Repetitive noxious stimuli during early development affect acute and long-term mechanical sensitivity in rats.

BACKGROUND: Prematurely born infants are frequently exposed to painful procedures in the neonatal intensive care unit, causing changes to the development of the nervous system lasting into adulthood. The current study aims to study acute and long-term consequences of neonatal repetitive noxious stimulation. METHODS: Rat pups received either 4 or 10 unilateral needle pricks per day, while control littermates received 4 or 10 tactile stimuli in the first postnatal week. Behavioural sensitivity was assessed in the neonatal phase, in adulthood, and after re-injury of the same dermatome in adulthood. RESULTS: An increase in the number of repetitive painful stimuli, from 4 to 10 needle pricks per day, resulted in increased mechanical hypersensitivity during the neonatal period. In adulthood, repetitive painful stimuli resulted in hyposensitivity to mechanical stimuli, while thermal sensitivity was unaffected. After re-injury of the same dermatome in adulthood, the number of repetitive noxious stimuli did not affect mechanical hypersensitivity. Both needle prick groups showed an increased duration of postoperative hypersensitivity compared to control. CONCLUSION: This study shows that repetitive noxious stimulation during the early postnatal period affects acute and long-term mechanical sensitivity. Therefore, the amount of nociceptive stimuli should be minimized or adequately treated in a clinical setting.

The association between genome-wide polymorphisms and chronic postoperative pain: a prospective observational study.

Chronic postoperative pain is common and can have a negative impact on quality of life. Recent studies show that genetic risk factors are likely to play a role, although only gene-targeted analysis has been used to date. This is the first genome-wide association study to identify single-nucleotide polymorphisms associated with the development of chronic postoperative pain based on two independent cohorts. In a discovery cohort, 330 women scheduled for hysterectomy were genotyped. A case-control association analysis compared patients without chronic postoperative pain and the 34 who had severe chronic postoperative pain 3 months after surgery. No single-nucleotide polymorphisms reached genome-wide significance, but several showed suggestive associations with chronic postoperative pain (p < 1 × 10-5 ). Single-nucleotide polymorphisms with significance p < 1 × 10-5 were followed up in a replication cohort consisting of 203 men and women scheduled for orthopaedic or abdominal surgery. Ten of these patients developed severe chronic postoperative pain. A single-nucleotide polymorphism in NAV3 was significantly replicated with chronic postoperative pain in the replication cohort (p = 0.009). Meta-analysis revealed that two loci (IQGAP1 and CRTC3) were significantly associated with chronic postoperative pain at 3 months (IQGAP1 p = 3.93 × 10-6 ß = 2.3863, CRTC3 p = 2.26 × 10-6 , ß = 2.4209). The present genome-wide association study provides initial evidence for genetic risk factors of chronic postoperative pain and supports follow-up studies.

Genetic polymorphisms and their association with the prevalence and severity of chronic postsurgical pain: a systematic review.

BACKGROUND: Although several patient characteristic, clinical, and psychological risk factors for chronic postsurgical pain (CPSP) have been identified, genetic variants including single nucleotide polymorphisms have also become of interest as potential risk factors for the development of CPSP. The aim of this review is to summarize the current evidence on genetic polymorphisms associated with the prevalence and severity of CPSP in adult patients. METHODS: A systematic review of the literature was performed, and additional literature was obtained by reference tracking. The primary outcome was CPSP, defined as pain at least 2 months after the surgery. Studies performed exclusively in animals were excluded. RESULTS: Out of the 1001 identified studies, 14 studies were selected for inclusion. These studies described 5269 participants in 17 cohorts. A meta-analysis was not possible because of heterogeneity of data and data analysis. Associations with the prevalence or severity of CPSP were reported for genetic variants in the COMT gene, OPRM1, potassium channel genes, GCH1, CACNG, CHRNA6, P2X7R, cytokine-associated genes, human leucocyte antigens, DRD2, and ATXN1 CONCLUSIONS: Research on the topic of genetic variants associated with CPSP is still in its initial phase. Hypothesis-free, genome-wide association studies on large cohorts are needed in this field. In addition, future studies may also integrate genetic risk factors and patient characteristic, clinical, and psychological predictors for CPSP.

[Pain, nociception and inflammation; insights into the mechanisms and possible therapeutic approaches]. / Pijn, nociceptie en inflammatie: inzichten in de mechanismen en mogelijke therapeutische aanpak.

Pain is a complex phenomenon and the disentangling of the underlying mechanisms, in which peripheral and central inflammation play an important role, leads to new insights and new therapeutic options. Peripheral inflammation is characterised by the release of a great variety of substances and inflammatory mediators, such as prostaglandines, cytokines and growth factors. The nociceptors at the extreme ends of the C-fibers register changes in the local milieu. It is the specific receptors and transducer proteins located on the nociceptor that cause a depolarisation and in that way send an action potential via the C-fibres to the central nervous system. Upon arrival of this action potential, an inflammatory response will also develop in the central nervous system in which microglial cells play a pivotal role. The interaction between the activated microglial cells and the central sensitization process (NMDA receptor) may result in chronification of the pain.

Translation of the rat thoracic contusion model; part 2 - forward versus backward locomotion testing.

STUDY DESIGN: Experimental animal study. OBJECTIVES: Locomotion analyses in rat spinal cord contusion injury (SCI) models are widely used for the evaluation of recovery of supraspinal locomotor control. However, many commonly used locomotion tests are inadequate to test for spinal cord integrity as they assess motor function that can be highly mediated through below-level propriospinal pattern-generating circuitry, independently of below-level perception. Here we report a behavioral motor test that is more sensitive for spinal cord integrity, even 6 weeks after injury: the backward locomotion rotating rod. SETTING: University of California - San Diego. METHODS: A modified rotating rod test was run in reverse. The rod diameter was increased and thin rubber lining was added. As a reference, we included commonly used motor tests: BBB score, catwalk gait analysis, motor-evoked potentials, single frame analyses, a forward rotating rod test and the 55° inclined ladder test. RESULTS: Unlike commonly used motor tests, the backward locomotion rotating rod test significantly discriminates between both sham-operated (falling latency: 20.4 s s.d.±4.5) vs mild SCI animals, and mild vs moderate SCI animals (differences between each group at acute, subacute and chronic phases: ⩾6 s, P⩽0.01). Moderate SCI animals were practically unable to make even slight backward hindpaw movements. The backward locomotion ability in the chronic phase correlates best with BBB locomotor scores from the acute phase. CONCLUSION: Our data show that backward locomotion is a highly sensitive and quick test to discriminate between sham, mild and moderate SCI, even after 6 weeks. Backward locomotion testing may improve the translational value of experimental results for the clinic.

Translation of the rat thoracic contusion model; part 1-supraspinally versus spinally mediated pain-like responses and spasticity.

STUDY DESIGN: Experimental animal study. OBJECTIVES: Stimulus-evoked below-level paw withdrawals in animal models of spinal cord injury (SCI) can be mediated solely by below-level spinal cord reflexes. Interpreting lowered thresholds for such responses as a model for chronic below-level pain after (thoracic contusion) SCI appears not appropriate, which requires reinterpretation of many prior results. However, how to reinterpret the changes in withdrawal thresholds and what can be a better alternative for pain/sensory assessments remains unclear. SETTING: University of California, San Diego. METHODS: We introduce a method using supraspinally mediated escape responses to assess pain-like sensitivity thresholds on a continuous/linear scale. To further understand the decrease in hindpaw withdrawal thresholds, we investigated whether they may be interpreted as spasticity. RESULTS: The escape response test can be used to assess SCI-induced changes in below-level sensory thresholds. These thresholds were found to increase soon after moderate or severe SCI, while, in parallel, hindpaw withdrawal thresholds decreased. However, the latter did not co-occur with spasticity, suggesting that SCI-induced increased withdrawal responses are probably best interpreted as a form of hyperreflexia with pathophysiological analogies of spasms and/or clonus, or a species-specific phenomenon. CONCLUSION: Decreased below-level withdrawal thresholds do not reflect pain-like hypersensitivity in rodent models of (thoracic contusion) SCI. A large body of previous preclinical SCI pain research needs reinterpretation. We actually found below-level thermal and mechanical hypoesthesia and we also excluded a relation between withdrawal hyperreflexia and spasticity. Withdrawal hyperreflexia might still prove useful to model spasms or clonus, which are, like hypoesthesia, also significant clinical problems after SCI.

Pain relief and quality-of-life improvement after spinal cord stimulation in painful diabetic polyneuropathy: a pilot study.

BACKGROUND: Painful diabetic polyneuropathy (PDP) is associated with high pain scores and is difficult to treat. Therefore, spinal cord stimulation (SCS) has been suggested as second-line treatment. In this study, the feasibility and efficacy of SCS in PDP were investigated, as well as the predictive value of clinical sensory testing for the treatment outcome. METHODS: Fifteen patients with intractable PDP in the lower limbs were recruited. During lead implantation, the feasibility of achieving adequate paraesthesia coverage using one stimulation lead was investigated. If trial stimulation was successful, a definitive neurostimulator was implanted. Pain intensity was scored using an 11-point numeric rating scale and patients' global impression of change scale. Additionally, neuropathic pain characteristics, quality of life, sleep quality and mood were assessed. The predictive value of clinical sensory testing for the treatment outcome was analysed. RESULTS: Adequate paraesthesia coverage was achieved in 14 out of 15 patients. Clinically relevant pain relief was present in 11 patients after trial stimulation and 10 patients at 12 months. The quality of life was significantly increased at 2 weeks and 3 months in patients with successful SCS treatment. Several neuropathic pain characteristics and quality of sleep were improved at 2 weeks and 12 months. Preoperative clinical sensory testing did not differentiate between treatment responders from non-responders. CONCLUSIONS: SCS seems to be an efficacious and feasible treatment for intractable PDP. In this exploratory study, it was not possible to predict the treatment outcome using clinical sensory testing. These results justify performing a randomized clinical trial.

Additive Effects of Environmental Enrichment and Ketamine on Neuropathic Pain Relief by Reducing Glutamatergic Activation in Spinal Cord Injury in Rats.

Spinal cord injury (SCI) impairs mobility and often results in complications like intractable neuropathic pain. A multi-approach management of this chronic pain condition has been encouraged, but little has been explored of the field. Here, we focus on the effect and underlying mechanism of environmental enrichment (EE), which promotes voluntary social and physical activities, combined with a clinical analgesic, ketamine, on SCI-induced neuropathic pain as well as motor dysfunction. We performed T13 spinal hemisection in rats, which induced unilateral motor impairment and neuropathic pain-like behaviors in the hindlimb. Treatment regimen started a week after SCI, which consists of ketamine administration (30 mg kg-1 day-1; intramuscular) for 10 days, or EE housing for 20 days, or their combination. Paw withdrawal response to mechanical and thermal stimuli, motor function, burrowing behaviors, and body weight was monitored. Spinal segments at T13 lesion and L4-L6 were collected for histopathological and protein analyses. The joint treatment of EE and ketamine provided greater relief of pain-like behaviors and locomotor recovery than did either paradigm alone. These improvements were associated with reduced cavitation area, astrogliosis, and perilesional phosphorylation of glutamate N-methyl-D-aspartate receptor (NMDAR). Concurrently, lumbar spinal analysis of NMDAR-linked excitatory markers in hypersensitization showed reduced activation of NMDAR, mitogen-activated protein kinase (MAPK) family, nuclear factor (NF)-κB, interleukin (IL)-1ß signaling, and restored excitatory amino acid transporter 2 level. Our data support a better therapeutic efficacy of the combination, EE, and ketamine, in the attenuation of neuropathic pain and motor recovery by reducing spinal glutamatergic activation, signifying a potential multifaceted neurorehabilitation strategy to improve SCI patient outcome.

Unity in diversity: A systematic review on the GHB using population.

BACKGROUND: Over the past decades gamma-hydroxybutyrate (GHB) has emerged as a popular drug with high potential of (ab)use due to its euphoric and relaxing effects. An overview of different populations using GHB is urgently needed, since this would enable development of adequate prevention and treatment policies to diminish the risks associated with GHB use. We systematically reviewed literature on different GHB using populations, comparing demographic characteristics, GHB use patterns, psychosocial aspects and psychiatric comorbidity. METHODS: We conducted a systematic review following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines using Rayyan software. Original studies published from January 1997 up to October 2019 on GHB use were included. Out of 80 full-text articles, 60 articles of 51 unique studies were included. Most studies included people using GHB 1) presenting at emergency departments (n = 22), 2) recruited from the general population (n = 11), or 3) presenting at addiction care (n = 8). RESULTS: Three main sub-populations of people using GHB are described in the literature: people using GHB recreationally without adverse effects; people using GHB recreationally with adverse effects, and people with dependence on GHB. These groups show considerable overlap in gender, age range, and comorbid substance use, as well as amount of GHB use per occasion. Differences are related to frequency and function of GHB use, the number of comas experienced, as well as work status, and psychiatric comorbidity. CONCLUSION: Policy interventions should aim at preventing the transition from recreational substance use to GHB use, as most users are experienced recreational substance users prior to starting GHB use. When people use GHB regularly, interventions should aim at reducing the level of GHB use and preventing GHB use-related harm. Longitudinal studies and population-based probability sampling are required for more insight in the dynamics of GHB use in different sub-populations, and the transition from one group to the other, ultimately leading to dependence on GHB.

Shared decision-making reduces drug use and psychiatric severity in substance-dependent patients.

BACKGROUND: In the last decades, shared decision-making (SDM) models have been developed to increase patient involvement in treatment decisions. The purpose of this study was to evaluate a SDM intervention (SDMI) for patients dependent on psychoactive substances in addiction health care programs. The intervention consisted of a structured procedure to reach a treatment agreement and comprised 5 sessions. METHODS: Clinicians in 3 treatment centres in the Netherlands were randomly assigned to the SDMI or a standard procedure to reach a treatment agreement. RESULTS: A total of 220 substance-dependent patients receiving inpatient treatment were randomised either to the intervention (n = 111) or control (n = 109) conditions. Reductions in primary substance use (F((1, 124)) = 248.38, p < 0.01) and addiction severity (F((8)) = 27.76, p < 0.01) were found in the total population. Significant change was found in the total population regarding patients' quality of life measured at baseline, exit and follow-up (F((2, 146)) = 5.66, p < 0.01). On the European Addiction Severity Index, SDMI showed significantly better improvements than standard decision-making regarding drug use (F((1, 164)) = 7.40, p < 0.01) and psychiatric problems (F((1, 164)) = 5.91, p = 0.02) at 3-month follow-up. CONCLUSION: SDMI showed a significant add-on effect on top of a well-established 3-month inpatient intervention. SDMI offers an effective, structured, frequent and well-balanced intervention to carry out and evaluate a treatment agreement.

CatWalk gait analysis in assessment of functional recovery after sciatic nerve injury.

Following peripheral nerve injury repair, improved behavioural outcome may be the most important evidence of functionality of axon regeneration after any repair strategy. A range of behavioural testing paradigms have been developed for peripheral nerve injury research. Complete injury of the adult rat sciatic nerve is frequently used in combination with walking track analysis. Despite its wide-spread use, these walking track analyses are unsuitable for the simultaneous assessment of both dynamic and static gait parameters. Conversely, a novel automated gait analysis system, i.e. CatWalk can simultaneously measure dynamic as well as static gait parameters and, importantly, it's easy to control for the speed of locomotion which can strongly affect gait parameters. In a previous study, CatWalk was already successfully used to examine deficits in both dynamic and static gait parameters using the sciatic nerve lesion model with a 1cm gap characterized by absence of recovery [Deumens R, Jaken RJ, Marcus MA, Joosten EA. The CatWalk gait analysis in assessment of both dynamic and static gait changes after adult rat sciatic nerve resection. J Neurosci Methods 2007;164:120-30]. Using the sciatic nerve crush injury model (validated with the static sciatic index) and a follow-up period of 12 weeks, we now show that CatWalk can also measure behavioural recovery. In particular dynamic gait parameters, coordination measures, and the intensity of paw prints are of interest in detecting recovery as far as these parameters completely return to pre-operative values after crush injury. We conclude that CatWalk can be used as a complementary approach to other behavioural testing paradigms to assess clinically relevant behavioural benefits, with a main advantage that CatWalk demonstrates both static and dynamic gait parameters at the same time.

Systematic review of the effects of shared decision-making on patient satisfaction, treatment adherence and health status.

BACKGROUND: In the last decade, the clinician-patient relationship has become more of a partnership. There is growing interest in shared decision-making (SDM) in which the clinician and patient go through all phases of the decision-making process together, share treatment preferences, and reach an agreement on treatment choice. The purpose of this review is to determine the extent, quality, and consistency of the evidence about the effectiveness of SDM. METHOD: This is a systematic review of randomised controlled trials (RCTs) comparing SDM interventions with non-SDM interventions. Eleven RCTs met the required criteria, and were included in this review. RESULTS: The methodological quality of the studies included in this review was high overall. Five RCTs showed no difference between SDM and control, one RCT showed no short-term effects but showed positive longer-term effects, and five RCTs reported a positive effect of SDM on outcome measures. The two studies included of people with mental healthcare problems reported a positive effect of SDM. CONCLUSIONS: Despite the considerable interest in applying SDM clinically, little research regarding its effectiveness has been done to date. It has been argued that SDM is particularly suitable for long-term decisions, especially in the context of a chronic illness, and when the intervention contains more than one session. Our results show that under such circumstances, SDM can be an effective method of reaching a treatment agreement. Evidence for the effectiveness of SDM in the context of other types of decisions, or in general, is still inconclusive. Future studies of SDM should probably focus on long-term decisions.

High frequency stimulation of the subthalamic nucleus improves speed of locomotion but impairs forelimb movement in Parkinsonian rats.

The subthalamic nucleus (STN) plays an important role in motor and non-motor behavior in Parkinson's disease, but its involvement in gait functions is largely unknown. In this study, we investigated the role of the STN on gait in a rat model of PD using the CatWalk method. Parkinsonian rats received bilateral high frequency stimulation (HFS) with different stimulation amplitudes of the STN. Rats were rendered parkinsonian by bilateral injections of 6-hydroxydopamine (6-OHDA) into the striatum. One group of 6-OHDA animals was implanted bilaterally with stimulation electrodes at the level of the STN. Stimulations were performed at 130 Hz (frequency), 60 micros (pulse width) and varying amplitudes of 0, 3, 30 and 150 microA. Rats were evaluated in an automated quantitative gait analysis method (CatWalk method). After behavioral evaluations, rats were killed and the brains processed for histological stainings to determine the impact of the dopaminergic lesion (tyrosine hydroxylase immunohistochemistry) and the localization of the electrode tip (hematoxylin-eosin histochemistry). Results show that bilateral 6-OHDA infusion significantly decreased (70%) the number of dopaminergic cells in the substantia nigra pars compacta (SNc). Due to 6-OHDA treatment, the gait parameters changed considerably. There was a general slowness. The most pronounced effects were seen at the level of the hind paws. Due to implantation of STN electrodes the step pattern changed. STN electrical stimulation improved the general slowness but induced slowing of the forelimb movement. Furthermore, we found that HFS with a medium amplitude significantly changed speed, the so-called dynamic aspect of gait. The static features of gait were only significantly influenced with low amplitude. Remarkably, STN stimulation affected predominantly the forepaws/limbs.

The CatWalk method: a detailed analysis of behavioral changes after acute inflammatory pain in the rat.

Experimental pain research is often complicated by the absence of an objective and detailed method to analyze behavioral changes. In the present study, acute pain was induced into the right knee of the rat (n=15) through the injection of 2mg carrageenan (CAR) in saline. A control group received vehicle injection into the knee (n=15). With the use of an automated quantitative gait analysis system, the CatWalk, it was possible to quantitatively analyze behavioral changes at post-injection time 2.5, 4, 24 and 48h. The CatWalk analysis of individual paw parameters like the intensity of the paw print or the time contact with the floor showed a significant effect after CAR injection into the knee. These CatWalk parameters were highly correlated with von Frey data and thus representative for the development of mechanical allodynia. Furthermore, detailed CatWalk analysis of the gait (i.e. coordinated interaction between left and right hindlimb) showed very fine, accurate and significant coordination changes in the experimental rats from 4h post-injection. In conclusion, the CatWalk method allows an objective and detailed detection of both pain-induced gait adaptations as well as the development of mechanical allodynia in an acute inflammatory pain model.

Neonatal Plasticity of the Nociceptive System: Mechanisms, Effects, and Treatment of Repetitive Painful Procedures During NICU Admittance.

INTRODUCTION: In the Neonatal Intensive Care Unit (NICU), prematurely born infants undergo a range of skin breaking and painful procedures. At the same time, the spinal nociceptive system is in a sensitive developmental stage. Both neonatal repetitive painful procedures and their treatment can induce plasticity of the neonatal spinal nociceptive system, causing long-lasting alterations to pain processing and pain reactivity. METHODS: This review focuses on developmental processes related to the nociceptive network in the spinal dorsal horn and more specifically at mechanisms related to 1. Modulation of afferent systems; 2. The role of interneurons; 3. Descending inhibitory pathways; and 4. The central neuro-immune responses and microglial cell responses. The effects and possible mechanisms underlying the long-term effects of repetitive painful procedures on the developing nociceptive system as well as subsequent pharmacological treatment (acetaminophen, morphine) in early life are discussed. RESULTS: Repetitive stimulation of the nociceptive system in a rat model with use of needle pricks in the hind-paw closely mimics the clinical situation for infants in the NICU. CONCLUSION: Activity dependent plasticity in early postnatal life induces long-lasting alterations that then may cause altered pain perception in adulthood. For a future choice of optimal analgesic drugs these considerations have to be taken into account beyond the classical classes of drugs used nowadays.

Endocannabinoid activation of CB1 receptors contributes to long-lasting reversal of neuropathic pain by repetitive spinal cord stimulation.

BACKGROUND: Spinal cord stimulation (SCS) has been shown to be effective in the management of certain neuropathic pain conditions, however, the underlying mechanisms are incompletely understood. In this study, we investigated repetitive SCS in a rodent neuropathic pain model, revealing long-lasting and incremental attenuation of hyperalgesia and a mechanism of action involving endocannabinoids. METHOD: Animals were implanted with monopolar electrodes at the time of partial sciatic nerve injury. Dorsal columns at spinal segments T12/13 were stimulated 3 days later (early SCS), and again at day 7 (late SCS) using low-frequency parameters. Hypersensitivity to cutaneous mechanical stimuli was assessed using von Frey filaments. Pharmacological agents, selected to identify endocannabinoid and opioid involvement, were administered intraperitoneally, 10 min before SCS. RESULTS: Early SCS caused partial reversal of mechanical hypersensitivity with corresponding changes in the biomarker of central sensitization, [phospho-Tyr1472 ]-GluN2B. The partial reversal of hyperalgesia by early SCS was amplified by co-administration of LY 2183240, an inhibitor of endocannabinoid reuptake/breakdown. This amplification was inhibited by a CB1 R antagonist, AM251, but not by a CB2 R antagonist, AM630. Early SCS-induced reversal of hyperalgesia was attenuated by naloxone, indicating a role for opioids. Late SCS resulted in an incremental level of reversal of hyperalgesia, which was inhibited by AM251, but not by CB2 or opioid receptor antagonists. CONCLUSION: The endocannabinoid system, and in particular the CB1 R, plays a pivotal role in the long-lasting and incremental reversal of hyperalgesia induced by repetitive SCS in a neuropathic pain model. SIGNIFICANCE: Alternative parameters for repetitive spinal cord stimulation (SCS) at 25/10 Hz elicit particularly long-lasting and incremental reversal of hyperalgesia in a neuropathic pain model through a mechanism involving endocannabinoids.

Spinal cord stimulation in experimental chronic painful diabetic polyneuropathy: Delayed effect of High-frequency stimulation.

BACKGROUND: Spinal cord stimulation (SCS) has been shown to provide pain relief in painful diabetic polyneuropathy (PDPN). As the vasculature system plays a great role in the pathophysiology of PDPN, a potential beneficial side-effect of SCS is peripheral vasodilation, with high frequency (HF) SCS in particular. We hypothesize that HF-SCS (500 Hz), compared with conventional (CON) or low frequency (LF)-SCS will result in increased alleviation of mechanical hypersensitivity in chronic experimental PDPN. METHODS: Diabetes was induced in 8-week-old female Sprague-Dawley rats with an intraperitoneal injection of 65 mg/kg of streptozotocin (n = 44). Rats with a significant decrease in mechanical withdrawal response to von Frey filaments over a period of 20 weeks were implanted with SCS electrodes (n = 18). Rats were assigned to a cross-over design with a random order of LF-, CON-, HF- and sham SCS and mechanical withdrawal thresholds were assessed with von Frey testing. RESULTS: Compared with sham treatment, the average 50% WT score for 5 Hz was 4.88 g higher during stimulation (p = 0.156), and 1.77 g higher post-stimulation (p = 0.008). CON-SCS resulted in 50% WT scores 5.7 g, and 2.51 g higher during (p = 0.064) and after stimulation (p < 0.004), respectively. HF-SCS started out with an average difference in 50% WT score compared with sham of 1.87 g during stimulation (p = 0.279), and subsequently the steepest rise to a difference of 5.47 g post-stimulation (p < 0.001). CONCLUSIONS: We demonstrated a delayed effect of HF-SCS on mechanical hypersensitivity in chronic PDPN animals compared with LF-, or CON-SCS. SIGNIFICANCE: This study evaluates the effect of SCS frequency (5-500 Hz) on mechanical hypersensitivity in the chronic phase of experimental PDPN. High frequency (500 Hz) - SCS resulted in a delayed effect- on pain-related behavioural outcome in chronic PDPN.

Effect of spinal cord stimulation in an animal model of neuropathic pain relates to degree of tactile "allodynia".

Spinal cord stimulation (SCS) is an established treatment for chronic neuropathic pain. However, in recent studies conflicting results regarding the effect of SCS were noted in a selected group of patients suffering from complex regional pain syndrome and mechanical allodynia. In the present study we investigated the pain relieving effect of SCS in a rat experimental model of neuropathic pain as related to the severity of mechanical allodynia. Adult male rats (n=45) were submitted to a unilateral sciatic nerve ligation. The level of allodynia was tested using the withdrawal response to tactile stimuli with the von Frey test. A portion of these rats developed marked tactile hypersensitivity in the nerve-lesioned paw (von Frey test), similar to "tactile allodynia" observed after nerve injury in humans. Prior to SCS treatment the rats were subdivided into three groups based on the level of allodynia: mild, moderate and severe. All allodynic rats were treated with SCS (n=27) for 30 min (f=50 Hz; pulse width 0.2 ms and stimulation at 2/3 of motor threshold) at 16 days post-injury. Our data demonstrate a differential effect of SCS related to the severity of the mechanical allodynia. SCS leads to a faster and better pain relief in mildly allodynic rats as compared with the more severely allodynic rats. Thus, we suggest that the selection and subdivision of patient groups similar to those defined in our experimental setting (mild, moderate and severe allodynic) may provide better pre-treatment prediction of possible therapeutic benefits of SCS.