BDNF in Neuropathic Pain; the Culprit that Cannot be Apprehended.

In males but not in females, brain derived neurotrophic factor (BDNF) plays an obligatory role in the onset and maintenance of neuropathic pain. Afferent terminals of injured peripheral nerves release colony stimulating factor (CSF-1) and other mediators into the dorsal horn. These transform the phenotype of dorsal horn microglia such that they express P2X4 purinoceptors. Activation of these receptors by neuron-derived ATP promotes BDNF release. This microglial-derived BDNF increases synaptic activation of excitatory dorsal horn neurons and decreases that of inhibitory neurons. It also alters the neuronal chloride gradient such the normal inhibitory effect of GABA is converted to excitation. By as yet undefined processes, this attenuated inhibition increases NMDA receptor function. BDNF also promotes the release of pro-inflammatory cytokines from astrocytes. All of these actions culminate in the increase dorsal horn excitability that underlies many forms of neuropathic pain. Peripheral nerve injury also alters excitability of structures in the thalamus, cortex and mesolimbic system that are responsible for pain perception and for the generation of co-morbidities such as anxiety and depression. The weight of evidence from male rodents suggests that this preferential modulation of excitably of supra-spinal pain processing structures also involves the action of microglial-derived BDNF. Possible mechanisms promoting the preferential release of BDNF in pain signaling structures are discussed. In females, invading T-lymphocytes increase dorsal horn excitability but it remains to be determined whether similar processes operate in supra-spinal structures. Despite its ubiquitous role in pain aetiology neither BDNF nor TrkB receptors represent potential therapeutic targets.

The Known Biology of Neuropathic Pain and Its Relevance to Pain Management.

Patients with neuropathic pain are heterogeneous in pathophysiology, etiology, and clinical presentation. Signs and symptoms are determined by the nature of the injury and factors such as genetics, sex, prior injury, age, culture, and environment. Basic science has provided general information about pain etiology by studying the consequences of peripheral injury in rodent models. This is associated with the release of inflammatory cytokines, chemokines, and growth factors that sensitize sensory nerve endings, alter gene expression, promote post-translational modification of proteins, and alter ion channel function. This leads to spontaneous activity in primary afferent neurons that is crucial for the onset and persistence of pain and the release of secondary mediators such as colony-stimulating factor 1 from primary afferent terminals. These promote the release of tertiary mediators such as brain-derived neurotrophic factor and interleukin-1ß from microglia and astrocytes. Tertiary mediators facilitate the transmission of nociceptive information at the spinal, thalamic, and cortical levels. For the most part, these findings have failed to identify new therapeutic approaches. More recent basic science has better mirrored the clinical situation by addressing the pathophysiology associated with specific types of injury, refinement of methodology, and attention to various contributory factors such as sex. Improved quantification of sensory profiles in each patient and their distribution into defined clusters may improve translation between basic science and clinical practice. If such quantification can be traced back to cellular and molecular aspects of pathophysiology, this may lead to personalized medicine approaches that dictate a rational therapeutic approach for each individual.

Lipid Tales: Optimizing Arylomycin Membrane Anchors.

Multidrug-resistant bacteria are spreading at alarming rates, and despite extensive efforts, no new antibiotic class with activity against Gram-negative bacteria has been approved in over 50 years. LepB inhibitors (LepBi) based on the arylomycin class of natural products are a novel class of antibiotics and function by inhibiting the bacterial type I signal peptidase (SPase) in Gram-negative bacteria. One critical aspect of LepBi development involves optimization of the membrane-anchored lipophilic portion of the molecule. We therefore developed an approach that assesses the effect of this portion on the complicated equilibria of plasma protein binding, crossing the outer membrane of Gram-negative bacteria and anchoring in the bacterial inner membrane to facilitate SPase binding. Our findings provide important insights into the development of antibacterial agents where the target is associated with the inner membrane of Gram-negative bacteria.

Neuropathic pain; what we know and what we should do about it.

Neuropathic pain can result from injury to, or disease of the nervous system. It is notoriously difficult to treat. Peripheral nerve injury promotes Schwann cell activation and invasion of immunocompetent cells into the site of injury, spinal cord and higher sensory structures such as thalamus and cingulate and sensory cortices. Various cytokines, chemokines, growth factors, monoamines and neuropeptides effect two-way signalling between neurons, glia and immune cells. This promotes sustained hyperexcitability and spontaneous activity in primary afferents that is crucial for onset and persistence of pain as well as misprocessing of sensory information in the spinal cord and supraspinal structures. Much of the current understanding of pain aetiology and identification of drug targets derives from studies of the consequences of peripheral nerve injury in rodent models. Although a vast amount of information has been forthcoming, the translation of this information into the clinical arena has been minimal. Few, if any, major therapeutic approaches have appeared since the mid 1990's. This may reflect failure to recognise differences in pain processing in males vs. females, differences in cellular responses to different types of injury and differences in pain processing in humans vs. animals. Basic science and clinical approaches which seek to bridge this knowledge gap include better assessment of pain in animal models, use of pain models which better emulate human disease, and stratification of human pain phenotypes according to quantitative assessment of signs and symptoms of disease. This can lead to more personalized and effective treatments for individual patients. Significance statement: There is an urgent need to find new treatments for neuropathic pain. Although classical animal models have revealed essential features of pain aetiology such as peripheral and central sensitization and some of the molecular and cellular mechanisms involved, they do not adequately model the multiplicity of disease states or injuries that may bring forth neuropathic pain in the clinic. This review seeks to integrate information from the multiplicity of disciplines that seek to understand neuropathic pain; including immunology, cell biology, electrophysiology and biophysics, anatomy, cell biology, neurology, molecular biology, pharmacology and behavioral science. Beyond this, it underlines ongoing refinements in basic science and clinical practice that will engender improved approaches to pain management.

Growth Arrest in Type IV Osteogenesis Imperfecta After Fassier-Duval Rod Insertion Treated by a Lengthening Magnetic Intramedullary Nail: A Case Report.

CASE: A child with Type IV Osteogenesis Imperfecta (OI) sustained a growth arrest of the distal femur after fixation of a left femur fracture with a Fassier-Duval expanding rod at 3 years old. Despite bar resection with fat interposition, the discrepancy progressed to 7.5 cm at maturity. Because the femur had grown to a sufficient diameter, he underwent successful lengthening with a magnetic intramedullary rod. CONCLUSION: Although it is a potential complication, growth arrest has not been reported in association with placement of an expanding nail in a child with osteogenesis imperfecta. This case illustrates this rare complication and treatment using a magnetic intramedullary rod.

Biomechanical Implications of Congenital Conditions of the Foot/Ankle.

Segmental foot and ankle models are often used as part of instrumented gait analysis when planning interventions for complex congenital foot conditions. More than 40 models have been used for clinical analysis, and it is important to understand the technical differences among models. These models have been used to improve clinical planning of pediatric foot conditions including clubfoot, planovalgus, and equinovarus. They have also been used to identify clinically relevant subgroups among pediatric populations, quantify postoperative outcomes, and explain variability in healthy populations.

A multicenter study to evaluate pain characteristics in osteogenesis imperfecta.

The objective was to describe pain characteristics and treatments used in individuals with varying severity of osteogenesis imperfecta (OI) and investigate pain-associated variables. This work was derived from a multicenter, longitudinal, observational, natural history study of OI conducted at 12 clinical sites of the NIH Rare Diseases Clinical Research Network's Brittle Bone Disorders Consortium. Children and adults with a clinical, biochemical, or molecular diagnosis of OI were enrolled in the study. We did a cross-sectional analysis of chronic pain prevalence, characteristics, and treatments used for pain relief and longitudinal analysis to find the predictors of chronic pain. We included 861 individuals with OI, in 41.8% chronic pain was present, with similar frequency across OI types. Back pain was the most frequent location. Nonsteroidal anti-inflammatory drugs followed by bisphosphonates were the most common treatment used. Participants with chronic pain missed more days from school or work/year and performed worse in all mobility metrics than participants without chronic pain. The variables more significantly associated with chronic pain were age, sex, positive history of rodding surgery, scoliosis, other medical problems, assistive devices, lower standardized height, and higher body mass index. The predictors of chronic pain for all OI types were age, use of a wheelchair, and the number of fractures/year. Chronic pain is prevalent in OI across all OI types, affects mobility, and interferes with participation. Multiple covariates were associated with chronic pain.

What are the long-term outcomes of lateral column lengthening for pes planovalgus in cerebral palsy?

BACKGROUND: Lateral column lengthening (LCL) is commonly performed on children and adolescents with cerebral palsy (CP) for correction of pes planovalgus (PPV). There are limited reports of the long-term outcomes of this procedure. The purpose of this study was to examine the long-term results of LCL for correction of PPV in individuals with CP by evaluating subjects when they had transitioned to adulthood and were entering the workforce. METHODS: Clinical assessments, quantitative gait analysis including the Milwaukee Foot Model (MFM) for segmental foot kinematics, and patient reported outcomes were collected from 13 participants with CP treated with LCL for PPV in childhood (average age 24.4 ± 5.7 years, average 15.3 ± 8.5 years since LCL). Additionally, 27 healthy adults average age 24.5 ± 3.6 years functioned as controls. RESULTS: Strength and joint range of motion were reduced in the PPV group (p < 0.05). Sixty nine percent showed operative correction of PPV based on radiologic criteria. Gait analysis showed reduced walking speed and stride length, as well as midfoot break and residual forefoot abduction. Patient reported outcomes indicated that foot pain was not the only factor that caused limited activity and participation. LCL surgery for PPV in childhood resulted in long-term operative correction. Decreased ankle passive range of motion and strength, subtalar joint arthritic changes, inefficient and less stable ambulation, and problems with participation (difficulties in physical function, education, and employment) were observed in the long-term. CONCLUSION: This study identified postoperative impairments and limitations to guide future clinical decision-making. These results provide clinicians and researchers the common residual and recurrent issues for these individuals as they age. The inclusion of contextual factors that influence the disease and impairments can equip these individuals with enhanced skills they need as they transition into adulthood.

Potent Killing of Pseudomonas aeruginosa by an Antibody-Antibiotic Conjugate.

Pseudomonas aeruginosa causes life-threatening infections that are associated with antibiotic failure. Previously, we identified the antibiotic G2637, an analog of arylomycin, targeting bacterial type I signal peptidase, which has moderate potency against P. aeruginosa. We hypothesized that an antibody-antibiotic conjugate (AAC) could increase its activity by colocalizing P. aeruginosa bacteria with high local concentrations of G2637 antibiotic in the intracellular environment of phagocytes. Using a novel technology of screening for hybridomas recognizing intact bacteria, we identified monoclonal antibody 26F8, which binds to lipopolysaccharide O antigen on the surface of P. aeruginosa bacteria. This antibody was engineered to contain 6 cysteines and was conjugated to the G2637 antibiotic via a lysosomal cathepsin-cleavable linker, yielding a drug-to-antibody ratio of approximately 6. The resulting AAC delivered a high intracellular concentration of free G2637 upon phagocytosis of AAC-bound P. aeruginosa by macrophages, and potently cleared viable P. aeruginosa bacteria intracellularly. The molar concentration of AAC-associated G2637 antibiotic that resulted in elimination of bacteria inside macrophages was approximately 2 orders of magnitude lower than the concentration of free G2637 required to eliminate extracellular bacteria. This study demonstrates that an anti-P. aeruginosa AAC can locally concentrate antibiotic and kill P. aeruginosa inside phagocytes, providing additional therapeutic options for antibiotics that are moderately active or have an unfavorable pharmacokinetics or toxicity profile. IMPORTANCE Antibiotic treatment of life-threatening P. aeruginosa infections is associated with low clinical success, despite the availability of antibiotics that are active in standard microbiological in vitro assays, affirming the need for new therapeutic approaches. Antibiotics often fail in the preclinical stage due to insufficient efficacy against P. aeruginosa. One potential strategy is to enhance the local concentration of antibiotics with limited inherent anti-P. aeruginosa activity. This study presents proof of concept for an antibody-antibiotic conjugate, which releases a high local antibiotic concentration inside macrophages upon phagocytosis, resulting in potent intracellular killing of phagocytosed P. aeruginosa bacteria. This approach may provide new therapeutic options for antibiotics that are dose limited.

Are sensory neurons exquisitely sensitive to interleukin 1ß?

Peripheral nerve injury frequently evokes chronic neuropathic pain. This is initiated by a transient inflammatory response that leads to persistent excitation of dorsal root ganglion (DRG) neurons by inflammatory cytokines such as interleukin 1ß(IL-1ß). In non-neuronal cells such as lymphocytes, interleukin 1 exerts actions at attomolar (aM; 10-18 M) concentrations. We now report that DRG neurons in defined-medium, neuron-enriched culture display increased excitability following 5-6 d exposure of 1aM IL-1ß. This response is mediated in part by type 1 interleukin receptors and involves decreased function of putative KCa1.1 channels. This finding provides new insights into the neuroimmune interactions responsible for neuropathic pain.

Single-molecule nanopore sequencing reveals extreme target copy number heterogeneity in arylomycin-resistant mutants.

Tandem gene amplification is a frequent and dynamic source of antibiotic resistance in bacteria. Ongoing expansions and contractions of repeat arrays during population growth are expected to manifest as cell-to-cell differences in copy number (CN). As a result, a clonal bacterial culture could comprise subpopulations of cells with different levels of antibiotic sensitivity that result from variable gene dosage. Despite the high potential for misclassification of heterogenous cell populations as either antibiotic-susceptible or fully resistant in clinical settings, and the concomitant risk of inappropriate treatment, CN distribution among cells has defied analysis. Here, we use the MinION single-molecule nanopore sequencer to uncover CN heterogeneity in clonal populations of Escherichia coli and Acinetobacter baumannii grown from single cells isolated while selecting for resistance to an optimized arylomycin, a member of a recently discovered class of Gram-negative antibiotic. We found that gene amplification of the arylomycin target, bacterial type I signal peptidase LepB, is a mechanism of unstable arylomycin resistance and demonstrate in E. coli that amplification instability is independent of RecA. This instability drives the emergence of a nonuniform distribution of lepB CN among cells with a range of 1 to at least 50 copies of lepB identified in a single clonal population. In sum, this remarkable heterogeneity, and the evolutionary plasticity it fuels, illustrates how gene amplification can enable bacterial populations to respond rapidly to novel antibiotics. This study establishes a rationale for further nanopore-sequencing studies of heterogeneous cell populations to uncover CN variability at single-molecule resolution.

Chronic BDNF simultaneously inhibits and unmasks superficial dorsal horn neuronal activity.

Brain-derived neurotrophic factor (BDNF) is critically involved in the pathophysiology of chronic pain. However, the mechanisms of BDNF action on specific neuronal populations in the spinal superficial dorsal horn (SDH) requires further study. We used chronic BDNF treatment (200 ng/ml, 5-6 days) of defined-medium, serum-free spinal organotypic cultures to study intracellular calcium ([Ca2+]i) fluctuations. A detailed quantitative analysis of these fluctuations using the Frequency-independent biological signal identification (FIBSI) program revealed that BDNF simultaneously depressed activity in some SDH neurons while it unmasked a particular subpopulation of 'silent' neurons causing them to become spontaneously active. Blockade of gap junctions disinhibited a subpopulation of SDH neurons and reduced BDNF-induced synchrony in BDNF-treated cultures. BDNF reduced neuronal excitability assessed by measuring spontaneous excitatory postsynaptic currents. This was similar to the depressive effect of BDNF on the [Ca2+]i fluctuations. This study reveals novel regulatory mechanisms of SDH neuronal excitability in response to BDNF.

Peripheral Voltage-Gated Cation Channels in Neuropathic Pain and Their Potential as Therapeutic Targets.

The persistence of increased excitability and spontaneous activity in injured peripheral neurons is imperative for the development and persistence of many forms of neuropathic pain. This aberrant activity involves increased activity and/or expression of voltage-gated Na+ and Ca2+ channels and hyperpolarization activated cyclic nucleotide gated (HCN) channels as well as decreased function of K+ channels. Because they display limited central side effects, peripherally restricted Na+ and Ca2+ channel blockers and K+ channel activators offer potential therapeutic approaches to pain management. This review outlines the current status and future therapeutic promise of peripherally acting channel modulators. Selective blockers of Nav1.3, Nav1.7, Nav1.8, Cav3.2, and HCN2 and activators of Kv7.2 abrogate signs of neuropathic pain in animal models. Unfortunately, their performance in the clinic has been disappointing; some substances fail to meet therapeutic end points whereas others produce dose-limiting side effects. Despite this, peripheral voltage-gated cation channels retain their promise as therapeutic targets. The way forward may include (i) further structural refinement of K+ channel activators such as retigabine and ASP0819 to improve selectivity and limit toxicity; use or modification of Na+ channel blockers such as vixotrigine, PF-05089771, A803467, PF-01247324, VX-150 or arachnid toxins such as Tap1a; the use of Ca2+ channel blockers such as TTA-P2, TTA-A2, Z 944, ACT709478, and CNCB-2; (ii) improving methods for assessing "pain" as opposed to nociception in rodent models; (iii) recognizing sex differences in pain etiology; (iv) tailoring of therapeutic approaches to meet the symptoms and etiology of pain in individual patients via quantitative sensory testing and other personalized medicine approaches; (v) targeting genetic and biochemical mechanisms controlling channel expression using anti-NGF antibodies such as tanezumab or re-purposed drugs such as vorinostat, a histone methyltransferase inhibitor used in the management of T-cell lymphoma, or cercosporamide a MNK 1/2 inhibitor used in treatment of rheumatoid arthritis; (vi) combination therapy using drugs that are selective for different channel types or regulatory processes; (vii) directing preclinical validation work toward the use of human or human-derived tissue samples; and (viii) application of molecular biological approaches such as clustered regularly interspaced short palindromic repeats (CRISPR) technology.

Mediators of Neuropathic Pain; Focus on Spinal Microglia, CSF-1, BDNF, CCL21, TNF-α, Wnt Ligands, and Interleukin 1ß.

Intractable neuropathic pain is a frequent consequence of nerve injury or disease. When peripheral nerves are injured, damaged axons undergo Wallerian degeneration. Schwann cells, mast cells, fibroblasts, keratinocytes and epithelial cells are activated leading to the generation of an "inflammatory soup" containing cytokines, chemokines and growth factors. These primary mediators sensitize sensory nerve endings, attract macrophages, neutrophils and lymphocytes, alter gene expression, promote post-translational modification of proteins, and alter ion channel function in primary afferent neurons. This leads to increased excitability and spontaneous activity and the generation of secondary mediators including colony stimulating factor 1 (CSF-1), chemokine C-C motif ligand 21 (CCL-21), Wnt3a, and Wnt5a. Release of these mediators from primary afferent neurons alters the properties of spinal microglial cells causing them to release tertiary mediators, in many situations via ATP-dependent mechanisms. Tertiary mediators such as BDNF, tumor necrosis factor α (TNF-α), interleukin 1ß (IL-1ß), and other Wnt ligands facilitate the generation and transmission of nociceptive information by increasing excitatory glutamatergic transmission and attenuating inhibitory GABA and glycinergic transmission in the spinal dorsal horn. This review focusses on activation of microglia by secondary mediators, release of tertiary mediators from microglia and a description of their actions in the spinal dorsal horn. Attention is drawn to the substantial differences in the precise roles of various mediators in males compared to females. At least 25 different mediators have been identified but the similarity of their actions at sensory nerve endings, in the dorsal root ganglia and in the spinal cord means there is considerable redundancy in the available mechanisms. Despite this, behavioral studies show that interruption of the actions of any single mediator can relieve signs of pain in experimental animals. We draw attention this paradox. It is difficult to explain how inactivation of one mediator can relieve pain when so many parallel pathways are available.

K+ Channels in Primary Afferents and Their Role in Nerve Injury-Induced Pain.

Sensory abnormalities generated by nerve injury, peripheral neuropathy or disease are often expressed as neuropathic pain. This type of pain is frequently resistant to therapeutic intervention and may be intractable. Numerous studies have revealed the importance of enduring increases in primary afferent excitability and persistent spontaneous activity in the onset and maintenance of peripherally induced neuropathic pain. Some of this activity results from modulation, increased activity and /or expression of voltage-gated Na+ channels and hyperpolarization-activated cyclic nucleotide-gated (HCN) channels. K+ channels expressed in dorsal root ganglia (DRG) include delayed rectifiers (Kv1.1, 1.2), A-channels (Kv1.4, 3.3, 3.4, 4.1, 4.2, and 4.3), KCNQ or M-channels (Kv7.2, 7.3, 7.4, and 7.5), ATP-sensitive channels (KIR6.2), Ca2+-activated K+ channels (KCa1.1, 2.1, 2.2, 2.3, and 3.1), Na+-activated K+ channels (KCa4.1 and 4.2) and two pore domain leak channels (K2p; TWIK related channels). Function of all K+ channel types is reduced via a multiplicity of processes leading to altered expression and/or post-translational modification. This also increases excitability of DRG cell bodies and nociceptive free nerve endings, alters axonal conduction and increases neurotransmitter release from primary afferent terminals in the spinal dorsal horn. Correlation of these cellular changes with behavioral studies provides almost indisputable evidence for K+ channel dysfunction in the onset and maintenance of neuropathic pain. This idea is underlined by the observation that selective impairment of just one subtype of DRG K+ channel can produce signs of pain in vivo. Whilst it is established that various mediators, including cytokines and growth factors bring about injury-induced changes in DRG function and excitability, evidence presently available points to a seminal role for interleukin 1ß (IL-1ß) in control of K+ channel function. Despite the current state of knowledge, attempts to target K+ channels for therapeutic pain management have met with limited success. This situation may change with the advent of personalized medicine. Identification of specific sensory abnormalities and genetic profiling of individual patients may predict therapeutic benefit of K+ channel activators.

A Multicenter Study of Intramedullary Rodding in Osteogenesis Imperfecta.

BACKGROUND: Osteogenesis imperfecta (OI), a heritable connective tissue disorder with wide clinical variability, predisposes to recurrent fractures and bone deformity. Management requires a multidisciplinary approach in which intramedullary rodding plays an important role, especially for moderate and severe forms. We investigated the patterns of surgical procedures in OI in order to establish the benefits of rodding. The main hypothesis that guided this study was that rodded participants with moderate and severe OI would have lower fracture rates and better mobility. METHODS: With data from the Linked Clinical Research Centers, we analyzed rodding status in 558 individuals. Mobility and fracture data in OI Types III and IV were compared between rodded and non-rodded groups. Univariate regression analyses were used to test the association of mobility outcomes with various covariates pertinent to rodding. RESULTS: Of the individuals with OI, 42.1% had undergone rodding (10.7% of those with Type I, 66.4% with Type III, and 67.3% with Type IV). Rodding was performed more frequently and at a younger age in femora compared with tibiae. Expanding intramedullary rods were used more frequently in femora. In Type III, the rate of fractures per year was significantly lower (p ≤ 0.05) for rodded bones. In Type III, the mean scores on the Gillette Functional Assessment Questionnaire (GFAQ) and Brief Assessment of Motor Function (BAMF) were higher in the rodded group. However, Type-IV non-rodded subjects had higher mean scores in nearly all mobility outcomes. OI type, the use of expanding rods in tibiae, and anthropometric measurements were associated with mobility outcomes scores. CONCLUSIONS: Current practice in 5 orthopaedic centers with extensive experience treating OI demonstrates that most individuals with moderate and severe types of OI undergo rodding procedures. Individuals with severe OI have improved mobility outcomes and lower fracture rates compared with their non-rodded peers, which suggests that early bilateral rodding benefits OI Type III. Our analysis showed a change in practice patterns in the final years of the study in the severe forms, with earlier and more simultaneous rodding procedures performed. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

Do Bisphosphonates Alleviate Pain in Children? A Systematic Review.

PURPOSE OF REVIEW: The goal of this systematic review is to analyze the effectiveness of bisphosphonates (BPs) to treat bone pain in children and adolescents who have diseases with skeletal involvement. RECENT FINDINGS: We included 24 studies (2 randomized controlled trials, 3 non-randomized controlled trials, 10 non-randomized open-label uncontrolled studies, 8 retrospective studies, and 1 study with design not specified). The majority of included studies assessed pain from a unidimensional approach, with pain intensity the most frequently evaluated dimension. Only 38% of studies used validated tools; visual analogue scale was the most frequently employed. BPs were used to alleviate bone pain in a wide variety of pediatrics conditions such as osteogenesis imperfecta, secondary osteoporosis, osteonecrosis related to chemotherapy, chronic non-bacterial osteitis, idiopathic juvenile osteoporosis, unresectable benign bone tumor, and cancer-related pain. Twenty of the 24 studies reported a positive effect of BPs for alleviating pain in different pathologies, but 58% of the studies were categorized as having high risk of bias. Intravenous BPs are helpful in alleviating bone pain in children and adolescents. It is advised that our results be interpreted with caution due to the heterogeneity of the doses used, duration of treatments, and types of pathologies included. In addition, this review shows the paucity of high-quality evidence in the available literature and further research is needed. TRIAL REGISTRATION: Before the completion of this review, the protocol was registered to PROSPERO (International prospective register of systematic reviews), PROSPERO 2020 ID # CRD42020158316. Available from: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020158316.

Time Course of Inflammation in Dorsal Root Ganglia Correlates with Differential Reversibility of Mechanical Allodynia.

Some individuals recover from the pain of nerve trauma within 12 months or less whereas others experience life-long intractable pain. This transition between reversible pain and the establishment of chronic neuropathic pain is poorly understood. We examined the role of persistent inflammation in the dorsal root ganglia (DRG) in the long-term maintenance of mechanical allodynia; an index of neuropathic pain. Male Sprague-Dawley rats underwent chronic constriction injury (CCI), spared nerve injury (SNI) or sham surgery. Both CCI and SNI animals displayed robust mechanical allodynia in the ipsilateral paw at 7 d post-surgery; however, only SNI animals maintained mechanical allodynia at 42 d post-surgery. DRGs were extracted at 7 d or 42 d post-surgery to assess inflammation via rt-qPCR or immunohistochemistry to measure colony stimulating factor 1 (CSF1) expression, satellite glial cell (SGC) activation, presence of Iba1 positive macrophages and interleukin1 ß (IL-1ß) mRNA levels. Whereas DRGs from SNI animals continued to display inflammatory markers at 42 d, those from CCI animals did not. Moreover, the level of allodynia displayed by each individual animal correlated with the extent of DRG inflammation. These data support the hypothesis that the amount of CSF1 immunoreactivity and the persistence of inflammation in ipsilateral DRGs contribute to the difference between transient and persistent mechanical allodynia observed in the CCI and SNI models. We also suggest that feedback loops involving cytokines and neurotransmitters may contribute to increased DRG activity in chronic neuropathic pain. Consequently, targeting persistent CSF1 production and peripheral neuroinflammation may be an effective approach to the management of chronic neuropathic pain.