Genome-wide association studies with experimental validation identify a protective role for B lymphocytes against chronic post-surgical pain.

BACKGROUND: Chronic post-surgical pain (CPSP) significantly impacts patients' recovery and quality of life. Although environmental risk factors are well-established, genetic risk remains less understood. METHODS: A meta-analysis of genome-wide association studies followed by partitioned heritability was performed on 1350 individuals across five surgery types: hysterectomy, mastectomy, abdominal, hernia, and knee. In subsequent animal studies, withdrawal thresholds to evoked mechanical stimulation were measured in Rag1 null mutant and wild-type mice after plantar incision and laparotomy. Cell sorting by flow cytometry tracked recruitment of immune cell types. RESULTS: We discovered 77 genome-wide significant single-nucleotide polymorphism (SNP) hits, distributed among 24 loci and 244 genes. Meta-analysis of all cohorts estimated a SNP-based narrow-sense heritability for CPSP at ∼39%, indicating a substantial genetic contribution. Partitioned heritability analysis across a wide variety of tissues revealed enrichment of heritability in immune system-related genes, particularly those associated with B and T cells. Rag1 null mutant mice lacking both T and B cells exhibited exacerbated and prolonged allodynia up to 42 days after surgery, which was rescued by B-cell transfer. Recruitment patterns of B cells but not T cells differed significantly during the first 7 days after injury in the footpad, lymph nodes, and dorsal root ganglia. CONCLUSIONS: These findings suggest a key protective role for the adaptive immune system in the development of chronic post-surgical pain.

Repetitive neonatal procedural pain affects stress-induced plasma corticosterone increase in young adult females but not in male rats.

Exposure to repetitive painful procedures in the neonatal intensive care unit results in long-lasting effects, especially visible after a "second hit" in adulthood. As the nociceptive system and the hypothalamic-pituitary-adrenal (HPA) axis interact and are vulnerable in early life, repetitive painful procedures in neonates may affect later-life HPA axis reactivity. The first aim of the present study was to investigate the effects of repetitive neonatal procedural pain on plasma corticosterone levels after mild acute stress (MAS) in young adult rats. Second, the study examined if MAS acts as a "second hit" and affects mechanical sensitivity. Fifty-two rats were either needle pricked four times a day, disturbed, or left undisturbed during the first neonatal week. At 8 weeks, the animals were subjected to MAS, and plasma was collected before (t0), after MAS (t20), and at recovery (t60). Corticosterone levels were analyzed using an enzyme-linked immunosorbent assay, and mechanical sensitivity was assessed with von Frey filaments. Results demonstrate that repetitive neonatal procedural pain reduces stress-induced plasma corticosterone increase after MAS only in young adult females and not in males. Furthermore, MAS does not affect mechanical sensitivity in young adult rats. Altogether, the results suggest an age- and sex-dependent effect of repetitive neonatal procedural pain on HPA axis reprogramming.

The Effect of Spinal Cord Stimulation on Spinal Dorsal Horn Lipid Expression in Experimental Painful Diabetic Polyneuropathy: A Matrix-Assisted Laser Desorption/Ionization Time-of-Flight Mass Spectrometry Imaging Study.

OBJECTIVES: Diabetes-induced peripheral nerve fiber damage can cause painful diabetic polyneuropathy (PDPN), induced by central sensitization through proinflammatory processes in the spinal dorsal horn. Disturbances in spinal dorsal horn lipid metabolism play a major role in proinflammatory regulation. Conventional (Con)-spinal cord stimulation (SCS) is an alternative treatment for pain relief in PDPN, whereas differential target multiplexed (DTM)-SCS could be more effective than Con-SCS, specifically targeting the spinal inflammatory response. We hypothesize that Con- and DTM-SCS differentially affect lipid metabolism in the spinal cord of PDPN animals. To study pain relief mechanisms, we analyzed lipid expression in the spinal dorsal horn using matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry imaging (MSI). MATERIAL AND METHODS: Diabetes was induced through streptozotocin (STZ) injection in 28 rats, of which 12 developed PDPN. These and four nondiabetic animals (sham STZ) were implanted with a quadripolar lead and stimulated with Con-, DTM-, or Sham-SCS for 48 hours. Mechanical sensitivity was assessed using Von Frey filaments after 24 and 48 hours. After 48 hours of SCS, the spinal cord was collected, and lipids were analyzed using MALDI-TOF MSI. RESULTS: STZ-induced hypersensitivity in the hind paws was reduced by Con- and DTM-SCS. PDPN induction decreased the expression of a glycosphingolipid in laminae 3 of the spinal dorsal horn. After 48 hours of Con- and DTM-SCS, expression levels of several lipids in the spinal dorsal horn decreased, including (HexCer 36:1;O, 40:1;O3), diacylglycerophosphocholines (PC 36:1, 38:6, 40:5), and diacylglycerophosphoserines (PS 36:4). CONCLUSIONS: Both Con- and DTM-SCS provide pain relief and decrease spinal dorsal horn lipid expression of PDPN animals, highlighting the complex effects of SCS on the spinal cord physiology. STZ-induced PDPN has a limited effect on lipid expression in the spinal dorsal horn.

Spinal Cord Stimulation Paradigms and Alleviation of Neuropathic Pain Behavior in Experimental Painful Diabetic Polyneuropathy.

OBJECTIVES: Spinal cord stimulation (SCS) is an alternative treatment option for painful diabetic polyneuropathy (PDPN). Differential target multiplexed (DTM)-SCS is proposed to be more effective than conventional (Con)-SCS. Animal studies are essential for understanding SCS mechanisms in PDPN pain relief. Although the Von Frey (VF) test is the gold standard for preclinical pain research, it has limitations. Operant testing using the conditioned place preference (CPP) test provides insights into spontaneous neuropathic pain relief and enhances the translatability of findings. This study aims to 1) use the CPP test to evaluate Con- and DTM-SCS effects on spontaneous neuropathic pain relief in PDPN animals and 2) investigate the correlation between mechanical hypersensitivity alleviation and spontaneous neuropathic pain relief. MATERIAL AND METHODS: Diabetes was induced through streptozotocin injection in 32 rats; 16 animals developed PDPN and were implanted with a quadripolar lead. Rats were conditioned for Con-SCS (n = 8) or DTM-SCS (n = 7), and a preference score compared with sham was determined. After conditioning, a 30-minute SCS protocol was conducted. Mechanical sensitivity was assessed using VF before, during, and after SCS. RESULTS: There were no significant chamber preference changes for DTM-SCS (p = 0.3449) or Con-SCS (p = 0.3632). Subgroups of responders and nonresponders were identified with significant increases in preference score for responders for both DTM-SCS (-266.6 to 119.8; p = 0.0238; n = 4) and Con-SCS (-350.7 to 88.46; p = 0.0148; n = 3). No strong correlation between SCS-induced spontaneous neuropathic pain relief and effects on mechanical hypersensitivity in PDPN animals is noted. CONCLUSIONS: The CPP test is a valuable tool to test the efficacy of the pain-relieving potential of various SCS paradigms in PDPN animals. The results of this study show no differences in spontaneous neuropathic pain relief between DTM- and Con-SCS in PDPN animals. Furthermore, there is no correlation between the effect of SCS in spontaneous pain relief and hind paw mechanical hypersensitivity.

Spinal Cord Stimulation Paradigms and Pain Relief: A Preclinical Systematic Review on Modulation of the Central Inflammatory Response in Neuropathic Pain.

OBJECTIVES: Spinal cord stimulation (SCS) is a last-resort treatment for patients with chronic neuropathic pain. The mechanism underlying SCS and pain relief is not yet fully understood. Because the inflammatory balance between pro- and anti-inflammatory molecules in the spinal nociceptive network is pivotal in the development and maintenance of neuropathic pain, the working mechanism of SCS is suggested to be related to the modulation of this balance. The aim of this systematic review is to summarize and understand the effects of different SCS paradigms on the central inflammatory balance in the spinal cord. MATERIALS AND METHODS: A systematic literature search was conducted using MEDLINE, Embase, and PubMed. All articles studying the effects of SCS on inflammatory or glial markers in neuropathic pain models were included. A quality assessment was performed on predetermined entities of bias. RESULTS: A total of 11 articles were eligible for this systematic review. In general, induction of neuropathic pain in rats results in a proinflammatory state and at the same time an increased activity/expression of microglial and astroglial cells in the spinal cord dorsal horn. Conventional SCS seems to further enhance this proinflammatory state and increase the messenger RNA expression of microglial markers, but it also results in a decrease in microglial protein marker levels. High-frequency and especially differential targeted multiplexed SCS can not only restore the balance between pro- and anti-inflammatory molecules but also minimize the overexpression/activation of glial cells. Quality assessment and risk of bias analysis of the studies included make it clear that the results of these preclinical studies must be interpreted with caution. CONCLUSIONS: In summary, the preclinical findings tend to indicate that there is a distinct SCS paradigm-related effect in the modulation of the central inflammatory balance of the spinal dorsal horn.

The development of descending serotonergic modulation of the spinal nociceptive network: a life span perspective.

The nociceptive network, responsible for transmission of nociceptive signals that generate the pain experience, is not fully developed at birth. Descending serotonergic modulation of spinal nociception, an important part of the pain network, undergoes substantial postnatal maturation and is suggested to be involved in the altered pain response observed in human newborns. This review summarizes preclinical data of the development of descending serotonergic modulation of the spinal nociceptive network across the life span, providing a comprehensive background to understand human newborn pain experience and treatment. Sprouting of descending serotonergic axons, originating from the rostroventral medulla, as well as changes in receptor function and expression take place in the first postnatal weeks of rodents, corresponding to human neonates in early infancy. Descending serotonergic modulation switches from facilitation in early life to bimodal control in adulthood, masking an already functional 5-HT inhibitory system at early ages. Specifically the 5-HT3 and 5-HT7 receptors seem distinctly important for pain facilitation at neonatal and early infancy, while the 5-HT1a, 5-HT1b, and 5-HT2 receptors mediate inhibitory effects at all ages. Analgesic therapy that considers the neurodevelopmental phase is likely to result in a more targeted treatment of neonatal pain and may improve both short- and long-term effects. IMPACT: The descending serotonergic system undergoes anatomical changes from birth to early infancy, as its sprouts and descending projections increase and the dorsal horn innervation pattern changes. Descending serotonergic modulation from the rostral ventral medulla switches from facilitation in early life via the 5-HT3 and 5-HT7 receptors to bimodal control in adulthood. A functional inhibitory serotonergic system mainly via 5-HT1a, 5-HT1b, and 5-HT2a receptors at the spinal level exists already at the neonatal phase but is masked by descending facilitation.

Conventional Dorsal Root Ganglion Stimulation in an Experimental Model of Painful Diabetic Peripheral Neuropathy: A Quantitative Immunocytochemical Analysis of Intracellular γ-Aminobutyric Acid in Dorsal Root Ganglion Neurons.

BACKGROUND AND OBJECTIVE: The sensory cell somata in the DRG contain all equipment necessary for extensive GABAergic signaling and are able to release GABA upon depolarization. With this study, we hypothesize that pain relief induced by conventional dorsal root ganglion stimulation (Con-DRGS) in animals with experimental painful diabetic peripheral neuropathy is related to the release of GABA from DRG neurons. With use of quantitative immunocytochemistry, we hypothesize DRGS to result in a decreased intensity of intracellular GABA-immunostaining in DRG somata. MATERIALS AND METHODS: Female Sprague-Dawley rats (n = 31) were injected with streptozotocin (STZ) in order to induce Diabetes Mellitus. Animals that developed neuropathic pain after four weeks (Von Frey) were implanted with a unilateral DRGS device at L4 (n = 14). Animals were then stimulated for 30 min with Con-DRGS (20 Hz, pulse width = 0.2 msec, amplitude = 67% of motor threshold, n = 8) or Sham-DRGS (n = 6), while pain behavior (von Frey) was measured. DRGs were then collected and immunostained for GABA, and a relation to size of sensory cell soma diameter (small: 12-26 µm, assumed to be C-fiber related sensory neurons; medium: 26-40 µm, assumed to be Aδ related sensory neurons; and large: 40-54 µm, assumed to be Aß related sensory neurons) was made. RESULTS: DRGS treated animals showed significant reductions in STZ-induced mechanical hypersensitivity. No significant differences in GABA immunostaining intensity per sensory neuron cell soma type (small-, medium-, or large-sized) were noted in DRGs of stimulated (Con-DRGS) animals versus Sham animals. No differences in GABA immunostaining intensity per sensory cell soma type in ipsi- as compared to contralateral DRGs were observed. CONCLUSION: Con-DRGS does not affect the average intracellular GABA immunofluorescence staining intensity in DRG sensory neurons of those animals which showed significant pain reduction. Similarly, no soma size related changes in intracellular GABA immunofluorescence were observed following Con-DRGS.

Polygenic risk scores indicates genetic overlap between peripheral pain syndromes and chronic postsurgical pain.

Chronic postsurgical pain (CPSP) is a debilitating chronic pain condition that has a substantial effect on quality of life. CPSP shows considerable clinical overlap with different chronic peripheral pain syndromes, suggesting a shared aetiology. This study aims to assess the genetic overlap between different chronic pain syndromes and CPSP, providing relevant biological context for potential chronic pain markers of CPSP. To analyse the genetic overlap between CPSP and chronic peripheral pain syndromes, recent GWAS studies were combined for polygenic risk scores (PRS) analysis, using a cohort of CPSP patients as starting point. Biological contextualisation of genetic marker, overlap between CPSP and chronic pain syndromes, was assessed through Gene Ontology (GO), using Pathway Scoring Algorithm (PASCAL) and REVIGO. PRS analyses suggest a significant genetic overlap between CPSP and 3 chronic pain disorders: chronic widespread pain (CWP, p value threshold = 0.003, R2 0.06, p = 0.003), rheumatoid arthritis (RA, p value threshold = 0.0177, R2 = 0.04, p = 0.017) and possibly sciatica (p value threshold = 0.00025, R2 = 0.03, p = 0.045). Whereas no significant genetic overlap was found with cluster headache and migraine, the outcome for osteoarthritis (OA) was inconsistent between the cohorts. This is likely related to cohort composition, as repeated random reallocation of patients' nullified CPSP/OA outcome variation between the discovery and replication cohorts. GO analyses suggested an aetiological involvement of genetic markers that control neurological signalling (specifically sodium channels) and inflammatory response. The current study reaffirms the impact of sample size, cohort composition and open data accessibility on the unbiased identification of genetic overlap across disorders. In conclusion, this study is the first to report genetic overlap between regulatory processes implicated in CPSP and chronic peripheral pain syndromes. Interaction between neurological signalling and inflammatory response may explain the genetic overlap between CPSP, CWP and RA. Enhanced understanding of mechanisms underlying chronification of pain will aid the development of new therapeutic strategies for CPSP with sodium channel biochemistry as a potential candidate.

Burst and Tonic Spinal Cord Stimulation in the Mechanical Conflict-Avoidance System: Cognitive-Motivational Aspects.

BACKGROUND: Clinical research suggests that a novel spinal cord stimulation (SCS) waveform, known as Burst-SCS, specifically targets cognitive-motivational aspects of pain. The objective of the present study was to assess the cognitive-motivational aspects of Tonic- and Burst SCS-induced pain relief, by means of exit latency in the mechanical conflict-avoidance system (MCAS), in a rat model of chronic neuropathic pain. METHODS: Exit latency on the MCAS operant testing setup was evaluated at various probe heights for rats (n = 26) with chronic neuropathic pain induced by a partial sciatic nerve ligation (PSNL). Von Frey paw withdrawal analysis was performed to assess mechanical hypersensitivity. In a second experiment (n = 12), the behavioral effect of Tonic SCS or biphasic Burst SCS on both Von Frey analysis and MCAS exit latency was assessed. RESULTS: Burst SCS exit latencies differed significantly from Tonic SCS exit latencies at 4 mm probe height (3.8 vs. 5.8 sec, respectively; p < 0.01) and 5 mm probe height (3.2 vs. 5.4 sec respectively; p < 0.05). This difference was not detected with reflex-based Von Frey testing (Tonic-SCS vs. Burst-SCS at 30 min stimulation: p = 0.73, and at 60 min stimulation; p = 0.42). CONCLUSIONS: Testing of MCAS exit latency allows for detection of cognitive-motivational pain relieving aspects induced by either Tonic- or Burst-SCS in treatment of chronic neuropathic rats. Our behavioral findings strongly suggest that Burst-SCS specifically affects, much more than Tonic-SCS, the processing of cognitive-motivational aspects of pain.

Nonlinear Relation Between Burst Dorsal Root Ganglion Stimulation Amplitude and Behavioral Outcome in an Experimental Model of Painful Diabetic Peripheral Neuropathy.

BACKGROUND AND OBJECTIVE: Dorsal root ganglion stimulation (DRGS) has recently emerged as a neuromodulation modality in the treatment of chronic neuropathic pain. The objective of this study was to compare the efficacy of different Burst-DRGS amplitudes in an experimental model of painful diabetic peripheral neuropathy (PDPN). METHODS: Diabetes mellitus was induced in female Sprague-Dawley rats by intraperitoneal injection of streptozotocin (STZ, n = 28). Animals were tested for mechanical hypersensitivity (von Frey paw withdrawal test) before, and four weeks after STZ injection. PDPN rats (n = 13) were implanted with a unilateral bipolar electrode at the L5 DRG. Animals received Burst-DRGS at 0%, 10%, 33%, 50%, 66%, and 80% of motor threshold (MT) in a randomized crossover design on post-implantation days 2-7 (n = 9). Mechanical hypersensitivity was assessed before stimulation onset, 15 and 30 min during stimulation, and 15 and 30 min after stimulation. RESULTS: Burst-DRGS at amplitudes of 33%, 50%, 66%, and 80% MT resulted in significant attenuation of STZ-induced mechanical hypersensitivity at 15 and 30 min during stimulation, as well as 15 min after cessation of stimulation. No effect on mechanical hypersensitivity was observed for Burst-DRGS at 0% MT and 10% MT. Optimal pain relief and highest responder rates were achieved with Burst-DRGS at 50-66% MT, with an estimated optimum at 52% MT. CONCLUSION: Our findings indicate a nonlinear relationship between Burst-DRGS amplitude and behavioral outcome, with an estimated optimal amplitude of 52% MT. Further optimization and analysis of DRGS driven by insights into the underlying mechanisms related to the various stimulation paradigms is warranted.

Burst and Tonic Spinal Cord Stimulation Both Activate Spinal GABAergic Mechanisms to Attenuate Pain in a Rat Model of Chronic Neuropathic Pain.

BACKGROUND: Experimental and clinical studies have shown that tonic spinal cord stimulation (SCS) releases gamma-aminobutyric acid (GABA) in the spinal dorsal horn. Recently, it was suggested that burst SCS does not act via spinal GABAergic mechanisms. Therefore, we studied spinal GABA release during burst and tonic SCS, both anatomically and pharmacologically, in a well-established chronic neuropathic pain model. METHODS: Animals underwent partial sciatic nerve ligation (PSNL). Quantitative immunohistochemical (IHC) analysis of intracellular GABA levels in the lumbar L4 to L6 dorsal spinal cord was performed after 60 minutes of burst, tonic, or sham SCS in rats that had undergone PSNL (n = 16). In a second pharmacological experiment, the effects of intrathecal administration of the GABAA antagonist bicuculline (5 µg) and the GABAB antagonist phaclofen (5 µg) were assessed. Paw withdrawal thresholds to von Frey filaments of rats that had undergone PSNL (n = 20) were tested during 60 minutes of burst and tonic SCS 30 minutes after intrathecal administration of the drugs. RESULTS: Quantitative IHC analysis of GABA immunoreactivity in spinal dorsal horn sections of animals that had received burst SCS (n = 5) showed significantly lower intracellular GABA levels when compared to sham SCS sections (n = 4; P = 0.0201) and tonic SCS sections (n = 7; P = 0.0077). Intrathecal application of the GABAA antagonist bicuculline (5 µg; n = 10) or the GABAB antagonist phaclofen (5 µg; n = 10) resulted in ablation of the analgesic effect for both burst SCS and tonic SCS. CONCLUSIONS: In conclusion, our anatomical and pharmacological data demonstrate that, in this well-established chronic neuropathic animal model, the analgesic effects of both burst SCS and tonic SCS are mediated via spinal GABAergic mechanisms.

Active Recharge Burst and Tonic Spinal Cord Stimulation Engage Different Supraspinal Mechanisms: A Functional Magnetic Resonance Imaging Study in Peripherally Injured Chronic Neuropathic Rats.

OBJECTIVES: To assess the supraspinal working mechanisms of the burst spinal cord stimulation (SCS) mode, we used functional magnetic resonance imaging (fMRI) in chronic neuropathic rats. We hypothesized that active recharge burst SCS would induce a more profound blood oxygenation level-dependent (BOLD) signal increase in areas associated with cognitive-emotional aspects of pain, as compared to tonic SCS. METHODS: Sprague Dawley rats (n = 17) underwent a unilateral partial sciatic nerve ligation, which resulted in chronic neuropathic pain. Quadripolar SCS electrodes were epidurally positioned on top of the dorsal columns at Th13. Isoflurane-anesthetized (1.5%) rats received either tonic SCS (n = 8) or burst SCS (n = 9) at 66% of motor threshold. BOLD fMRI was conducted before, during, and after SCS using a 9.4-T horizontal bore scanner. RESULTS: Overall, both tonic and burst SCS induced a significant increase of BOLD signal levels in areas associated with the location and intensity of pain, and areas associated with cognitive-emotional aspects of pain. Additionally, burst SCS significantly increased BOLD signal levels in the raphe nuclei, nucleus accumbens, and caudate putamen. Tonic SCS did not induce a significant increase in BOLD signal levels in these areas. CONCLUSIONS: In conclusion, active recharge burst and tonic SCS have different effects on the intensity and localization of SCS-induced activation responses in the brain. This work demonstrates that active recharge burst is another waveform that can engage brain areas associated with cognitive-emotional aspects of pain as well as areas associated with location and intensity of pain. Previous studies showing similar engagement used only passive recharge burst.

Dopaminergic neurotransmission and genetic variation in chronification of post-surgical pain.

Chronic post-surgical pain (CPSP) is a debilitating condition affecting 10-50% of surgical patients. The current treatment strategy for CPSP is not optimal, and the identification of genetic variation in surgical patients might help to improve prediction and treatment of CPSP. The neurotransmitter dopamine (DA) has been associated with several chronic pain disorders. This narrative review focuses on DA neurotransmission as a potential target in the treatment of CPSP. The current knowledge on genetic variation within DA neurotransmission and its role in CPSP susceptibility are reviewed. Three genes involved in DA neurotransmission (COMT, GCH1, and DRD2) have been associated with variability in pain sensitivity, development of CPSP, and analgesic requirement. The direction of the effect of the association is sometimes inconclusive because of contradictory results, but ample evidence suggests a modulatory role of DA. Because of this modulatory role, DA is an excellent pharmacological target in the treatment of pain. Pharmacotherapy focused on DA neurotransmission has potential in both prevention (via D1-like receptors) and treatment (via D2-like receptors and DA reuptake inhibitors) of CPSP. The development of prediction models including genetic risk factors is necessary to better identify patients at risk.

Dorsal Root Ganglion Stimulation in Experimental Painful Diabetic Peripheral Neuropathy: Burst vs. Conventional Stimulation Paradigm.

OBJECTIVES: Painful diabetic peripheral neuropathy (PDPN) is a long-term complication of diabetes mellitus (DM). Dorsal Root Ganglion Stimulation (DRGS) has recently emerged as a neuromodulation modality in the treatment of chronic neuropathic pain. The objective of this study was to compare the effect of burst DRGS (Burst-DRGS) and conventional DRGS (Con-DRGS) in an experimental model of PDPN. MATERIALS AND METHODS: DM was induced in female Sprague-Dawley rats by intraperitoneal injection of streptozotocin (STZ, n = 48). Animals were tested for mechanical hypersensitivity (50% hind paw withdrawal threshold on Von Frey test) before, and 4 weeks after STZ injection. PDPN rats were then implanted with a unilateral bipolar lead at the L5 DRG (n = 22) and were stimulated for 30 min at days 2 and 3 postimplantation. Animals received Con-DRGS and Burst-DRGS in a randomized crossover design (n = 10), or received Sham-DRGS (n = 7) for 30 min, and were tested for mechanical hypersensitivity at baseline, 15 and 30 min during DRGS, and 15 and 30 min following DRGS. Five animals were withdrawn from the study due to electrode-related technical problems. RESULTS: Con-DRGS and Burst-DRGS normalized STZ-induced mechanical hypersensitivity at 15 and 30 min during stimulation. A significant difference in terms of mechanical hypersensitivity was observed between both of the stimulated groups and the Sham-DRGS group at 15 and 30 min during stimulation. Interestingly, Burst-DRGS showed signs of a residual effect at 15 min after cessation of stimulation, while this was not the case for Con-DRGS. CONCLUSIONS: Under the conditions tested, Con-DRGS and Burst-DRGS are equally effective in attenuating STZ-induced mechanical hypersensitivity in an animal model of PDPN. Burst-DRGS showed signs of a residual effect at 15 min after cessation of stimulation, which requires further investigation.

Conventional-SCS vs. Burst-SCS and the Behavioral Effect on Mechanical Hypersensitivity in a Rat Model of Chronic Neuropathic Pain: Effect of Amplitude.

OBJECTIVE: Various spinal cord stimulation (SCS) modes are used in the treatment of chronic neuropathic pain disorders. Conventional (Con) and Burst-SCS are hypothesized to exert analgesic effects through different stimulation-induced mechanisms. Preclinical electrophysiological findings suggest that stimulation intensity is correlated with the effectiveness of Burst-SCS. Therefore, we aimed to investigate the relation between amplitude (charge per second) and behavioral effects in a rat model of chronic neuropathic pain, for both Conventional Spinal Cord Stimulation (Con-SCS) and biphasic Burst-SCS. MATERIALS AND METHODS: Animals (n = 12 rats) received a unilateral partial sciatic nerve ligation, after which they were implanted with quadripolar electrodes in the epidural space at thoracic level 13. Mechanical hypersensitivity was assessed using paw withdrawal thresholds (WTs) to von Frey monofilaments, at various SCS intensities (amplitudes) and multiple time points during 60 minutes of stimulation and 30 minutes post stimulation. RESULTS: Increasing amplitude was shown to improve the efficacy of Con-SCS, whereas the efficacy of Burst-SCS showed a non-monotonic relation with amplitude. Con-SCS at 66% MT (n = 5) and Burst-SCS at 50% MT (n = 6) were found to be equally effective in normalizing mechanical hypersensitivity. However, in the assessed time period Burst-SCS required significantly more mean charge per second to do so (p < 0.01). When applied at comparable mean charge per second, Con-SCS resulted in a superior behavioral outcome (p < 0.01), compared with Burst-SCS. CONCLUSION: Biphasic Burst-SCS requires significantly more mean charge per second in order to achieve similar pain relief, as compared with Con-SCS, in an experimental model of chronic neuropathic pain.

Burst Spinal Cord Stimulation in Peripherally Injured Chronic Neuropathic Rats: A Delayed Effect.

OBJECTIVE: Two well-known spinal cord stimulation (SCS) paradigms, conventional (Con) and burst SCS, are hypothesized to exert their antinociceptive effects through different stimulation-induced mechanisms. We studied the course of the behavioral antinociceptive effect during 60 minutes of SCS and 30 minutes post-SCS in a rat model of chronic neuropathic pain. METHODS: Animals underwent a unilateral partial sciatic nerve ligation, after which quadripolar electrodes were implanted into the epidural space at vertebral level T13 (n = 43 rats). While receiving either Con SCS or biphasic burst SCS, the pain behavior of the rats was assessed by means of paw withdrawal thresholds (WTs) in response to the application of von Frey monofilaments. RESULTS: After 15 minutes of Con SCS (n = 21), WTs significantly differed from baseline (P = 0.04), whereas WTs of the burst SCS group (n = 22) did not. After 30 minutes of SCS, WTs of the Con SCS and burst SCS groups reached similar levels, both significantly different from baseline, indicating a comparable antinociceptive effect for these SCS paradigms. Yet, the WTs of the burst SCS group were still significantly increased compared with baseline at 30 minutes post-stimulation, whereas the WTs of the Con SCS group were not. CONCLUSIONS: To conclude, biphasic burst SCS results in a delayed antinociceptive effect after onset of the stimulation, as compared with Con SCS, in a chronic neuropathic pain model. Furthermore, biphasic burst SCS seems to exhibit a delayed wash-out of analgesia after stimulation is turned off.

Experimental spinal cord stimulation and neuropathic pain: mechanism of action, technical aspects, and effectiveness.

Spinal cord stimulation (SCS) is a valuable treatment for chronic intractable neuropathic pain. Although SCS has gone through a technological revolution over the last four decades, the neurophysiologic and biochemical mechanisms of action have only been partly elucidated. Animal experimental work has provided some evidence for spinal as well as supraspinal mechanisms of neuropathic pain relief of SCS. A SCS computer model of the electrical properties of the human spinal cord revealed many basic neurophysiologic principles that were clinically validated later on. The main question in clinical SCS is how to further improve the effectiveness of SCS as there is still a significant failure rate of 30%. In this context, experimental studies are needed to elucidate which target pain neuron(s) are involved, as well as with what exact electrical stimulation this target neuron can be influenced to produce an optimal supapression of neuropathic pain. This article reviews the basic clinical and experimental technical aspects in relation to the effectiveness of SCS in view of recent understanding of the dorsal horn pain circuit involved. These data may then result in experiments needed for an improved understanding of the mechanisms underlying SCS and consequently lead to improvement and increased effectiveness of SCS in neuropathic pain as a clinical therapy.

Genome-wide association study suggests a critical contribution of the adaptive immune system to chronic post-surgical pain.

Chronic post-surgical pain affects a large proportion of people undergoing surgery, delaying recovery time and worsening quality of life. Although many environmental variables have been established as risk factors, less is known about genetic risk. To uncover genetic risk factors we performed genome-wide association studies in post-surgical cohorts of five surgery types- hysterectomy, mastectomy, abdominal, hernia, and knee- totaling 1350 individuals. Genetic associations between post-surgical chronic pain levels on a numeric rating scale (NRS) and additive genetic effects at common SNPs were evaluated. We observed genome-wide significant hits in almost all cohorts that displayed significance at the SNP, gene, and pathway levels. The cohorts were then combined via a GWAS meta-analysis framework for further analyses. Using partitioned heritability, we found that loci at genes specifically expressed in the immune system carried enriched heritability, especially genes related to B and T cells. The relevance of B cells in particular was then demonstrated in mouse postoperative pain assays. Taken altogether, our results suggest a role for the adaptive immune system in chronic post-surgical pain.