulnar nerve territory occurred in 9 of 13 patients (for these subjects, range 5-28 mm), whereas spread of pinprick hyperalgesia beyond all borders of the ulnar nerve territory occurred in 12 of 13 subjects (range 1-31 mm). Spread of brush allodynia beyond the A beta border of the ulnar nerve territory occurred in 10 of 13 subjects (range 4-35 mm); and spread of pinprick hyperalgesia beyond the A delta border of the ulnar nerve territory occurred in 12 of 13 subjects (range 1-31 mm). It is concluded that activation of C-nociceptors evokes a state of central sensitization that may manifest itself by the appearance of extraterritorial pain abnormalities.

The effect of Ketamine on stimulation of primary and secondary hyperalgesic areas induced by capsaicin -- a double-blind, placebo-controlled, human experimental study

The non-competitive NMDA-antagonist, Ketamine, was infused (i.v.) in healthy volunteers to study the effect on central excitability with the presence of cutaneous hyperalgesia. Hyperalgesia was established experimentally on the dorsum of the foot by topical application of capsaicin (1%). Different thermal and mechanical conditioning stimuli were applied to the primary and secondary hyperalgesic areas to modulate the central nociceptive excitability monitored by the nociceptive reflex. When the elicited reflex was combined with an activation of the secondary hyperalgesic area by continuous, non-painful, electrical stimulation, a facilitation of the reflex was observed. This indicates that summation of activity in non-nociceptive and nociceptive afferents can occur under mild pathological conditions. Conditioning thermal stimuli of the primary hyperalgesic area were employed to intensify the allodynia prior to testing this interaction between tactile and nociceptive activity. The same reflex facilitation was inhibited by Ketamine. Furthermore, Ketamine decreased the pain intensity associated with the stimuli eliciting the reflex. Psychophysical measures to single and repeated electrical and thermal (laser) stimuli applied within the hyperalgesic areas were also obtained. The intensity of pain sensations produced by single, painful, electrical stimuli applied to the primary hyperalgesic region was reduced after Ketamine infusion. Finally, five repeated, electrical stimuli applied to the secondary hyperalgesic area were used to assess the temporal summation threshold. Ketamine caused an increase in the summation threshold compared to the placebo treatment. In conclusion, these results demonstrate that (1) summation of activity in non-nociceptive and nociceptive afferents occurs under hyperalgesic conditions and, (2) this summation can be inhibited by NMDA-antagonists. Therefore, the study shows an apparent involvement of NMDA-receptors in some of the central mechanisms underlying secondary hyperalgesia.

Different roles of α2-adrenoceptors of the medulla versus the spinal cord in modulation of mustard oil-induced central hyperalgesia in rats

We attempted to determine the roles of spinal versus medullary α 2-adrenoceptors in modulation of central hyperalgesia in rats. Central hyperalgesia was produced by applying mustard oil (50%) to the skin of the ankle of one hindpaw. The threshold for eliciting a hindlimb flexion reflex was determined by applying a series of calibrated monofilaments to the glabrous skin of the hindpaw contralaterally (= control) or ipsilaterally to the mustard oil-treated ankle (= outside the area of primary hyperalgesia). Medetomidine (an α 2-adrenoceptor agonist; 1 μg), atipamezole (an α 2-adrenoceptor antagonist; 2.5 μg) or saline was microinjected into the lateral reticular nucleus of the medulla, the nucleus raphe magnus, or intrathecally to the lumbar spinal cord 12 min before the mustard oil treatment. Following saline injections, mustard oil produced a significant decrease of the hindlimb withdrawal threshold in the mustard oil-treated limb but not in the contralateral limb. Atipamezole in the lateral reticular nucleus produced a complete reversal of the hyperalgesia but no effect on the threshold of the intact limb. However, atipamezole in the raphe magnus nucleus or in the lumbar spinal cord did not produce a significant attenuation of the hyperalgesia. Medetomidine in the spinal cord, but not in the lateral reticular nucleus, reversed the hyperalgesia. At this dose range (up to 3 μg), medetomidine in the spinal cord of nonhyperalgesic control rats did not produce any significant change in the withdrawal response of hindlimbs or in the tail-flick latency. The results indicate that neurogenic inflammation induces significant plastic changes in the function of α 2-adrenergic pain regulatory mechanisms. In rats with mustard oil-induced central hyperalgesia, an α 2-adrenoceptor antagonist produces an antihyperalgesic effect due to an action on the caudal ventrolateral medulla, whereas an α 2-adrenoceptor agonist produces an enhanced antinociceptive effect due to a direct action on the spinal cord.

Clinical Update on Other Pain Syndromes

Objective: To review clinical features, pathophysiology, and management of localized and regional pain syndromes. Findings: Localized pain syndromes often follow tissue damage and are characterized by persisting pain, secondary hyperalgesia, and allodynia. Evidence for ongoing peripheral nociception is lacking, with central [dorsal horn and beyond] sensitization allowing explanation of clinical features. Regional pain syndromes have similar characteristics but involve larger areas of pain, hyperalgesia, and allodynia, usually including the spine. The role of spine-related reflex mechanisms, particularly mechanoreceptor input, seems important. Central sensitization of the dorsal horn pain transmission neurones in localized pain syndromes seems dominated by peripheral nociceptive input, but in regional pain syndromes supraspinal influences appear to play the more important role. Management of both variants needs to be multi- and inter-disciplinary for best results. Conclusions: Pain syndromes limited only t...

Mechanisms of allodynia

We examined whether stimulation of sensitive mechanoreceptors from an area of allodynia evokes nociceptor activity expressed as axon reflexes. Experiments were conducted on human volunteers. Cutaneous blood flow was measured with a laser Doppler flowmeter. Allodynia was induced with mustard oil (25-100%) or by intradermal injections of capsaicin (25-50 micrograms) in the skin of the forearm or the hand. Tactile stimulation of normal skin or outside zones of allodynia did not evoke axon reflexes. The same stimulation in areas of allodynia evoked pain as well as axon reflexes. Cooling the area of primary hyperalgesia or blocking the A fibres in the nerve that innervated the allodynia area abolished the allodynia and the axon reflex. These results demonstrate central interactions between sensitive mechanoreceptors and nociceptors concomitant with the development of allodynia.