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.

Ninety-Hz Spinal Cord Stimulation-Induced Analgesia Is Dependent on Active Charge Balance and Is Nonlinearly Related to Amplitude: A Sham-Controlled Behavioral Study in a Rodent Model of Chronic Neuropathic Pain.

BACKGROUND: Ninety-Hz active-recharge spinal cord stimulation (SCS) applied at below sensory-threshold intensity, as used with fast-acting subperception therapy spinal cord stimulation, has been shown clinically to produce significant analgesia, but additional characterization is required to better understand the therapy. This preclinical study investigates the behavioral effect of multiple 90-Hz SCS variants in a rodent model of neuropathic pain, focusing on charge balance and the relationship between 90-Hz efficacy and stimulation intensity. MATERIALS AND METHODS: Rats (n = 24) received a unilateral partial sciatic nerve ligation to induce neuropathic pain and were implanted with a quadripolar lead at T13. Mechanical hypersensitivity was assessed before, during, and after 60 minutes of SCS. After a prescreen with 50-Hz SCS 67% motor threshold ([MT], the positive control), rats underwent a randomized-crossover study including sham SCS and several 90-Hz SCS paradigms (at 40% MT or 60% MT, either using active or pseudopassive recharge) (experiment 1, n = 16). A second, identical experiment (experiment 2) was performed to supplement data with 90-Hz SCS at 20% and 80% MT (experiment 2, n = 8). RESULTS: Experiment 1: At 40% MT, 90-Hz active-recharge SCS produced a significantly larger recovery to baseline than did 90-Hz pseudopassive SCS at both tested intensities and sham SCS. Experiment 2: Only the 90-Hz SCS active recharge at 40% MT and 50-Hz SCS positive control caused mean recovery to baseline that was statistically better than that of sham SCS. CONCLUSIONS: The degree to which 90-Hz SCS reduced mechanical hypersensitivity during stimulation depended on the nature of charge balance, with 90-Hz active-recharge SCS generating better responses than did 90-Hz pseudopassive recharge SCS. In addition, our findings suggest that the amplitude of 90-Hz active-recharge SCS must be carefully configured for efficacy.

Burst Spinal Cord Stimulation as Compared With L2 Dorsal Root Ganglion Stimulation in Pain Relief for Nonoperated Discogenic Low Back Pain: Analysis of Two Prospective Studies.

INTRODUCTION: Chronic discogenic low back pain (CD-LBP) is caused by degenerated disks marked by neural and vascular ingrowth. Spinal cord stimulation (SCS) has been shown to be effective for pain relief in patients who are not responsive to conventional treatments. Previously, the pain-relieving effect of two variations of SCS has been evaluated in CD-LBP: Burst SCS and L2 dorsal root ganglion stimulation (DRGS). The aim of this study is to compare the effectivity in pain relief and pain experience of Burst SCS with that of conventional L2 DRGS in patients with CD-LBP. MATERIALS AND METHODS: Subjects were implanted with either Burst SCS (n = 14) or L2 DRGS with conventional stimulation (n = 15). Patients completed the numeric pain rating score (NRS) for back pain and Oswestry disability index (ODI) and EuroQoL 5D (EQ-5D) questionnaires at baseline, and at three, six, and 12 months after implantation. Data were compared between time points and between groups. RESULTS: Both Burst SCS and L2 DRGS significantly decreased NRS, ODI, and EQ-5D scores as compared with baseline. L2 DRGS resulted in significantly lower NRS scores at 12 months and significantly increased EQ-5D scores at six and 12 months. CONCLUSIONS: Both L2 DRGS and Burst SCS resulted in reduction of pain and disability, and increased quality of life in patients with CD-LBP. L2 DRGS provided significantly increased pain relief and improvement in quality of life when compared with Burst SCS. CLINICAL TRIAL REGISTRATION: The clinical trial registration numbers for the study are NCT03958604 and NL54405.091.15.

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.

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.

Conventional, high frequency and differential targeted multiplexed spinal cord stimulation in experimental painful diabetic peripheral neuropathy: Pain behavior and role of the central inflammatory balance.

Spinal cord stimulation (SCS) is a last resort treatment for pain relief in painful diabetic peripheral neuropathy (PDPN) patients. However, the effectivity of SCS in PDPN is limited. New SCS paradigms such as high frequency (HF) and differential target multiplexed (DTM) might improve responder rates and efficacy of SCS-induced analgesia in PDPN patients, and are suggested to modulate the inflammatory balance and glial response in the spinal dorsal horn. The aim of this study was to research the effects of Con-, HF- and DTM-SCS on pain behavior and the spinal inflammatory balance in an animal model of PDPN. Streptozotocin-induced PDPN animals were stimulated for 48 hours with either Con-SCS (50Hz), HF-SCS (1200Hz) or DTM-SCS (combination of Con- and HF-SCS). Mechanical hypersensitivity was assessed using Von Frey (VF) test and the motivational aspects of pain were assessed using the mechanical conflict avoidance system (MCAS). The inflammatory balance and glial response were analyzed in the dorsal spinal cord based on RNA expression of pro- and anti-inflammatory cytokines (Tnf-α, Il-1ß, Il-4, Il-10), a microglia marker (Itgam), an astrocyte marker (Gfap), a T-cell marker (Cd3d), microglia proliferation markers (Irf8, Adgre1) and P2X4, p13-MAPK, BDNF signaling markers (P2x4, Mapk14, Bdnf). The results show that Con-, HF-, and DTM-SCS significantly decreased hypersensitivity after 48 hours of stimulation compared to Sham-SCS in PDPN animals, but at the same time did not affect escape latency in the MCAS. At the molecular level, Con-SCS resulted in a significant increase in spinal pro-inflammatory cytokine Tnf-α after 48 hours compared to DTM-SCS and Sham-SCS. In summary, Con-SCS showed a shift of the inflammatory balance towards a pro-inflammatory state whilst HF- and DTM-SCS shifted the balance towards an anti-inflammatory state. These findings suggest that the underlying mechanism of Con-SCS induced pain relief in PDPN differs from that induced by HF- and DTM-SCS.

Replacement Adaptor 09106 for patients with a dynamic graciloplasty or patients with sacral neuromodulation and abdominal implantable pulse generators: a retrospective, single centre, Stage 2a/2b development IDEAL case series.

AIM: Due to the introduction of a new implantable pulse generator (IPG), the Interstim II, patients with either a dynamic graciloplasty or an abdominally placed IPG for sacral neuromodulation could not undergo surgery to replace their IPG in the case of end of battery life. For these patients, the Medtronic Replacement Adaptor 09106 was created. This retrospective case series aims to study safety and feasibility of the Medtronic Replacement Adaptor 09106 in patients with abdominally placed IPGs. METHODS: Seventeen patients (11 women, six men) received a replacement adaptor with a follow-up of 6 months. Outcome measures consisted of a bowel habit diary. Adverse events were classified using the Clavien-Dindo classification. RESULTS: Outcome measures in the bowel habit diaries after replacement (feasibility) did not differ significantly from outcome measures before replacement. Adverse events occurred in four out of 17 patients (24%): two patients initially showed pocket site pain (Clavien-Dindo Grade I), which resolved without intervention. One patient suffered from poor wound closure (Clavien-Dindo Grade II) and one patient had persisting pocket pain (Clavien-Dindo Grade IIIa) for which a pocket revision was performed. Statistical analyses were performed making paired comparisons using a Wilcoxon signed rank test. CONCLUSION: The Medtronic Replacement Adaptor 09106 is a valuable option for patients with dynamic graciloplasty or sacral neuromodulation and abdominal IPG and has complication rates similar to replacement of the Interstim without Replacement Adaptor 09106.

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.

A prospective study of BurstDR™ spinal cord stimulation for non-operated discogenic low back pain.

INTRODUCTION: Chronic discogenic low back pain (CD-LBP) is caused by degeneration of the disc due to trauma to the annulus or by unprovoked degeneration, resulting in chronic pain. Spinal cord stimulation (SCS) employing the BurstDR™ waveform has been shown to be an effective treatment in a variety of chronic pain conditions. The aim of this prospective case study was to determine the effect of BurstDR™ SCS on pain relief, disability, and patient satisfaction in a population with CD-LBP. METHODS: Seventeen subjects with CD-LBP received a SCS trial with BurstDR™ stimulation. Patients with >50% pain relief after a trial period of 2 weeks were permanently implanted (n = 15). Patients then rated LBP and leg pain using the numeric rating scale (NRS), Oswestry disability index (ODI), patient global impression of change (PGIC), EQ-5D quality of life, and painDETECT for neuropathic pain at baseline following trial, 3, 6, and 12 months after permanent implantation. RESULTS: Treatment with BurstDR™ SCS resulted in significant reduction of LBP as the NRS was reduced from 71.7 ± 7.3 at baseline to 42.5 ± 18.1 at 12 months. Average pain relief at 12 months was 42.5%. In patients with leg pain (n = 8), pain was significantly reduced from 66.9 ± 8.2 to 11.7 ± 10.4 at 12 months. PainDETECT scores for neuropathic pain significantly reduced from 18.9 ± 4.8 at baseline, and 14.8 ± 3.2 at 12 months. Baseline ODI score significantly reduced from 41.2 ± 12.8 to 25.8 ± 8.6 at 12 months. PGIC scores remained low from 2.6 ± 1.6 at 3 months, 2.5 ± 1.0 at 6 months, and 2.5 ± 1.3 at 12 months. EQ-5D-5L rates remained constant from baseline 56.10 ± 23.9 to 68.6 ± 12.9 at 12 months. CONCLUSION: BurstDR™ SCS resulted in significant reduction of back pain, leg pain, and quality of life in patients with CD-LBP and decreased the level of disability and generated positive patient satisfaction scores.

Early-life exposure to selective serotonin reuptake inhibitors: Long-term effects on pain and affective comorbidities.

A growing body of evidence indicates that early-life exposure to selective serotonin reuptake inhibitor has long-term consequences on the offspring's pain in addition to affective disorders like anxiety disorder and major depression. Serotonin, besides its role in regulating pain and emotions, promotes neuronal network formation. The prefrontal cortex and the amygdala are two key brain regions involved in the modulation of pain and its affective comorbidities. Thus, the aim of this review is to understand how early-life selective serotonin reuptake inhibitor exposure alters the developing prefrontal cortex and amygdala and thereby underlies the long-term changes in pain and its affective comorbidities in later life. While there is still limited data on the effects of early-life selective serotonin reuptake inhibitor exposure on pain, there is a substantial body of evidence on its affective comorbidities. From this perspective paper, four conclusions emerged. First, early-life selective serotonin reuptake inhibitor exposure results in long-term nociceptive effects, which needs to be consistently studied to clarify. Second, it results in enhanced depressive-like behaviour and diminished exploratory behaviour in adult rodents. Third, early-life selective serotonin reuptake inhibitor exposure alters serotonergic levels, transcription factors expression, and brain-derived neurotrophic factor levels, resulting in hyperconnectivity within the amygdala and the prefrontal cortex. Finally, it affects antinociceptive inputs of the prefrontal cortex and the amygdala in the spinal cord. We conclude that early-life selective serotonin reuptake inhibitor exposure affects the maturation of prefrontal cortex and amygdala circuits and thereby enhances their antinociceptive inputs in the spinal cord.

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.

A systematic review on descending serotonergic projections and modulation of spinal nociception in chronic neuropathic pain and after spinal cord stimulation.

Chronic neuropathic pain is a debilitating ordeal for patients worldwide and pharmacological treatment efficacy is still limited. As many pharmacological interventions for neuropathic pain often fail, insights into the underlying mechanism and role of identified receptors is of utmost importance. An important target for improving treatment of neuropathic pain is the descending serotonergic system as these projections modulate nociceptive signaling in the dorsal horn. Also with use of last resort treatments like spinal cord stimulation (SCS), the descending serotonergic projections are known to be involved in the pain relieving effect. This systematic review summarizes the involvement of the serotonergic system on nociceptive modulation in the healthy adult rodent and the chronic neuropathic rodent and summarizes all available literature on the serotonergic system in the SCS-treated neuropathic rodent. Medline, Embase and Pubmed databases were used in the search for articles. Descending serotonergic modulation of nociceptive signaling in spinal dorsal horn in normal adult rat is mainly inhibitory and mediated by 5-HT1a, 5-HT1b, 5-HT2c, 5-HT3 and 5-HT4 receptors. Upon injury and in the neuropathic rat, this descending serotonergic modulation becomes facilitatory via activation of the 5-HT2a, 5-HT2b and 5-HT3 receptors. Analgesia due to neuromodulatory intervention like SCS restores the inhibitory function of the descending serotonergic system and involves 5-HT2, 5-HT3 and 5-HT4 receptors. The results of this systematic review provide insights and suggestions for further pharmacological and or neuromodulatory treatment of neuropathic pain based on targeting selected serotonergic receptors related to descending modulation of nociceptive signaling in spinal dorsal horn. With the novel developed SCS paradigms, the descending serotonergic system will be an important target for mechanism-based stimulation induced analgesia.

Methadone effectively attenuates acute and long-term consequences of neonatal repetitive procedural pain in a rat model.

BACKGROUND: Painful procedures in early life cause acute pain and can alter pain processing at a spinal level lasting into adulthood. Current methods of analgesia seem unable to prevent both acute and long-term hypersensitivity associated with neonatal pain. The current study aims to prevent acute and long-term hypersensitivity associated with neonatal procedural pain using methadone analgesia in rat pups. METHODS: Sprague-Dawley rat pups received either methadone (1 mg/kg) or saline prior to repetitive needle pricks into the left hind paw from the day of birth (postnatal day (P)0) to P7. Control littermates received a tactile stimulus. Mechanical sensitivity was assessed during the neonatal period (P0-P7), from weaning to adulthood (3-7 weeks) and following surgical re-injury of the same dermatome in adulthood. RESULTS: Methadone administration completely reversed acute hypersensitivity from P0 to P7. In addition, neonatal methadone analgesia prevented prolonged hypersensitivity after re-injury in adulthood, without affecting sensitivity from weaning to adulthood. CONCLUSIONS: The current study shows that neonatal methadone analgesia can attenuate acute as well as long-term hypersensitivity associated with neonatal procedural pain in a rat model. IMPACT: Methadone treatment attenuates acute and long-term hypersensitivity associated with neonatal pain in a rat model. Clinical effectiveness studies are urgently warranted to assess acute and long-term analgesic effectivity of methadone.

Neonatal procedural pain affects state, but not trait anxiety behavior in adult rats.

The influence of neonatal experiences upon later-life affective behavior is increasingly recognized, but the reported effects on anxiety are often contradictory. The observed effect may depend upon the type of anxiety (state or trait) affected. The current study aims to investigate whether neonatal repetitive needle pricking alters anxiety behavior in adulthood, by assessing both state and trait anxiety in rats. Sprague-Dawley rat pups received four unilateral needle pricks per day, while controls received four tactile stimuli or were left completely undisturbed during the first postnatal week. Mechanical sensitivity was assessed in the neonatal phase and throughout the development. State anxiety was assessed in the open field test and trait anxiety in the elevated zero maze. The results show that repetitive needle pricking leads to acute mechanical hypersensitivity, but does not affect baseline mechanical sensitivity throughout development. In adulthood, animals previously exposed to neonatal procedural pain (including repetitive handling and removal from litter) showed lower state anxiety but did not differ in trait anxiety, as compared with the undisturbed controls. These findings indicate that early-life procedural pain decreases state but not trait anxiety behavior in later life in a rodent model of repetitive needle pricking.

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.

Dorsal Root Ganglion Stimulation for the Management of Intractable Painful Polyneuropathy: A Prospective Pilot Study.

OBJECTIVES: Dorsal root ganglion stimulation (DRGS) is a promising neurostimulation modality in the treatment of painful polyneuropathy. The aim of this prospective pilot study was to investigate the effect of DRGS on pain intensity in patients with intractable painful polyneuropathy. MATERIALS AND METHODS: Nine patients with chronic, intractable painful polyneuropathy in the lower limbs were recruited. In each subject, between two and four DRGS leads were placed at the level of the L5 and S1 dorsal root ganglion. If trial stimulation was successful, a definitive implantable pulse generator (IPG) was implanted. Pain intensity was scored using an 11-point numeric rating scale (NRS) and reported as median and interquartile range (IQR), and compared to baseline values using the Wilcoxon signed-rank test. Additionally, patients' global impression of change (PGIC), pain extent, presence of neuropathic pain, physical functioning, quality of life, and mood were assessed. RESULTS: Eight out of nine patients had a successful trial phase, of which seven received an IPG. Daytime pain decreased from a median (IQR) NRS score of 7.0 (5.9-8.3) to 2.0 (1.0-3.5) and 3.0 (1.6-4.9) in the first week and at six months after implantation, respectively. Similar effects were observed for night time and peak pain scores. CONCLUSIONS: The results of this study suggest that DRGS significantly reduces both pain intensity and PGIC in patients with intractable painful polyneuropathy in the lower extremities. Large-scale clinical trials are needed to prove the efficacy of DRGS in intractable painful polyneuropathy.

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.