Role In Central Sensitization Research Articles

A Preliminary Investigation of the Mechanism of P2RX3- mediated Central Sensitization in Migraine

Migraine is a prevalent neurological disorder affecting approximately 15% of the global population, but its pathogenesis has not yet been elucidated. Migraine pathogenesis is importantly associated with central sensitization, and P2RX3 plays a key role in central sensitization. In this study, we investigated the mechanism of P2RX3 in central sensitization of migraine, with the aim of providing a new theoretical basis for migraine treatment.

Inflammation-induced mast cell-derived nerve growth factor: a key player in chronic vulvar pain?

Provoked vulvodynia (PV) is characterized by localized chronic vulvar pain. It is associated with a history of recurrent inflammation, mast cell (MC) accumulation, and neuronal sprouting in the vulva. However, the mechanism of how vulvar-inflammation promotes neuronal sprouting and gene-expression adaptation in the spinal cord, leading to hypersensitivity and painful sensations, is unknown. Here, we found that vulvar tissue from women with PV (n=8) is characterized by MC accumulation and neuronal sprouting compared to women without PV (n=4). In addition, we observed these changes in an animal study of PV. Thus, we found that repeated vulvar zymosan-inflammation challenges lead to long-lasting mechanical and thermal vulvar hypersensitivity, which was mediated by MC accumulation, neuronal sprouting, overexpression of the pain channels (TRPV1 and TRPA1) in vulvar neurons, as well as a long-term increase of gene expression related to neuroplasticity, neuroinflammation, and nerve growth factor (NGF) in the spinal cord/DRG(L6-S3). However, regulation of the NGF pathway by stabilization of MC activity with ketotifen fumarate (KF) during vulvar inflammation attenuated the local increase of NGF and histamine, as well as the elevated transcription of pro-inflammatory cytokines, and NGF pathway in the spinal cord. Additionally, KF treatment during inflammation modulates MC accumulation, neuronal hyperinnervation, and overexpression of the TRPV1 and TRPA1 channels in the vulvar neurons, consequently preventing the development of vulvar pain. A thorough examination of the NGF pathway during inflammation revealed that blocking NGF activity by using an NGF-non-peptide-inhibitor (Ro08-2750) regulates the upregulation of genes related to neuroplasticity, and NGF pathway in the spinal cord, as well as modulates neuronal sprouting and overexpression of the pain channels, resulting in a reduced level of vulvar hypersensitivity. On the other hand, stimulation of the NGF pathway in the vulvar promotes neuronal sprouting, overexpression of pain channels, and increase of gene expression related to neuroplasticity, neuroinflammation, and NGF in the spinal cord, resulting in long-lasting vulvar hypersensitivity. In conclusion, our findings suggest that vulvar allodynia induced by inflammation is mediated by MC accumulation, neuronal sprouting, and neuromodulation in the vulvar. Additionally, chronic vulvar pain may involve a long-term adaptation in gene expression in the spinal cord, which probably plays a critical role in central sensitization and pain maintenance. Strikingly, regulating the NGF pathway during the critical period of inflammation prevents vulvar pain development via modulating the neuronal changes in the vestibule and spinal cord, suggesting a fundamental role for the NGF pathway in PV development.

Interleukin 17 as a central component of the pathogenesis of pain associated with immunoinflammatory process: A new “target” of pharmacotherapy

Modern pathogenetic therapy of inflammatory rheumatic diseases (IRD) is aimed not only at reducing disease activity (although achieving remission and low disease activity remains the main goal of treatment), but also at eliminating as quickly and completely as possible the main symptoms that cause a decrease in the quality of life of patients. Particular importance is attached to effective control of chronic pain – the main and most distressing manifestation of IRD. To solve this problem, the pathogenesis of chronic pain in IRD continues to be actively studied, aimed at finding new ”targets” of pharmacotherapy. Thus, the role of central sensitization (CS) and comorbid fibromyalgia in the formation of clinical manifestations of IRD is now clearly proven. Signs of CS, depending on the instrument of its detection, are determined in 20–40% of patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA) and axial spondyloarthritis (AxSpA).Interleukin (IL) 17 plays a fundamental role in the development of chronic pain in IIRD. This cytokine takes a leading position in the development of the ”cytokine cascade”, inducing the synthesis of various cytokines and chemokines, as well as chemotaxis and activation of neutrophils and T cells. Induction of synthesis of inflammatory mediators (including prostaglandin E2) determines the role of IL-17 in activation of nociceptors and their sensitization. IL-17 also takes an active part in neuroimmune interactions by activating glia cells and affecting receptors present on the membrane of neurons of the posterior horns of the spinal cord. This defines the role of IL-17 as one of the inductors of CS development. Pharmacologic blockade of IL-17 is a known pathway to suppress the activity of IIRPs such as PsA and AxSpA. However, this mechanism also allows for significant effects on chronic pain. In particular, the IL-17 inhibitor ixekizumab has shown high analgesic potential in a series of studies in PsA and AxSpA (SPIRIT-P1 and SPIRIT-P2, COAST V and COAST W). It is important to note that this drug demonstrated a very rapid analgesic effect: pain intensity was significantly reduced already 7 days after the first injection. These data suggest a specific effect of ixekizumab on the nociceptive system, independent of the anti-inflammatory effect. This fact allows us to consider ixekizumab as a drug of choice for the treatment of patients with PsA and AxSpA who experience severe pain and have signs of CS and fibromyalgia.

Injured sensory neurons-derived galectin-3 contributes to neuropathic pain via programming microglia in the spinal dorsal horn

Emerging studies have demonstrated spinal microglia play a critical role in central sensitization and contribute to chronic pain. Although several mediators that contribute to microglia activation have been identified, the mechanism of microglia activation and its functionally diversified mechanisms in pathological pain are still unclear. Here we report that injured sensory neurons-derived Galectin-3 (Gal3) activates and reprograms microglia in the spinal dorsal horn (SDH) and contributes to neuropathic pain. Firstly, Gal3 is predominantly expressed in the isolectin B4 (IB4)-positive non-peptidergic sensory neurons and significantly up-regulated in dorsal root ganglion (DRG) neurons and primary afferent terminals in SDH in the partial sciatic nerve ligation (pSNL)-induced neuropathic pain model. Gal3 knockout (Gal3 KO) mice showed a significant decrease in mechanical allodynia and Gal3 inhibitor TD-139 produced a significant anti-allodynia effect in the pSNL model. Furthermore, pSNL-induced microgliosis was compromised in Gal3 KO mice. Additionally, intrathecal injection of Gal3 produces remarkable mechanical allodynia by direct activation of microglia, which have enhanced inflammatory responses with TNF-α and IL-1β up-regulation. Thirdly, using single-nuclear RNA sequencing (snRNA-seq), we identified that Gal3 targets microglia and induces reprogramming of microglia, which may contribute to neuropathic pain establishment. Finally, Gal3 enhances excitatory synaptic transmission in excitatory neurons in the SDH via microglia activation. Our findings reveal that injured sensory neurons-derived Gal3 programs microglia in the SDH and contribute to neuropathic pain.

Central sensitization: its prevalence and impact on quality of life among hemodialyzed patients.

Data on the role of central sensitization in hemodialyzed patients are scarce. The aim was to identify the impact of central sensitization on quality of life and elucidate the risk factors for the development of central sensitization in patients receiving hemodialysis. Central sensitization, quality of life, psychological well-being, and sleep were assessed by the Central Sensitization Inventory (CSI), abbreviated version of the World Health Organization Quality of Life Instrument (WHOQOL-BREF), Hospital Anxiety and Depression Scale (HADS), and Jenkins Sleep Evaluation Scale (JSS), respectively. The effect of central sensitization on quality of life and the predictors of the development of central sensitization were assessed by regression analyses. The frequency of central sensitization was 48% in the study population (n = 100). Patients with central sensitization had significantly higher pain intensity, worse sleep quality, and more impaired psychological status (p < 0.05 for all). The CSI score negatively affected all quality of life domains on its own (p < 0.001 for all, adjusted R2 ranged from 0.17 to 0.47). Dialysis vintage (OR, 0.8; 95% CI, 0.7 to 1.0), pain (OR, 1.5; 95% CI, 1.1 to 2.0), JSS (OR, 1.3; 95% CI, 1.1 to 1.5), and HADS-total (OR, 1.1; 95% CI, 1.0 to 1.2) were determined as the independent risk factors for central sensitization (p < 0.05 for all). This study confirms that given the high frequency of central sensitization and its significant negative impact on quality of life, the presence of central sensitization should be investigated in patients undergoing hemodialysis.

Exploring venlafaxine effects on chronic vulvar pain: Changes in mood and pain regulation networks

The etiology of idiopathic pain conditions, such as Provoked vulvodynia (PV), is multifactorial. The efficiency of venlafaxine, serotonin-noradrenaline reuptake inhibitor (SNRIs) in modulating vulvar pain led to the hypothesis that PV might involve central mechanisms. Here, we investigate whether vulvar pain is associated with gene-expression changes in mood, stress and pain systems, including amygdala (Amg), medial prefrontal cortex (mPFC), and periaqueductal gray matter (PAG). Additionally, we examined the analgesic and anxiolytic effects of venlafaxine. We found that the development of chronic vulvar pain in an animal model of PV is associated by overexpression of genes related to neuronal-activity and neuroinflammation in the Amg, mPFC, and PAG. Additionally, changes in the expression of GABA and serotonin synthesis, and reuptake were noted in the Amg and mPFC. Unsurprisingly, anxiety-like behavior and emotional-disorder were observed in rats with chronic vulvar pain. Nevertheless, treatment with venlafaxine (37.5 mg/kg) for one month significantly improves the vulvar hypersensitivity, as well as reduces the anxiety level. More critically, the long-term gene expression adaptation in serotonin receptor and synthesis, GABA synthesis, neuroplasticity, and neuroinflammation in the Amg, mPFC, and PAG, were modulated by venlafaxine in rats with vulvar pain. Our findings suggest that vulvar allodynia induced by inflammation might associated with gene expression changes in brain areas that are involved in mood, stress and pain regulation. These changes probably play a role in central sensitization, and anxiety. Strikingly, enhancing the activity of serotonin and noradrenaline via venlafaxine treatment in rats with vulvar pain induces analgesic and anxiolytic effects.

Scientific Knowledge Graph and Trend Analysis of Central Sensitization: A Bibliometric Analysis.

BackgroundCentral sensitization refers to a state of hypersensitivity in the central nervous system and is associated with the development and maintenance of chronic pain. Central sensitization plays an essential role in various diseases. Nevertheless, there has been no bibliometric analysis before in this field. The purpose of this study was to provide critical themes and trends in the area of central sensitization, to build a network of knowledge, and to facilitate the future development of relevant basic and clinical research.MethodsPublications on central sensitization were extracted from the Science Citation Index-Expanded. We used R software to systematically analyze the countries, institutions, authors, journals, references, and keywords of the publications. Besides, conceptual structure, intellectual structure, and social structure were constructed.ResultsA total of 4466 publications were included. Research in the field of central sensitization generally showed a steady upward trend. The three structural networks showed that the United States is the leading country in this field. Arendt-Nielsen L and Woolf CJ were the most productive and influential authors, respectively. “Pain” was the journal with the most studies. Most journals that published and cited articles about central sensitization were academically influential. Cluster analysis revealed that research in central sensitization contains three main conceptual clusters, and the themes of research evolve frequently. Current research focuses on the pathogenesis of central sensitization in neuropathic pain, the role of central sensitization in different diseases, and related clinical double-blind trials.ConclusionCentral sensitization received widespread attention. The United States led the way in academic activity. In this field, the current situation of cooperation and communication between different countries and institutions is positive. The present research hotspots were the pathogenesis of central sensitization in neuropathic pain, the role of central sensitization in different diseases, and related clinical double-blind trials.

Comorbidities associated with temporomandibular joint disorders and the role of central sensitization: literature review

Comorbidities associated with temporomandibular joint disorders and the role of central sensitization: literature review

Prostaglandin E2 sensitizes the cough reflex centrally via EP3 receptor-dependent activation of NaV 1.8 channels

BackgroundCough hypersensitivity is a major characteristic feature associated with several types of cough, including chronic cough, but its underlying mechanisms remain to be fully understood. Inflammatory mediators, such as prostaglandin E2 (PGE2), have been implicated in both peripheral induction and sensitization of the cough reflex. In this study, using a conscious guinea pig model of cough, we investigated whether PGE2 can sensitize the cough reflex via central actions and, if so, via which mechanisms.MethodsAll drugs were administered by intracerebroventricular (i.c.v.) route and whole-body plethysmograph set-up was used for both induction, using aerosolized citric acid (0.2 M), and recording of cough. Immunohistochemistry was performed to confirm the expression of NaV 1.8 channels in the nucleus tractus solitarius (nTS).ResultsWe show that both PGE2 and the non-selective EP1/EP3 agonist, sulprostone, dose-dependently enhanced the citric acid-induced cough (P ≤ 0.001, P ≤ 0.01, respectively). Pretreatment with the EP1 antagonist, ONO-8130, did not affect the sulprostone-induced cough sensitization, whilst the EP3 antagonist, L-798,106, dose-dependently inhibited this effect (P ≤ 0.05). Furthermore, treatment with either the EP2 agonist, butaprost or the EP4 agonist, L-902,688, had no effect on cough sensitization. Additionally, pretreatment with either the TRPV1 antagonist, JNJ-17203212 or the TRPA1 antagonist, HC-030031, alone or in combination, nor with the NaV 1.1, 1.2, 1.3, 1.4, 1.6 and 1.7 channel blocker, tetrodotoxin, had any effect on the cough. In contrast, pretreatment with the NaV 1.8 antagonist, A-803467, dose-dependently inhibited this effect (P ≤ 0.05). Furthermore, NaV 1.8 channels were shown to be expressed in the nTS.ConclusionCollectively, our findings show that PGE2 sensitizes the cough reflex centrally via EP3 receptor-dependent activation of NaV 1.8 but independently of TRPV1,TRPA1 and TTX-sensitive sodium channel activation. These results indicate that PGE2 plays an important role in central sensitization of the cough reflex and suggest that central EP3 receptors and/or NaVv 1.8 channels may represent novel antitussive molecular targets.Graphical

Kinesin Nanomotors Mediated Trafficking of NMDA-Loaded Cargo as A Novel Target in Chronic Pain.

Chronic pain is among the most prevalent burdensome disorders worldwide. The N-methyl-d-aspartate (NMDA) receptor system plays a critical role in central sensitization, a primary feature of chronic pain. Despite the proven efficacy of exogenous ligands to this receptor system in preclinical studies, evidence for the clinical efficacy of NMDA antagonists for the treatment of chronic pain is weak. Researchers are studying alternate approaches, rather than direct inhibition of the NMDA receptors in pain processing neurons. This indirect approach utilizes the modulation of molecular switches that regulates the synthesis, maturation, and transport of receptors from cellular organelles to the synaptic membrane. Kinesins are nanomotors that anterogradely transport the cargo using microtubule tracks across the neurons. Various members of the kinesin family, including KIF17, KIF11, KIF5b, and KIF21a, regulate the intracellular transport of NMDA receptors. Pharmacological targeting of these ATP-driven nanomotors could be a useful tool for manipulating the NMDAR functioning. It could provide the potential for the development of a novel strategy for the management of chronic pain.

Orai1 is a crucial downstream partner of group I metabotropic glutamate receptor signaling in dorsal horn neurons.

Group I metabotropic glutamate receptors (group I mGluRs) have been implicated in several central nervous system diseases including chronic pain. It is known that activation of group I mGluRs results in the production of inositol triphosphate (IP3) and diacylglycerol that leads to activation of extracellular signal-regulated kinases (ERKs) and an increase in neuronal excitability, but how group I mGluRs mediate this process remains unclear. We previously reported that Orai1 is responsible for store-operated calcium entry and plays a key role in central sensitization. However, how Orai1 is activated under physiological conditions is unknown. Here, we tested the hypothesis that group I mGluRs recruit Orai1 as part of its downstream signaling pathway in dorsal horn neurons. We demonstrate that neurotransmitter glutamate induces STIM1 puncta formation, which is not mediated by N-Methyl-D-aspartate (NMDA) or α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. Glutamate-induced Ca2+ entry in the presence of NMDA or AMPA receptor antagonists is eliminated in Orai1-deficient neurons. Dihydroxyphenylglycine (DHPG) (an agonist of group I mGluRs)-induced Ca2+ entry is abolished by Orai1 deficiency, but not affected by knocking down of transient receptor potential cation channel 1 (TRPC1) or TRPC3. Dihydroxyphenylglycine-induced activation of ERKs and modulation of neuronal excitability are abolished in cultured Orai1-deficient neurons. Moreover, DHPG-induced nociceptive behavior is markedly reduced in Orai1-deficient mice. Our findings reveal previously unknown functional coupling between Orai1 and group I mGluRs and shed light on the mechanism underlying group I mGluRs-mediated neuronal plasticity.

POS1014 CENTRAL SENSITIZATION HAS MAJOR IMPACT ON QUALITY OF LIFE IN PATIENTS WITH AXIAL SPONDYLOARTHRITIS

Background:Maintaining optimal health-related quality of life (QoL) is the ultimate goal of treatment in axial spondyloarthritis (axSpA). Chronic pain has a large potential impact on QoL. Central sensitization (CS) may explain part of the chronic pain in axSpA. However, the role of central sensitization (CS) herein has only been studied to a limited degree and current axSpA guidelines pay little attention to identification and treatment of CS.Objectives:To explore the relationship between CS and QoL in axSpA.Methods:Consecutive outpatients with axSpA from the Groningen Leeuwarden Axial Spondyloarthritis (GLAS) cohort were included. CS was assessed with the Central Sensitization Inventory (CSI; 0-100), QoL with the AS Quality of Life questionnaire (ASQoL; 0-18) and disease activity with the AS Disease Activity Score (ASDASCRP). A high probability of CS was defined as CSI score ≥40 and active disease as ASDASCRP score ≥2.1. Patient characteristics and clinical assessments were compared between groups with CSI score &lt;40 and ≥40.(1) Multivariable regression analysis was conducted to investigate the relationship between CSI and ASQoL scores, correcting for potential confounders.Results:Of the 178 axSpA patients with available CSI score, 149 completed the ASQoL. Mean age of the 178 included patients was 47.4 ± 14.1 years, 78 (44%) were female, mean symptom duration was 21.4 ± 13.6 years and 88 (52%) were using bDMARDS. Mean CSI score was 38.0 ± 14.1, mean ASQoL 6.0 ± 5.3 and mean ASDASCRP 2.1 ± 1.0. CSI score ≥40 was significantly associated with higher mean ASQoL (9.7 vs. 3.3), higher mean ASDASCRP (2.6 vs. 1.7), female gender (60% vs. 29%) and more often entheseal involvement (61% vs. 26%) (Table 1).Table 1.Selection of patient characteristics, disease activity and clinical outcome variables for patients with axSpA, divided in subgroups for CSI score with a cutoff point of 40.CharacteristicsAll patientsn = 178CSI&lt;40n = 98 (55%)CSI≥40n = 80 (45%)Age (years)47.4 ± 14.148.7 ± 15.045.8 ± 12.7Female78 (44)27 (29)44 (60)*Symptom duration (years)21.4 ± 13.621.5 ± 13.521.2 ± 13.8HLA-B27+133 (79)70 (79)54 (79)Smoker45 (27)28 (32)15 (23)BMI (kg/m2)26.7 ± 5.026.2 ± 4.427.5 ± 5.8Completed higher education181 (71)48 (70)34 (76)Biological use88 (52)49 (52)39 (51)RDCI (0-9)0.0 (0.0 – 1.0)0.0 (0.0 – 1.0)0.0 (0.0 – 1.8)Peripheral arthritis210 (6)5 (6)5 (8)Entheseal involvement364 (40)23 (26)38 (61)*ASDASCRP2.1 ± 1.01.7 ± 0.92.6 ± 1.0*CRP (mg/ml)2.9 (1.1 – 6.8)2.6 (1.1-6.0)3.6 (1.4 – 7.0)ASQoL (0-18)6.0 ± 5.33.3 ± 3.69.7 ± 4.9*CSI (0-100)38.0 ± 14.128.0 (23 – 34)50.0 (43.0 –56.0)N/AValues are n (%), mean ± SD or median (IQR).1International Standard Classification of Education (ISCED) level &gt;4; 2Swollen Joint Count &gt;0; 3Maastricht Ankylosing Spondylitis Enthesitis Score &gt;0. *p&lt;0.001. ASDASCRP: Ankylosing Spondylitis Disease Activity Score; ASQoL: Ankylosing Spondylitis Quality of Life questionnaire; CRP: C-reactive protein; CSI: Central Sensitization Inventory; RDCI: Rheumatic Disease Comorbidity Index.Patients with low ASDASCRP (&lt;2.1) and also low CSI score (&lt;40) showed good QoL (median ASQoL 1.1). Patients with low ASDASCRP combined with high CSI score (≥40) and patients with high ASDASCRP (≥2.1) combined with low CSI score reported worse QoL (median ASQoL 5.6 and 4.1, respectively). Patients with high ASDASCRP and also high CSI score reported the worst QoL (median ASQoL 12.0). (Figure 1).Figure 1.ASQoL score in patients with axSpA with CSI score ≥40 and &lt;40, divided for ASDASCRP (cutoff 2.1)Additionally, in univariable analysis, the CSI score explained a large proportion of the variation of the ASQoL (R2=0.46). This association remained significant after correction for ASDASCRP, gender, symptom duration, entheseal involvement, smoking status, BMI category, educational level and comorbidities in multivariable analysis (CSI p&lt;0.001).Conclusion:In daily clinical practice, CS seems strongly related to patient-reported QoL in patients with long-term axSpA.

Роль центральной сенситизации в формировании и поддержании хронической боли у пациентов с заболеваниями суставов

Роль центральной сенситизации в формировании и поддержании хронической боли у пациентов с заболеваниями суставов

Effect of intravenous paracetamol for post-operative pain relief after tonsillectomy - A study of 70 cases

INTRODUCTION: Tonsillectomy is one of the commonest surgical procedures performed in the field of otorhinolaryngology. The most common and distressing symptoms, which follow anaesthesia and surgery, are pain and emesis. The provision of adequate analgesia after tonsillectomy presents the anaesthesiologist with difficulties, as this is a painful procedure and may be associated with significant bleeding into the airway. As evidence continues to accumulate concerning the role of central sensitisation in post operative pain, many researchers have followed methods to prevent central neuropathic changes from occurring, through the utilization of pre-emptive analgesic techniques. Effective preventive analgesic technique may not only be useful in reducing the acute pain, but also chronic post surgical pain and disabilities. Paracetamol is an effective analgesic and an antipyretic agent. The efficiency and tolerability for intravenous Paracetamol are well established. It has a favourable safety profile and it is the most commonly prescribed drug for the treatment of mild to moderate pain. The objective of the present study is to evaluate the post operative analgesia, the haemodynamic profile and the side effects of IV Paracetamol. AIM OF THE STUDY: 1. To evaluate the efficacy of Intravenous Paracetamol as a pre-emptive analgesic in relieving the post operative pain. 2. To study the hemodynamic variables during the post-operative period. 3. To establish the safety of Intravenous paracetamol in patients. MATERIALS AND METHODS: Study Design: Prospective, randomized, double blinded, comparative study. Double blinding was done by taking appropriate dose of intravenous paracetamol calculated in mg/kg and was added to a solution of normal saline to make a volume of 100 ml. This was labelled as drug A. Plain 100 ml of normal saline was labelled as drug B. Neither the person administering the drug nor the person observing the patient in the post operative period did not know the drug. Study Population: After obtaining the institutional ethical committee approval and written informed consent from the parent/guardian, 70 ASA I physical status patients undergoing tonsillectomy were selected between the age group of 6-16 years and weighing between 10-30 kg. Sample Size: 35 patients in the paracetamol group (P group) and 35 in the control group (N group). Probability sampling: All the70 patients were randomised in two groups and the entire patients stood an equal chance of getting into any group. Data collection: 1. Age, Sex, Weight, 2. Pre operative and intra operative pulse rate and blood pressure, Spo2, 3. Duration of surgery, 4. Sedation score using Ramsays Sedation Scale, 5. Visual analogue pain scale at the end of surgery, 1h 2h, 3h, 4h, 5h, 6h. 6. Post operative complications such as: • Drug intolerance, • Nausea and vomiting, • Epigastric pain, • Bleeding, Exclusion Criteria: 1. Upper and lower respiratory tract infections, 2. Cardiac valvular abnormalities, 3. Abnormal bleeding and clotting time, 4. Obstructive sleep apnea, 5. Known history of allergy to paracetamol, 6. Past history of jaundice, 7. Patients on aspirin, 8. Any other concurrent antipyretic, analgesic or anti inflammatory Medications. OBSERVATION AND RESULTS: Data were analysed using SPSS version 13.0 computer software at level of significance p = 0.05. Numerical variables were presented as mean and standard deviation (SD) and categorical variables were presented as frequency (%). Unpaired Student ‘t’ test was used for between-group comparisons between categorical variables. Time to first analgesic administration was analysed by the Kaplan–Meier survival analysis. SUMMARY: 1. Intravenous Paracetamol achieved significant post operative pain relief up to 6 hours. 2. Intravenous Paracetamol delayed the requirement of first dose of rescue analgesic for a mean duration of 6 hours in the post-operative period. 3. Intravenous Paracetamol had a better haemodynamic profile in the post-operative period. 4. Intraveous Paracetamol had a smooth and better post-operative recovery profile rendering a calm, co-operative and tranquil patient. 5. Intravenous Paracetamol did not exhibit any adverse effects in the patients. CONCLUSION: 1. Intravenous Paracetamol can be used as an effective analgesic for providing pre-emptive analgesia. 2. Intravenous Paracetamol provides excellent post operative pain relief. 3. Intraveous Paracetamol has a better hemodynamic profile. 4. Intraveous Paracetamol is safe for use in patients.

Effect of intravenous paracetamol for post-operative pain relief after tonsillectomy - A study of 70 cases

INTRODUCTION: Tonsillectomy is one of the commonest surgical procedures performed in the field of otorhinolaryngology. The most common and distressing symptoms, which follow anaesthesia and surgery, are pain and emesis. The provision of adequate analgesia after tonsillectomy presents the anaesthesiologist with difficulties, as this is a painful procedure and may be associated with significant bleeding into the airway. As evidence continues to accumulate concerning the role of central sensitisation in post operative pain, many researchers have followed methods to prevent central neuropathic changes from occurring, through the utilization of pre-emptive analgesic techniques. Effective preventive analgesic technique may not only be useful in reducing the acute pain, but also chronic post surgical pain and disabilities. Paracetamol is an effective analgesic and an antipyretic agent. The efficiency and tolerability for intravenous Paracetamol are well established. It has a favourable safety profile and it is the most commonly prescribed drug for the treatment of mild to moderate pain. The objective of the present study is to evaluate the post operative analgesia, the haemodynamic profile and the side effects of IV Paracetamol. AIM OF THE STUDY: 1. To evaluate the efficacy of Intravenous Paracetamol as a pre-emptive analgesic in relieving the post operative pain. 2. To study the hemodynamic variables during the post-operative period. 3. To establish the safety of Intravenous paracetamol in patients. MATERIALS AND METHODS: Study Design: Prospective, randomized, double blinded, comparative study. Double blinding was done by taking appropriate dose of intravenous paracetamol calculated in mg/kg and was added to a solution of normal saline to make a volume of 100 ml. This was labelled as drug A. Plain 100 ml of normal saline was labelled as drug B. Neither the person administering the drug nor the person observing the patient in the post operative period did not know the drug. Study Population: After obtaining the institutional ethical committee approval and written informed consent from the parent/guardian, 70 ASA I physical status patients undergoing tonsillectomy were selected between the age group of 6-16 years and weighing between 10-30 kg. Sample Size: 35 patients in the paracetamol group (P group) and 35 in the control group (N group). Probability sampling: All the70 patients were randomised in two groups and the entire patients stood an equal chance of getting into any group. Data collection: 1. Age, Sex, Weight, 2. Pre operative and intra operative pulse rate and blood pressure, Spo2, 3. Duration of surgery, 4. Sedation score using Ramsays Sedation Scale, 5. Visual analogue pain scale at the end of surgery, 1h 2h, 3h, 4h, 5h, 6h. 6. Post operative complications such as: • Drug intolerance, • Nausea and vomiting, • Epigastric pain, • Bleeding, Exclusion Criteria: 1. Upper and lower respiratory tract infections, 2. Cardiac valvular abnormalities, 3. Abnormal bleeding and clotting time, 4. Obstructive sleep apnea, 5. Known history of allergy to paracetamol, 6. Past history of jaundice, 7. Patients on aspirin, 8. Any other concurrent antipyretic, analgesic or anti inflammatory Medications. OBSERVATION AND RESULTS: Data were analysed using SPSS version 13.0 computer software at level of significance p = 0.05. Numerical variables were presented as mean and standard deviation (SD) and categorical variables were presented as frequency (%). Unpaired Student ‘t’ test was used for between-group comparisons between categorical variables. Time to first analgesic administration was analysed by the Kaplan–Meier survival analysis. SUMMARY: 1. Intravenous Paracetamol achieved significant post operative pain relief up to 6 hours. 2. Intravenous Paracetamol delayed the requirement of first dose of rescue analgesic for a mean duration of 6 hours in the post-operative period. 3. Intravenous Paracetamol had a better haemodynamic profile in the post-operative period. 4. Intraveous Paracetamol had a smooth and better post-operative recovery profile rendering a calm, co-operative and tranquil patient. 5. Intravenous Paracetamol did not exhibit any adverse effects in the patients. CONCLUSION: 1. Intravenous Paracetamol can be used as an effective analgesic for providing pre-emptive analgesia. 2. Intravenous Paracetamol provides excellent post operative pain relief. 3. Intraveous Paracetamol has a better hemodynamic profile. 4. Intraveous Paracetamol is safe for use in patients.

Central sensitization and its role in chronic pain: What can ketamine do?

Central sensitization plays a crucial role in the development of chronic pain. NMDA receptors play a key role in central sensitization. Ketamine, an NMDA receptor antagonist, can help in refractory chronic pain. Although intravenous is the most common route utilized for delivery of ketamine, other routes such as oral, subcutaneous, topical and intranasal, have been explored. Here we review key research articles regarding the use of ketamine for chronic pain.

The role of central sensitization in migraine

The role of central sensitization in migraine

Platelets Play a Central Role in Sensitization to Allergen

Platelet activation occurs in patients with allergic inflammation, and platelets can be activated directly by allergen via an IgE-dependent process. Platelets have been shown to activate APCs such as CD11c+ dendritic cells in vitro. Although CD11c+ dendritic cells are a requisite for allergen sensitization, the role of platelets in this process is unknown. In this study, we investigated whether platelets were necessary for allergen sensitization. Balb/c mice sensitized to ovalbumin were exposed to subsequent aerosolized allergen (ovalbumin challenge). We analyzed lung CD11c+ cell activation, colocalization with platelets, and some other indices of inflammation. The role of platelets at the time of allergen sensitization was assessed through platelet depletion experiments restricted to the period of sensitization. Platelets colocalized with airway CD11c+ cells, and this association increased after allergen sensitization as well as after subsequent allergen exposure. Temporary platelet depletion (>95%) at the time of allergen sensitization led to a suppression of IgE and IL-4 synthesis and to a decrease in the pulmonary recruitment of eosinophils, macrophages, and lymphocytes after subsequent allergen exposure. Furthermore, in mice previously depleted of platelets at the time of sensitization, the recovered platelet population was shown to have reduced expression of FcεRI. Pulmonary CD11c+ cell recruitment was suppressed in these mice after allergen challenge, suggesting that the migration of CD11c+ cells in vivo may be dependent on direct platelet recognition of allergen. We conclude that platelets are necessary for efficient host sensitization to allergen. This propagates the subsequent inflammatory response during secondary allergen exposure and increases platelet association with airway CD11c+ cells.

Reduced anterior cingulate grey matter volume in painful hand osteoarthritis

ObjectiveIncreasing evidence supports the role of central sensitisation in osteoarthritis (OA) pain. In this study, we used neuroimaging to compare pain-processing regions of the brain in participants with and without hand OA. We then assessed for volumetric changes in these brain regions following treatment with centrally acting analgesics.MethodsParticipants with hand OA (n = 28) underwent T1-weighted MRI of the brain before and after 12 weeks of treatment with pregabalin, duloxetine or placebo. Grey matter volume in the anterior cingulate cortex (ACC), insular cortex and thalamus was compared to non-OA control subjects (n = 11) using FreeSurfer regional volumetric analysis and voxel-based morphometry, and evaluated for differences pre- and post-treatment.ResultsRelative to non-OA controls, hand OA participants had areas of reduced grey matter volume in the ACC at baseline (p = 0.007). Regional volumetric differences in the ACC persisted after 13 weeks’ treatment with pregabalin or duloxetine (p = 0.004) with no significant differences between treatment cohorts, despite improvements in NRS pain scores for pregabalin (p = 0.005) and duloxetine (p = 0.050). The ACC grey matter changes persisted despite a significant improvement in pain in the pregabalin and duloxetine groups vs. placebo. No structural differences were observed in the insular cortex or thalamus at baseline or following treatment.ConclusionOur study found evidence of reduced ACC grey matter volume in participants with hand arthritis that persisted after treatment with centrally acting analgesics pregabalin and duloxetine, respectively. The sustained changes observed in the ACC in our study could reflect the relatively short duration of treatment, or that the differences observed are irreversible volume changes due to chronic pain that are established over time.

Time‐dependent lumbar spinal cord astrocytic hyperactivation occurs in the deep dorsal horn during the maintenance of nerve growth factor‐induced low back pain

Low back pain (LBP) is a complex condition that is a substantial global socioeconomic problem. LBP is poorly managed, in part, due to a lack of efficacious treatments. Determining the underlying mechanisms contributing to LBP will help to discover new therapies to impact this global crisis. In this study, we used a preclinical model of LBP induced by nerve growth factor (NGF) injections into the lumbar paraspinal muscles. It was previously shown that NGF injections induce persistent low back mechanical hyperalgesia (hypersensitivity to a noxious mechanical stimulus) and nociceptive neuronal hyperexcitability in the lumbar spinal cord deep dorsal horn (DDH), which contributes to central sensitization. Central sensitization is key to the development of persistent pain. Neuroimmune activation (astrocytic &amp; microglial hyperactivation &amp; enhanced proinflammatory cytokines) also plays a critical role in central sensitization. We previously reported that astrocytic hyperactivation occurred in the ipsilateral lumbar spinal cord superficial dorsal horn, where pain is processed and modulated, during the maintenance of NGF‐induced persistent LBP. Recent reports examining the induction of persistent LBP suggest that glial hyperactivation also occurs in the DDH, where pain projection neurons are located. The objective of this study was to investigate astrocytic hyperactivation in the DDH during the maintenance of persistent LBP. We hypothesized that NGF injections would induce astrocytic hyperactivation in the lumbar spinal cord DDH during the maintenance of LBP. We tested our hypothesis using the NGF LBP model and immunofluorescence with confocal microscopy. We administered two injections (50μl) 5 days apart on Day 0 (D0) and Day 5 (D5) of NGF (0.8μM) or vehicle (PBS) into the left paraspinal muscles (5th lumbar vertebral level) in male rats. Low back mechanical hyperalgesia (LBP) was assessed before injections on D0 and D5, and at other time points (D2, D5+4 hours, D7, D10, &amp; D14). Lumbar spinal cords (L1–L6; formalin fixed &amp; transversely sectioned at 30μm) were evaluated for immunofluorescence labeling of the astrocyte marker, glial fibrillary acidic protein (GFAP), in the DDH bilaterally (Image J; inter‐ and intra‐rater reliability ICC= 0.77 &amp; 0.83). NGF‐injected rats displayed significant reductions in ipsilateral low back noxious mechanical thresholds post‐injection on D5 through D14 compared to controls. At D14, NGF rats (n=4) demonstrated a significant increase in mean fluorescence intensity for GFAP, in the DDH ipsilateral to injections with characteristic appearances of hyperactivated astrocytes (i.e., hypertrophic cell bodies &amp; processes) compared to vehicle (n=4). No significant changes were observed at D5 (4 hours post‐NGF injection) or D7. These findings suggest that time‐dependent astrocytic hyperactivation occurs in the DDH during the maintenance of LBP, further supporting the role that spinal cord neuroimmune activation plays in persistent LBP. This study provides a foundation that may help identify novel therapies to improve treatment efficacy and impact the problem of LBP.Support or Funding InformationSLU Center for Neuroscience SCFN‐SGP‐01This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.