Secondary Hyperalgesia In Humans Research Articles

A back-translational study of descending interactions with the induction of hyperalgesia by high-frequency electrical stimulation in rat and human.

In humans and animals, high-frequency electrocutaneous stimulation (HFS) induces an "early long-term potentiation-like" sensitisation, where synaptic plasticity is underpinned by an ill-defined interaction between peripheral input and central modulatory processes. The relative contributions of these processes to the initial pain or nociceptive response likely differ from those that underpin development of the heightened response. To investigate the impact of HFS-induced hyperalgesia on pain and nociception in perception and neural terms, respectively, and to explore the impact of descending inhibitory pathway activation on the development of HFS-induced hyperalgesia, we performed parallel studies utilising identical stimuli to apply HFS concurrent to (1) a conditioned pain modulation paradigm during psychophysical testing in healthy humans or (2) a diffuse noxious inhibitory controls paradigm during in vivo electrophysiological recording of spinal neurones in healthy anaesthetised rats. High-frequency electrocutaneous stimulation alone induced enhanced perceptual responses to pinprick stimuli in cutaneous areas secondary to the area of electrical stimulation in humans and increased the excitability of spinal neurones which exhibited stimulus intensity-dependent coded responses to pinprick stimulation in a manner that tracked with human psychophysics, supporting their translational validity. Application of a distant noxious conditioning stimulus during HFS did not alter perceived primary or secondary hyperalgesia in humans or the development of primary or secondary neuronal hyperexcitability in rats compared with HFS alone, suggesting that, upon HFS-response initiation in a healthy nervous system, excitatory signalling escapes inhibitory control. Therefore, in this model, dampening facilitatory mechanisms rather than augmenting top-down inhibitions could prevent pain development.

Corrigendum to: Capsaicin-Induced Changes in Electrical Pain Perception Threshold Can Be Used to Assess the Magnitude of Secondary Hyperalgesia in Humans.

Corrigendum to: Capsaicin-Induced Changes in Electrical Pain Perception Threshold Can Be Used to Assess the Magnitude of Secondary Hyperalgesia in Humans.

Within- and between-session reliability of secondary hyperalgesia induced by electrical high-frequency stimulation.

An increasing number of studies are focusing on secondary hyperalgesia to better understand central sensitization, as this phenomenon may play an important role in persistent pain. Recent studies have shown that, compared to the classical high-frequency stimulation protocol (HFS) at 100Hz, a protocol using 42Hz stimulation induces a more intense and a larger area of secondary hyperalgesia (SH). The aim of this study was to investigate the within- and between-session reliability of SH induced by this optimized HFS protocol. Thirty-two healthy subjects received HFS to their volar forearm in two sessions, separated by at least 2weeks. SH was assessed by measuring the area size of increased sensitivity to pinprick stimuli after applying HFS, the sensitivity to pinprick stimuli after applying HFS and the change in pinprick sensitivity after versus before HFS. Assessments were made before HFS, and 30, 35 and 40min after HFS. Relative and absolute reliability were analysed using intraclass correlation coefficients (ICCs), coefficients of variation (CVs), standard error of means (SEMs) and the minimum detectable changes (MDCs). The area of SH showed good to excellent within-session and between-session relative reliability (ICCs>0.80), except for the change in pinprick sensitivity, which showed close to poor between-session relative reliability (ICC=0.53). Furthermore, measures of absolute reliability generally demonstrated large between-subject variability and significant fluctuations across repeated measurements. HFS-induced hyperalgesia is suitable to discriminate or compare individuals but it may not be sensitive to changes due to an intervention. It is crucial to evaluate central sensitization adequately in humans. This study formally establishes the reliability of secondary hyperalgesia induced by electrical high-frequency stimulation. The results of this study will improve future studies investigating secondary hyperalgesia in humans.

Capsaicin-Induced Changes in Electrical Pain Perception Threshold Can Be Used to Assess the Magnitude of Secondary Hyperalgesia in Humans.

Areas of secondary hyperalgesia can be assessed using quantitative sensory testing (QST). Delivering noxious electrocutaneous stimulation could provide added benefit by allowing multiple measurements of the magnitude of hyperalgesia. We aimed to characterize the use of electrical pain perception (EPP) thresholds alongside QST as a means by which to measure changes in pain thresholds within an area of secondary mechanical hyperalgesia. EPP and heat pain thresholds (HPTs) were measured at five distinct points at baseline and following 1% capsaicin cream application, one within a central zone and four within a secondary zone. Areas of secondary mechanical hyperalgesia were mapped using QST. In a further 14 participants, capsaicin-induced reduction in EPP thresholds was mapped using a radial lines approach across 24 points. There was a reduction in EPP threshold measured at the four points within the secondary zone, which was within the mapped area of mechanical secondary hyperalgesia. The magnitude of secondary hyperalgesia could be split into a mild (∼4% reduction) and severe (∼21% reduction) area within an individual subject. There was no reduction in HPT within the secondary zone, but there was a reduction in both HPT and EPP threshold within the primary zone. EPP mapping revealed differences in the magnitude and spread of hyperalgesia across all subjects. Measuring capsaicin-induced reduction in EPP thresholds can be used to map hyperalgesic areas in humans. This semi-automated approach allows rapid assessment of the magnitude of hyperalgesia, both within an individual subject and across a study population.

A systematic review of experimental methods to manipulate secondary hyperalgesia in humans: protocol

BackgroundNeuropathic pain affects 7–10% of people, but responds poorly to pharmacotherapy, indicating a need for better treatments. Mechanistic research on neuropathic pain frequently uses human surrogate models of the secondary hyperalgesia that is a common feature of neuropathic pain. Experimentally induced secondary hyperalgesia has been manipulated with pharmacological and non-pharmacological methods to clarify the relative contributions of different mechanisms to secondary hyperalgesia. However, this literature has not been systematically synthesised. The aim of this systematic review is to identify, describe, and compare methods that have been used to manipulate experimentally induced secondary hyperalgesia in healthy humans.MethodsA systematic search strategy will be supplemented by reference list checks and direct contact with identified laboratories to maximise the identification of data reporting the experimental manipulation of experimentally induced secondary hyperalgesia in healthy humans. Duplicated screening, risk of bias assessment, and data extraction procedures will be used. Authors will be asked to provide data as necessary. Data will be pooled and meta-analyses conducted where possible, with subgrouping according to manipulation method. Manipulation methods will be ranked for potency and risk.DiscussionThe results of this review will provide a useful reference for researchers interested in using experimental methods to manipulate secondary hyperalgesia in humans and will help to clarify the relative contributions of different mechanisms to secondary hyperalgesia.Systematic review registrationThis protocol will be registered on PROSPERO before the review begins. Review records will be updated on PROSPERO once the review is complete. This review is intended for publication in a peer-reviewed journal. Analyses and scripts will be made publicly available.

Quickly responding C-fibre nociceptors contribute to heat hypersensitivity in the area of secondary hyperalgesia.

A recent animal study showed that high frequency electrical stimulation (HFS) of C-fibres induces a gliogenic heterosynaptic long-term potentiation at the spinal cord that is hypothesized to mediate secondary hyperalgesia in humans. Here this hypothesis was tested by predominantly activating C-fibre nociceptors in the area of secondary mechanical hyperalgesia induced by HFS in humans. It is shown that heat perception elicited by stimuli predominantly activating C-fibre nociceptors is greater, as compared to the control site, after HFS in the area of secondary mechanical hyperalgesia. This is the first study that confirms in humans the involvement of C-fibre nociceptors in the changes in heat sensitivity in the area of secondary mechanical hyperalgesia induced by HFS. It has recently been shown that high frequency electrical stimulation (HFS) of C-fibres induces a gliogenic heterosynaptic long-term potentiation (LTP) at the spinal cord in animals, which has been hypothesized to be the underlying mechanism of secondary hyperalgesia in humans. Here we tested this hypothesis using a method to predominantly activate quickly responding C-fibre nociceptors in the area of secondary hyperalgesia induced by HFS in humans. HFS was delivered to one of the two volar forearms in 18 healthy volunteers. Before, 20min and 45min after HFS, short-lasting (10ms) high-intensity CO2 laser heat stimuli delivered to a very small area of the skin (0.15mm2 ) were applied to the area of increased mechanical pinprick sensitivity at the HFS-treated arm and the homologous area of the contralateral control arm. During heat stimulation the electroencephalogram, reaction times and intensity of perception (numerical rating scale 0-100) were measured. After HFS, we observed a greater heat sensitivity, an enhancement in the number of detected trials, faster reaction times and an enhancement of the N2 wave of C-fibre laser-evoked potentials at the HFS-treated arm compared to the control arm. This is the first study that confirms in humans the involvement of C-fibre nociceptors in enhanced heat sensitivity in the area of secondary mechanical hyperalgesia induced by HFS.

Discrepancies between cortical and behavioural long-term readouts of hyperalgesia in awake freely moving rats.

BackgroundIt is still unclear to what extent the most common animal models of pain and analgesia, based on indirect measures such as nocifensive behaviours, provide valid measures of pain perception.MethodsTo address this issue, we developed a novel animal model comprising a more direct readout via chronically (>1 month) implanted multichannel electrodes (MCE) in rat primary somatosensory cortex (S1; known to be involved in pain perception in humans) and compared this readout to commonly used behavioural pain‐related measures during development of hyperalgesia. A translational method to induce hyperalgesia, UVB irradiation of the skin, was used. Localized CO 2 laser stimulation was made of twenty skin sites (20 stimulations/site/observation day) on the plantar hind paw, before and during the time period when enhanced pain perception is reported in humans after UVB irradiation.ResultsWe demonstrate a 2–10 fold significant enhancement of cortical activity evoked from both irradiated and adjacent skin and a time course that corresponds to previously reported enhancement of pain magnitude during development of primary and secondary hyperalgesia in humans. In contrast, withdrawal reflexes were only significantly potentiated from the irradiated skin area and this potentiation was significantly delayed as compared to activity in S1.ConclusionsThe present findings provide direct evidence that chronic recordings in S1 in awake animals can offer a powerful, and much sought for, translational model of the perception of pain magnitude during hyperalgesia.What does this study add? In a novel animal model, chronic recordings of nociceptive activity in primary somatosensory cortex (S1) in awake freely moving rats are compared to behavioural readouts during UVB‐induced hyperalgesia. Evoked activity in rat S1 replicates altered pain perception in humans during development of hyperalgesia, but withdrawal reflexes do not.

Is heat pain detection threshold associated with the area of secondary hyperalgesia following brief thermal sensitization? A study of healthy volunteers - design and detailed plan of analysis.

BackgroundSeveral factors are believed to influence the development and experience of pain.Human clinical pain models are central tools, in the investigation of basic physiologic pain responses, and can be applied in patients as well as in healthy volunteers. Each clinical pain model investigates different aspects of the human pain response.Brief thermal sensitization induces a mild burn injury, resulting in development of primary hyperalgesia at the site of stimulation, and secondary hyperalgesia surrounding the site of stimulation. Central sensitization is believed to play an important role in the development of secondary hyperalgesia; however, a possible association of secondary hyperalgesia following brief thermal sensitization and other heat pain models remains unknown. Our aim with this study is to investigate how close the heat pain detection threshold is associated with the size of the area of secondary hyperalgesia induced by the clinical heat pain model: Brief thermal sensitization.Methods and designWe aim to include 120 healthy participants. The participants will be tested on two separate study days with the following procedures: i) Brief thermal sensitization, ii) heat pain detection threshold and iii) pain during thermal stimulation. Additionally, the participants will be tested with the Pain Catastrophizing Scale and Hospital Anxiety and Depression Scale questionnaires.We conducted statistical simulations based on data from our previous study, to estimate an empirical power of 99.9 % with α of 0.05. We define that an R2 < 0.25 and predictive intervals larger than +/−150 cm2 are indications of a weak association.DiscussionThe area of secondary hyperalgesia may serve as a quantitative measure of the central sensitization induced by cutaneous heat stimulation, and thus may be a biomarker of an individual’s pain sensitivity. The number of studies investigating secondary hyperalgesia is growing; however basic knowledge of the physiologic aspects of secondary hyperalgesia in humans is still incomplete. We therefore find it interesting to investigate if HPDT, a known quantitative sensory test, is associated with areas of secondary hyperalgesia following brief thermal sensitizationTrial registrationClinicaltrials.gov (Identifier: NCT02527395). Danish Research Ethics Committee (Identifier: H-8-2014-012). Danish Data Protection Agency (Identifier: 30-1436).Electronic supplementary materialThe online version of this article (doi:10.1186/s12871-016-0193-2) contains supplementary material, which is available to authorized users.

Does Naloxone Reinstate Secondary Hyperalgesia in Humans after Resolution of a Burn Injury? A Placebo-Controlled, Double-Blind, Randomized, Cross-Over Study

IntroductionDevelopment of secondary hyperalgesia following a cutaneous injury is a centrally mediated, robust phenomenon. The pathophysiological role of endogenous opioid signalling to the development of hyperalgesia is unclear. Recent animal studies, carried out after the resolution of inflammatory pain, have demonstrated reinstatement of tactile hypersensitivity following administration of μ-opioid-receptor-antagonists. In the present study in humans, we analyzed the effect of naloxone when given after the resolution of secondary hyperalgesia following a first-degree burn injury.MethodsTwenty-two healthy volunteers were included in this placebo-controlled, randomized, double-blind, cross-over study. Following baseline assessment of thermal and mechanical thresholds, a first-degree burn injury (BI; 47°C, 7 minutes, thermode area 12.5 cm2) was induced on the lower leg. Secondary hyperalgesia areas around the BI-area, and separately produced by brief thermal sensitization on the contralateral thigh (BTS; 45°C, 3 minutes, area 12.5 cm2), were assessed using a polyamide monofilament at pre-BI and 1, 2, and 3 hours post-BI. At 72 hrs, BI and BTS secondary hyperalgesia areas were assessed prior to start of a 30 minutes intravenous infusion of naloxone (total dose 21 microg/kg) or placebo. Fifteen minutes after start of the infusion, BI and BTS secondary hyperalgesia areas were reassessed, along with mechanical and thermal thresholds.ResultsSecondary hyperalgesia areas were demonstrable in all volunteers 1–3 hrs post-BI, but were not demonstrable at 72 hrs post-burn in 73–86% of the subjects. Neither magnitude of secondary hyperalgesia areas nor the mechanical and thermal thresholds were associated with naloxone-treated compared to placebo-treated subjects.ConclusionNaloxone (21 microg/kg) did not reinstate secondary hyperalgesia when administered 72 hours after a first-degree burn injury and did not increase BTS-generated hyperalgesia. The negative results may be due to the low dose of naloxone or insufficient tissue injury to generate latent sensitization.

CENTRAL AND PERIPHERAL MECHANISMS IN INTERSTITIAL SYMPTOMS

No AccessJournal of UrologyEditorials1 Mar 2005CENTRAL AND PERIPHERAL MECHANISMS IN INTERSTITIAL SYMPTOMS Susan K. Lutgendorf and Karl J. Kreder Susan K. LutgendorfSusan K. Lutgendorf More articles by this author and Karl J. KrederKarl J. Kreder More articles by this author View All Author Informationhttps://doi.org/10.1097/01.ju.0000153674.22884.cfAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail "CENTRAL AND PERIPHERAL MECHANISMS IN INTERSTITIAL SYMPTOMS." The Journal of Urology, 173(3), p. 682 References 1 : Effects of an experimental arthritis on the sensory properties of fine articular afferent units. J Neurophysiol1985; 54: 1109. Google Scholar 2 : Time course of mechanosensitivity changes in articular afferents during a developing experimental arthritis. J Neurophysiol1988; 60: 2180. Google Scholar 3 : Neuroanatomy of the pain system and of the pathways that modulate pain. J Clin Neurophysiol1997; 14: 2. Google Scholar 4 : Central changes in processing of mechanoreceptive input in capsaicin-induced secondary hyperalgesia in humans. J Physiol1992; 448: 765. Google Scholar 5 : State-dependent opioid control of pain. Nat Rev Neurosci2004; 5: 565. Google Scholar 6 : Disturbances in bladder function associated with emotional stress. JAMA1949; 141: 1139. Google Scholar 7 : Comorbidity of interstitial cystitis with other unexplained clinical conditions. J Urol2004; 172: 1242. Google Scholar 8 : Autonomic response to stress in interstitial cystitis. J Urol2004; 172: 227. Link, Google Scholar 9 : Diurnal cortisol variations and symptoms in patients with interstitial cystitis. J Urol2002; 167: 1338. Link, Google Scholar 10 : Disruption of bladder epithelium barrier function after spinal cord injury. Am J Physiol Renal Physiol2003; 284: F966. Google Scholar Department of Psychology (Lutgendorf)Department of Urology; University of Iowa; Iowa City, Iowa (Kreder)© 2005 by American Urological Association, Inc.FiguresReferencesRelatedDetails Volume 173Issue 3March 2005Page: 682 Advertisement Copyright & Permissions© 2005 by American Urological Association, Inc.MetricsAuthor Information Susan K. Lutgendorf More articles by this author Karl J. Kreder More articles by this author Expand All Advertisement PDF downloadLoading ...

Effect of pre- or post-traumatically applied i.v. lidocaine on primary and secondary hyperalgesia after experimental heat trauma in humans

Hyperalgesia on intradermal capsaicin application can be attenuated by systemic application of local anesthetics. We tested whether low doses of local anesthetics applied pre- or post-traumatically can reduce heat trauma-induced primary and secondary hyperalgesia in humans. Six healthy volunteers consented to the randomized, double-blind, and cross-over designed study. In each subject, a first-degree burn injury was induced three times (corresponding to a pre-traumatic, post-traumatic and control group) at an interval of at least 3 weeks. Heat was applied by a computer-controlled Peltier thermode (47°C, 5 min). In the pre-traumatic group, lidocaine infusion was commenced 30 min prior to heat trauma, and in the post-traumatic group immediately after heat trauma for a total infusion time of 60 min each. Volunteers rated pain on a visual analogue scale (VAS) between threshold and tolerance maximum (0–100% VAS). Primary hyperalgesia was quantified by determining mechanical (von Frey hairs) and thermal (Peltier thermode) pain thresholds. Secondary hyperalgesia was quantified by determining the area in which normally unpleasant von Frey hairs evoked pain or tenderness. Baseline thermal and mechanical pain thresholds did not differ between groups. Heat application always resulted in a first-degree burn injury including both primary and secondary hyperalgesia. The former remained by and large stable for about 4 h whereas the latter continuously increased within the first 2 h. Lidocaine did not affect primary hyperalgesia, irrespective of pre- or post-traumatic application, but substantially reduced the development of secondary hyperalgesia on pre-traumatic, and for tendency on post-traumatic infusion (treatment groups did not differ significantly). Burn injury-induced erythema was smallest in the pre-traumatic group and largest in the control group; however, the level of significance was not reached. Plasma concentrations of lidocaine were always higher than 1.5 μg/ml 30 min after bolus application of lidocaine and reached a peak of 2–3 μg/ml after about 1 h. Thus, local anesthetics at concentrations that do not block nerve conduction substantially affect ongoing central changes in pain processing that are induced by a real tissue trauma. A significant preemptive effect could not be demonstrated. The anti-hyperalgesic effect of lidocaine is likely based on action of central (spinal) sites, but peripheral sites may also be addressed.

Effect of systemic N-methyl-D-aspartate receptor antagonist (dextromethorphan) on primary and secondary hyperalgesia in humans

Dextromethorphan is a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist known to inhibit wind-up and central hyperexcitability of dorsal horn neurones. We studied 24 healthy, unmedicated male volunteers, aged 21-28 yr, in a randomized, double-blind, placebo-controlled, crossover study. Burn injuries were produced on the medial surface of the dominant calf with a 25 x 50 mm rectangular thermode. On three separate days, at least 1 week apart, subjects were given oral dextromethorphan 60 mg, 120 mg or placebo. Dextromethorphan reduced the magnitude of secondary hyperalgesia to pinprick but not to stroke. Dextromethorphan had no influence on primary hyperalgesia, pain during prolonged noxious heat stimulation or heat pain detection thresholds in undamaged skin. Side effects were frequent but clinically acceptable. The effects of dextromethorphan were in agreement with experimental studies indicating that dextromethorphan is a NMDA receptor antagonist. The effects of dextromethorphan in the burn injury model were similar to those of ketamine and distinct from those of local anaesthetics and opioids.

Effect of systemic N-methyl-D-aspartate receptor antagonist (ketamine) on primary and secondary hyperalgesia in humans

Ketamine reduces nociception by binding noncompetitively to the N-methyl-D-aspartate (NMDA) receptor, activation of which increases spinal hypersensitivity. We studied 19 healthy, unmedicated male volunteers, aged 20-31 yr. Burn injuries were produced on the medial surface of the dominant calf with a 25 x 50 mm rectangular thermode. On 3 separate days, at least 1 week apart, subjects received a bolus of either ketamine 0.15 mg kg-1, ketamine 0.30 mg kg-1 or placebo, delivered by a mechanical infusion pump over 15 min. The bolus was followed by continuous infusion of ketamine 0.15 mg kg-1 h-1, ketamine 0.30 mg kg-1 h-1 or placebo, respectively, for 135 min. Ketamine reduced the magnitude of both primary and secondary hyperalgesia, and also pain evoked by prolonged noxious heat stimulation, in a dose-dependent manner. In contrast, ketamine did not alter phasic heat pain perception (perception of transient, painful, thermal stimuli) in undamaged skin. The analgesic effects of ketamine in the burn injury model are in agreement with results from experimental studies, and can be distinguished from those of local anaesthetics and opioids. Side effects caused by continuous infusion of ketamine 0.15 and 0.30 mg kg-1 h-1 were frequent but clinically acceptable.

Central changes in processing of mechanoreceptive input in capsaicin-induced secondary hyperalgesia in humans.

1. Capsaicin, the algesic substance in chilli peppers, was injected intradermally in healthy human subjects. A dose of 100 micrograms given in a volume of 10 microliters caused intense pain lasting for a few minutes after injection and resulted in a narrow area of hyperalgesia to heat and a wide surrounding area of hyperalgesia to mechanical stimuli (stroking) lasting for 1-2 h. 2. Nerve compression experiments with selective block of impulse conduction in myelinated (A) but not in unmyelinated (C) fibres indicated that afferent signals in C fibres contributed to pain from capsaicin injection and to heat hyperalgesia, whereas conduction in afferent A fibres was necessary for the perception of mechanical hyperalgesia. 3. Electrical intraneural microstimulation normally eliciting non-painful tactile sensations was accompanied by pain when the sensation was projected to skin areas within the region of mechanical hyperalgesia induced by capsaicin injection. 4. The threshold for pain evoked by intraneural microstimulation was reversibly lowered and pain from suprathreshold stimulation was exaggerated during the period of mechanical hyperalgesia, regardless of lidocaine anaesthesia of the cutaneous innervation territory of the stimulated fibres. 5. The results indicate that hyperalgesia to stroking on a skin area surrounding a painful intradermal injection of capsaicin is due to reversible changes in the central processing of mechanoreceptive input from myelinated fibres which normally evoke non-painful tactile sensations.