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.

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.

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.

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.

Pain prevalence in cancer patients: status quo or opportunities for improvement?

PURPOSE OF REVIEW: Cancer incidence increases worldwide and thus more patients will suffer from cancer pain. As cancer pain severely affects quality of life, the decrease of pain should be of high priority for every clinician. In the last decade, attention for cancer pain and for its treatment has increased, and new pharmacological based treatment options became available. This gave reason to hypothesize a decrease in pain prevalence in cancer patients over the last decade. RECENT FINDINGS: Despite increased attention to cancer pain, pain prevalence in cancer patients has not significantly changed over the last decade as compared to the four decades before. This absence of change might be because of comorbidities cancer patients have, but also to undertreatment of pain, because of a lack of knowledge and pain measurement. Other factors underlying this absence of change are the use of incorrect coanalgesics in the case of treatment of neuropathic pain, as well as the present absence of potent analgesics with little side effects. SUMMARY: Consistent screening of pain in cancer patients and consequent correct treatment of pain might result in an impressive decrease in cancer pain. For further reduction of pain, new pharmacological analgesics need to be developed.

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.

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.

Methadone is superior to fentanyl in treating neuropathic pain in patients with head-and-neck cancer.

BACKGROUND: Cancer pain is still inadequately treated in up to 60% of cancer patients. Based on the additional effect on the N-Methyl-d-Aspartate receptor, we expected that methadone (Met) could provide better pain relief than fentanyl (Fen) in cancer pain with a neuropathic pain component. METHODS: A randomised controlled trial was performed with 52 strong opioids naive patients with head-and-neck cancer with substantial pain (pain Numerical Rating Scale [NRS] > 4) and a neuropathic pain component (Douleur Neuropathique [DN4] > 4). Twenty-six patients were treated with Met and 26 with Fen. Patients were evaluated at 1, 3 and 5 weeks. The primary outcomes were reduction in average pain, clinical success (defined as 50% average pain decrease) and reduction in pain interference. Secondary outcomes were global perceived effect (GPE) and side-effects. FINDINGS: Reduction in NRS was higher with the use of Met at 1, 3 and 5 weeks (pain change 2.9, 3.1 and 3.1) compared to Fen (1.4, 1.7 and 2.0). This difference was significant at 1 (p = 0.011) and at 3 weeks (p = 0.03). Clinical success (>50% improvement) was higher with Met at 1 week (15% versus 50%, p = 0.012). The change in pain interference, the GPE and side-effect profile were not significantly different between the groups. INTERPRETATION: This is the first study to compare the effects of Met to Fen in cancer patients with a neuropathic pain component. Based on the results of this study, Met should be considered in the treatment of oncological pain with a neuropathic component.

Neonatal paracetamol treatment reduces long-term nociceptive behaviour after neonatal procedural pain in rats.

BACKGROUND: Pain from skin penetrating procedures (procedural pain) during infancy in the neonatal intensive care unit (NICU) may result in changes of nociceptive sensitivity in later life. This supports the need for pain management during such vulnerable periods in life. This study, therefore, analyses the short- and long-term consequences of neonatal paracetamol (acetaminophen) treatment on pain behaviour in an experimental rat model of neonatal procedural pain. METHODS: A repetitive needle-prick model was used, in which neonatal rats received four needle pricks into the left hind paw per day from postnatal day 0 to day 7 (P0-P7). Paracetamol (50 mg/kg/day s.c.) was administered daily (P0-P7), and sensitivity to mechanical stimuli was compared with a needle-prick/saline-treated group and to a tactile control group. At 8 weeks of age, all animals underwent an ipsilateral paw-incision, modelling postoperative pain, and the duration of hypersensitivity was assessed. RESULTS: Neonatal paracetamol administration had no effect upon short-term mechanical hypersensitivity during the first postnatal week or upon long-term baseline sensitivity from 3 to 8 weeks. However, neonatal paracetamol administration significantly reduced the postoperative mechanical hypersensitivity in young adults, caused by repetitive needle pricking. CONCLUSION: Paracetamol administration during neonatal procedural pain does not alter short-term or long-term effects on mechanical sensitivity, but does reduce the duration of increased postoperative mechanical hypersensitivity in a clinically relevant neonatal procedural pain model. WHAT DOES THIS STUDY ADD: Paracetamol can be used safely in neonatal rats. Neonatal paracetamol treatment had no effect upon short-term mechanical hypersensitivity during the first postnatal week, nor upon long-term baseline sensitivity from 3 to 8 weeks. Paracetamol treatment during the first postnatal week significantly reduced the postoperative mechanical hypersensitivity in young adult rats.

Pain prevalence and its determinants after spinal cord injury: a systematic review.

Pain prevalence studies are important as they illustrate the magnitude of pain problems in a certain patient population, such as patients living with a spinal cord injury (SCI). Strikingly, reported pain prevalence rates in SCI patients are found to vary greatly, while determinants for the differences between pain prevalence reports remain unclear. We here aim to identify determinants for the differences (heterogeneity) in pain prevalence reports through a systematic review of all SCI pain prevalence reporting studies. Literature search was done using Medline, Cumulative Index to Nursing and Allied Health Literature, ISI Web of Knowledge and Embase. Data abstraction was performed while blinded and was followed by meta-(regression)-analyses. We identified 82 studies. Study design-related determinants of SCI pain prevalence reports were pain definition strictness (mild, moderate or high), primary study goal (pain study or not), data source (retrospective or not), and in a limited number of cases response/attrition rates. While correcting for these items, population characteristics correlating with pain prevalence rates were both proportion of patients with a depression and average time after injury (positive correlations). Between-study heterogeneity may remain even after the identification/correction of above-mentioned causes of heterogeneity.Pain after SCI does seem to relate to the duration of the injury and depression, yet major causes of bias in reported pain prevalence are found to be related to the primary study goal (pain study or not), choice of pain definition and the use of retrospective data.

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.

Schwann cell migration and neurite outgrowth are influenced by media conditioned by epineurial fibroblasts.

The regenerative capacity of the peripheral nervous system is largely related to Schwann cells undergoing proliferation and migration after injury and forming growth-supporting substrates for severed axons. Novel data show that fibroblasts to a certain extent regulate the pro-regenerative behavior of Schwann cells. In the setting of peripheral nerve injury, the fibroblasts that form the epineurium come into close contact with both Schwann cells and peripheral axons, but the potential influence on these latter two cell types has not been studied yet. In the present study we explored whether culture media, conditioned by epineurial fibroblasts can influence Schwann cells and/or neurite outgrowth from dorsal root ganglia neurons in vitro. Our data indicate that epineurial fibroblast-conditioned culture media substantially increase Schwann cell migration and the outgrowth of neurites. Schwann cell proliferation remained largely unaffected. These same read-out parameters were assayed in a condition where epineurial fibroblasts were subjected to stretch-cell-stress, a mechanical stressor that plays an important role in traumatic peripheral nerve injuries. Stretch-cell-stress of epineurial fibroblasts did not further change the positive effects of conditioned media on Schwann cell migration and neurite outgrowth. From these data we conclude that an as yet unknown pro-regenerative role can be attributed to epineurial fibroblasts, implying that such cells may affect the outcome of severe peripheral nerve injury.

The effect of spinal cord stimulation frequency in experimental painful diabetic polyneuropathy.

BACKGROUND: Spinal cord stimulation (SCS) has been shown to be an effective treatment for painful diabetic polyneuropathy (PDP). An increase of efficacy is needed since only 67% of patients benefit from SCS. This study aimed to develop an animal model for SCS in PDP and study the effect of various stimulation frequencies on the functional outcome. As the pathophysiology of PDP is complex, including vasoconstriction and nerve injury, the frequency of SCS may result in different outcomes. METHODS: Diabetes mellitus was induced by an intraperitoneal injection of streptozotocin in 8-week-old female Sprague-Dawley rats (n=76; glucose >15 mmol/L; n=51). A SCS device was implanted at level Th13 4 weeks later. SCS of the dorsal columns was applied for 30 min and the effect on mechanical hypersensitivity was evaluated. RESULTS: Mechanical hypersensitivity developed in 26 rats, which were included (low-frequency, n=6; mid-frequency, n=8; high frequency, n=9; and sham, n=3). SCS of the dorsal columns was applied for 40 min, and the effect on mechanical hypersensitivity was evaluated. In all treatment groups, SCS resulted in reversal of mechanical hypersensitivity and a clinically relevant reduction was achieved in 70% of animals. No differences in efficacy were found between the different treatment groups. CONCLUSIONS: The pain-relieving effect of SCS in PDP was studied in an experimental model. Our study shows that SCS on mechanical hypersensitivity in PDP rats is equally effective when applied at low, mid and high frequency.