Central Sensitization Processes Research Articles

Slowly repeated evoked pain (SREP) as a central sensitization marker in episodic migraine patients

Migraine headache is a pain condition characterized by severe and recurrent unilateral head pain. Among other mechanisms, central pain sensitization processes seem to be involved in the disorder. An experimental protocol based on slowly repeated evoked pain (SREP) has been shown to indicate pain sensitization in fibromyalgia patients and differentiate these patients from healthy individuals and rheumatoid arthritis patients. This study examined SREP sensitization in migraine patients and explored its potential usefulness as a central sensitization marker. The SREP protocol was administered to 40 episodic migraine (EM) patients not currently experiencing a headache and 40 healthy controls. SREP consisted of a series of 9 suprathreshold painful pressure stimuli of 5 s duration and a 30 s interstimulus interval. SREP sensitization was indexed by the increase in pain ratings across the stimuli. Pain threshold, pain tolerance and temporal summation of pain were also assessed. SREP sensitization was observed in EM, but not in healthy individuals (p < .001). SREP differentiated between EM and healthy individuals with up to 75% diagnostic accuracy. Pain threshold, pain tolerance and temporal summation of pain did not show significant discriminative ability. An SREP index value of 0.5 was the most sensitive cut-off for detecting central pain sensitization when prioritizing diagnostic sensitivity (0.88). Results provide evidence for SREP as a possible central sensitization marker with potential clinical utility in migraine patients. Inclusion of SREP in Quantitative Sensory Testing protocols may enhance the assessment of altered pain modulation in different pain conditions.

Qualitative review on N-methyl-D-aspartate receptor expression in rat spinal cord during the postnatal development: Implications for central sensitization and pain.

The N‐methyl‐D‐aspartate receptor (NMDAR) is an important mediator of central sensitization and nociception in the rat spinal dorsal horn. The NMDAR subunits and splice variants determine the properties of the receptor. Understanding the expression of NMDAR subunits in spinal cord during the neonatal development is important as it may have consequences for the process of central sensitization and nociception in later life. In this review, a systematic literature search was conducted using three databases: Medline, Embase, and PubMed. A quality assessment was performed on predetermined entities of bias. Thirteen articles were identified to be relevant. The results show that NMDAR subunits and splice variants are dynamically expressed during postnatal development in the spinal dorsal horn. During the first 2 weeks, the expression of less excitable GluN2A subunit and more sensitive GluN2B subunit increases while the expression of high excitable GluN2C subunit decreases. During the 2nd week of postnatal development GluN1 subunits with exon 21 spliced in but exon 22 spliced out are predominantly expressed, increasing phosphorylation, and transport to the membrane. The data suggest that in rats, the nociceptive system is most susceptible to central sensitization processes during the first two postnatal weeks. This may have important consequences for nociception and pain responses in later life. From this, we conclude that targeted therapy directed toward specific NMDAR subunits is a promising candidate for mechanism‐based treatment of pain in neonates.

Antinociceptive Effects of Lipid Raft Disruptors, a Novel Carboxamido-Steroid and Methyl β-Cyclodextrin, in Mice by Inhibiting Transient Receptor Potential Vanilloid 1 and Ankyrin 1 Channel Activation

Transient Receptor Potential Vanilloid 1 and Ankyrin 1 (TRPV1, TRPA1) cation channels are expressed in nociceptive primary sensory neurons, and play an integrative role in pain processing and inflammatory functions. Lipid rafts are liquid-ordered plasma membrane microdomains rich in cholesterol, sphingomyelin, and gangliosides. We earlier proved that lipid raft disintegration by cholesterol depletion using a novel carboxamido-steroid compound (C1) and methyl β-cyclodextrin (MCD) significantly and concentration-dependently inhibit TRPV1 and TRPA1 activation in primary sensory neurons and receptor-expressing cell lines. Here we investigated the effects of C1 compared to MCD in mouse pain models of different mechanisms. Both C1 and MCD significantly decreased the number of the TRPV1 activation (capsaicin)-induced nocifensive eye-wiping movements in the first hour by 45% and 32%, respectively, and C1 also in the second hour by 26%. Furthermore, C1 significantly decreased the TRPV1 stimulation (resiniferatoxin)-evoked mechanical hyperalgesia involving central sensitization processes, while its inhibitory effect on thermal allodynia was not statistically significant. In contrast, MCD did not affect these resiniferatoxin-evoked nocifensive responses. Both C1 and MCD had inhibitory action on TRPA1 activation (formalin)-induced acute nocifensive reactions (paw liftings, lickings, holdings, and shakings) in the second, neurogenic inflammatory phase by 36% and 51%, respectively. These are the first in vivo data showing that our novel lipid raft disruptor carboxamido-steroid compound exerts antinociceptive and antihyperalgesic effects by inhibiting TRPV1 and TRPA1 ion channel activation similarly to MCD, but in 150-fold lower concentrations. It is concluded that C1 is a useful experimental tool to investigate the effects of cholesterol depletion in animal models, and it also might open novel analgesic drug developmental perspectives.

Efficacy of Manual Therapy on Pain, Impact of Disease, and Quality of Life in the Treatment of Fibromyalgia: A Systematic Review

Background: Myofascial mobilization has been used as an intervention for patients with fibromyalgia (FM) for acting on ascending nociceptive pathways possibly involved in the central sensitization process, modulating the pain experience. However, there is still a gap in its efficacy compared with another hands-on approach because manual therapy has nonspecific effects, such as placebo. Objectives: This systematic review aims to review the scientific literature for an overview of the efficacy of manual therapy in pain, disease impact, and quality of life in patients with FM compared with control or other treatments through randomized clinical trials. Study Design: This study involved systematic review of published randomized controlled trials (RCTs). Setting: This study examined all RCTs evaluating the effect of manual therapy on pain, impact of disease, and quality of life for patients with FM. Methods: Systematic review. The research was performed in 9 databases: MEDLINE/PubMed, CINAHL, Web of Science, Scopus, ScienceDirect, Lilacs, SciELO, PEDro, and Cochrane. Searches were carried out from the end of the project until September 2019, with no language and year restrictions. Randomized controlled clinical trials that used the following outcome measures were included: Visual Analog Scale, Fibromyalgia Impact Questionnaire, and SF-36 Quality of Life Questionnaire. The risk of bias and quality of studies was assessed using the PEDro scale; the Cochrane risk-of-bias tool; and Grading of Recommendations Assessment, Development, and Evaluation System. Results: Seven studies were included (368 patients). The quantitative analysis was performed on 4 studies because of the lack of data in the others. Myofascial release was the most used modality. The level of evidence ranged from very low to moderate, mainly because of the inconsistency and inaccuracy of results. Limitations: The present systematic review presented limitations because of the heterogeneity of the included studies and only a short-term analysis of the intervention results. It was observed that other information, such as pressure, repetition, and/or sustaining manual therapy techniques, could be better described in future protocols, aiming at a better comparison between the techniques and their subsequent reproducibility. Conclusions: Current evidence of manual therapy in patients with FM, based on a very low to moderate quality of evidence, was inconclusive and insufficient to support and recommend the use of manual therapy in this population. To date, only general osteopathic treatment has achieved clinically relevant pain improvement when compared with control. Key words: Fibromyalgia, manual therapy, pain, quality of life, impact of disease, physiotherapy, manipulation techniques, mobilization

Understanding central sensitization for advances in management of carpal tunnel syndrome.

Carpal tunnel syndrome is the most common nerve compression disorder of the upper extremity, and it is traditionally considered a peripheral neuropathy associated with a localized compression of the median nerve just at the level of the carpal tunnel. Surgery and physiotherapy are treatment approaches commonly used for this condition; however, conflicting clinical outcomes suggest that carpal tunnel syndrome may be more complex. There is evidence supporting the role of peripheral nociception from the median nerve in carpal tunnel syndrome; however, emerging evidence also suggests a potential role of central sensitization. The presence of spreading pain symptoms (e.g. proximal pain), widespread sensory changes, or bilateral motor control impairments in people presenting with strictly unilateral sensory symptoms supports the presence of spinal cord changes. Interestingly, bilateral sensory and motor changes are not directly associated with electrodiagnostic findings. Other studies have also reported that patients presenting with carpal tunnel syndrome exhibit neuroplastic brainstem change supporting central sensitization. Current data would support the presence of a central sensitization process, mediated by the peripheral drive originating in the compression of the median nerve, in people with carpal tunnel syndrome. The presence of altered nociceptive gain processing should be considered in the treatment of carpal tunnel syndrome by integrating therapeutic approaches aiming to modulate long-lasting nociceptive barrage into the central nervous system (peripheral drive) and strategies aiming to activate endogenous pain networks (central drive).

Chronic Pain in Hidradenitis Suppurativa Explained Through the Process of Central Sensitization

Chronic Pain in Hidradenitis Suppurativa Explained Through the Process of Central Sensitization

Efficacy of Physical Therapy on Nociceptive Pain Processing Alterations in Patients with Chronic Musculoskeletal Pain: A Systematic Review and Meta-analysis.

Chronic musculoskeletal pain is a major health, social, and economic problem. Most of the subjects who suffer from chronic musculoskeletal pain present processes of central sensitization. Temporal summation and conditioned pain modulation are the two most commonly used clinical measures of this. The objective of this review is to evaluate the effects of physical therapy on temporal summation (TS) and conditioned pain modulation (CPM) in patients with chronic musculoskeletal pain. This is a systematic review and meta-analysis. We searched the MEDLINE, EMBASE, CINAHL, EBSCO, PubMed, PEDro, Cochrane Collaboration Trials Register, Cochrane Database of Systematic Reviews, and SCOPUS databases. Different mesh terms and key words were combined for the search strategy, with the aim of encompassing all studies that have used any type of physical therapy treatment in patients with chronic musculoskeletal pain and have measured both TS and CPM. Eighteen studies remained for qualitative analysis and 16 for quantitative analysis. Statistically significant differences with a 95% confidence interval (CI) were obtained for TS (-0.21, 95% CI = -0.39 to -0.03, Z = 2.50, P = 0.02, N = 721) and CPM (0.34, 95% CI = 0.12 to 0.56, Z = 2.99, P = 0.003, N = 680) in favor of physical therapy as compared with control. Manual therapy produces a slight improvement in TS, and physical therapy modalities in general improve CPM. No significant differences between the subgroups of the meta-analysis were found. The methodological quality of the studies was high. Physical therapy produces a slight improvement in central sensitization (CS)-related variables, with TS decreased and CPM increased when compared with a control group in patients with CMP. Only significant differences in TS were identified in the manual therapy subgroup.

Up-regulation of astrocyte excitatory amino acid transporter 2 alleviates central sensitization in a rat model of chronic migraine.

Central sensitization is the potential pathogenesis of chronic migraine (CM) and is related to persistent neuronal hyperexcitability. Dysfunction of excitatory amino acid transporter 2 (EAAT2) leads to the accumulation of glutamate in the synaptic cleft, which may contribute to central sensitization by overactivating glutamate N-methyl-D-aspartate receptors and enhancing synaptic plasticity. However, the therapeutic potential of CM by targeting glutamate clearance remains largely unexplored. The purpose of this study was to investigate the role of EAAT2 in CM central sensitization and explore the effect of EAAT2 expression enhancer LDN-212320 in CM rats. The glutamate concentration was measured by high-performance liquid chromatography in a rat model of CM. Then, q-PCR and western blots were performed to detect EAAT2 expression, and the immunoreactivity of astrocytes was detected by immunofluorescence staining. To understand the effect of EAAT2 on central sensitization of CM, mechanical and thermal hyperalgesia and central sensitization-associated proteins were examined after administration of LDN-212320. In addition, the expression of synaptic-associated proteins was examined and Golgi-Cox staining was used to observe the dendritic spine density of trigeminal nucleus caudalis neurons. Also, the synaptic ultrastructure was observed by transmission electron microscope (TEM) to explore the changes of synaptic plasticity. In our study, elevated glutamate concentration and decreased EAAT2 expression were found in the trigeminal nucleus caudalis of CM rats, administration of LDN-212320 greatly up-regulated the protein expression of EAAT2, alleviated hyperalgesia, decreased the concentration of glutamate and the activation of astrocytes. Furthermore, reductions in calcitonin gene-related peptide, substance P(SP), and phosphorylated NR2B were examined after administration of LDN-212320. Moreover evaluation of the synaptic structure, synaptic plasticity-, and central sensitization-related proteins indicated that EAAT2 might participate in the CM central sensitization process by regulating synaptic plasticity. Taken together, up-regulation of EAAT2 expression has a protective effect in CM rats, and LDN-212320 may have clinical therapeutic potential. Cover Image for this issue: https://doi.org/10.1111/jnc.14769.

Comparison of Safety and Efficacy of Pregabalin versus Gabapentin for the treatment of Uremic Pruritus in Patients with Chronic Kidney Disease on Maintenance Haemodialysis.

Background:Uremic pruritus (UP) affects many patients suffering from chronic kidney disease (CKD) and has a negative impact on the quality of life. The severity of UP ranges from sporadic discomfort to complete restlessness during both day and night time. It has become increasingly evident that central transmission and sensitization processes similar to those observed in chronic pain are important mechanisms of pruritus.Methodology:This was a randomized single-blind prospective-interventional study carried out for 6 weeks. Male and female patients aged between 20 and 85 years with end-stage renal disease undergoing maintenance hemodialysis and who had substantial pruritus defined as persistent were included in our study. Informed consent was obtained from each patient before enrolling in the study. Patients were randomly divided into two groups (Group A and B), with Group A receiving pregabalin 25 mg and Group B receiving gabapentin 100 mg. The efficacy and safety of drugs were assessed after 6 weeks using visual analog scale and 5D itch scale.Results:We used gabapentin 100 mg or pregabalin 25 mg for 42 consecutive patients with CKD on maintenance hemodialysis with a mean age of patients in Group A (pregabalin 25 mg) 55.29 ± 14.58 and B (gabapentin 100 mg) 58.10 ± 11.09. Both gabapentin and pregabalin produced a significant difference in itching intensity with P < 0.001; however, there was no statistically significant difference between the effectiveness of two drugs in reducing itch. While receiving gabapentin, 11 of 21 patients (52.38%) reported fatigue, dizziness, somnolescence, which was statistically significant (P ≤ 0.001) and 4 of these patients discontinued use of the drug due to excessive somnolence, all after the first dose. A statistically significant difference was found in each domain of 5D-Pruritus scale after gabapentin and pregabalin therapy.

Botulinski toksin tip A - osnovni farmakološki profil i terapijska primena

Botulinum toxin Type A (BoNT/A), produced by the Gram-positive anaerobic bacteria Clostridium botulinum, is one of the most potent toxins in nature, and a very useful therapeutic tool for combating various neurological and autonomic disorders. The main pharmacological features of BoNT/A are neurospecificity, long-lasting effect, and safety. These features are grounded on its peculiar molecular mechanism of action: after specific binding to the neuronal membrane, it is internalized into the neuronal cytosol, where it specifically cleaves one of the proteins necessary for neurotransmitters release. The consequent reversible neuroparalysis lasts for several months and explains the long-lasting clinical effects after a single local toxin application. Although already approved for the prevention of chronic migraine, the basic and clinical investigations have repeatedly shown the potential of BoNT/A in relieving other chronic pain conditions. Accumulated data from experimental pain models demonstrated that BoNT/A reduces pathological pain hypersensitivity after axonal transport to the central nervous system, where it interferes with complex processes of central sensitization. Future experiments are needed to explain in more depth BoNT/A molecular mechanism of action and pharmacokinetic peculiarities.

Pain Level of Postoperative Orthopedic Patients at Dr. Soetomo General Hospital

Introduction: Postoperative pain is the most undesirable consequence of the surgery. If it is not managed properly, it can lead to a long healing. However, assessment and treatment of postoperative pain in surgical wards still have not received attention. Differences in patient’s pain level after surgery and after being transferred to the surgical ward is very important in monitoring the effectiveness postoperative pain management. Objective: This study was conducted to determine the overview of pain level experienced by patients following orthopedic surgery and to know the individual factors that can affect the patient's pain level. Method and Material: This research was observational analytic with 43 orthopedic postoperative patients as a sample. The Patients’ pain level were measured by the Numeric Rating Scale (NRS) at one hour after surgery and 24 hours after surgery. Result and Discussion: The Pain level one hour after surgery varied between pain level 0 as much as 53% to pain level 8 as much as 4.7%. The results of measurements of pain 24 hours after surgery only 23.3% of the patients who did not complain of pain, and there was a patient who experienced pain level 10. The results of the statistical calculation, the difference between the level of pain one hour and 24 hours post-surgery obtained value of p=0.037 (p&lt;0.05). Conclusion: There was a significant difference between the pain level at one hour and 24 hours post-surgery. It might be due to the process of peripheral and central sensitization in patients with delayed pain management. It also may be influenced by individual factors as well as medical personnel.

Relations between a standardized experimental stressor and cutaneous sensory function in patients with chronic pruritus and healthy controls: an experimental case-control study.

BackgroundWhile chronic pruritus (CP) is a frequent symptom, many aspects of its underlying pathophysiological mechanisms still need elucidation. Research on sensory cutaneous function and on the influence of stress has been conducted mainly in patients with atopic dermatitis but is lacking for patients with CP.ObjectiveTo assess whether a standardized social stressor influences cutaneous sensory function in patients with CP in comparison with healthy controls (HC).MethodsCase–control study; 33 CP and 30 HC were submitted to the standardized quantitative sensory testing protocol before and after the Trier Social Stress Test and 1 h later. Intraepidermal nerve fibre density (IENFD) was determined.ResultsMechanical pain sensitivity and mechanical detection thresholds were significantly higher in CP than in HC, and mechanical detection thresholds increased more in CP than in HC over the three measurements. In both groups, cold pain threshold increased and heat pain threshold decreased from before to after the stress test and remained constant 1 h later. Only in CP, almost all QST tests induced at least a small amount of pruritus, which was not significantly altered by the stress test. IENFD in pruritic skin was significantly reduced in CP when compared to healthy controls.ConclusionPeripheral thermal sensory function was not altered in CP despite reduced IENFD in lesional skin, but we could demonstrate central sensitization processes specifically in CP and influences of an acute stressor inducing more sensitivity to thermal pain in both groups.

Neurogenic inflammation in fibromyalgia.

Fibromyalgia is a high impact chronic pain disorder with a well-defined and robust clinical phenotype. Key features include widespread pain and tenderness, high levels of sleep disturbance, fatigue, cognitive dysfunction and emotional distress. Abnormal processing of pain and other sensory input occurs in the brain, spinal cord and periphery and is related to the processes of central and peripheral sensitization. As such, fibromyalgia is deemed to be one of the central sensitivity syndromes. There is increasing evidence of neurogenically derived inflammatory mechanisms occurring in the peripheral tissues, spinal cord and brain in fibromyalgia. These involve a variety of neuropeptides, chemokines and cytokines with activation of both the innate and adaptive immune systems. This process results in several of the peripheral clinical features of fibromyalgia, such as swelling and dysesthesia, and may influence central symptoms, such as fatigue and changes in cognition. In turn, emotional and stress-related physiological mechanisms are seen as upstream drivers of neurogenic inflammation in fibromyalgia.

Complex regional pain syndrome-up-to-date.

Complex regional pain syndrome (CRPS) was described for the first time in the 19th century by Silas Weir Mitchell. After the exclusion of other causes, CRPS is characterised by a typical clinical constellation of pain, sensory, autonomic, motor, or trophic symptoms which can no longer be explained by the initial trauma. These symptoms spread distally and are not limited to innervation territories. If CRPS is not improved in the acute phase and becomes chronic, the visible symptoms change throughout because of the changing pathophysiology; the pain, however, remains. The diagnosis is primarily clinical, although in complex cases further technical examination mainly for exclusion of alternative diagnoses is warranted. In the initial phase, the pathophysiology is dominated by a posttraumatic inflammatory reaction by the activation of the innate and adaptive immune system. In particular, without adequate treatment, central nociceptive sensitization, reorganisation, and implicit learning processes develop, whereas the inflammation moderates. The main symptoms then include movement disorders, alternating skin temperature, sensory loss, hyperalgesia, and body perception disturbances. Psychological factors such as posttraumatic stress or pain-related fear may impact the course and the treatability of CRPS. The treatment should be ideally adjusted to the pathophysiology. Pharmacological treatment maybe particularly effective in acute stages and includes steroids, bisphosphonates, and dimethylsulfoxide cream. Common anti-neuropathic pain drugs can be recommended empirically. Intravenous long-term ketamine administration has shown efficacy in randomised controlled trials, but its repeated application is demanding and has side effects. Important components of the treatment include physio- and occupational therapy including behavioural therapy (eg, graded exposure in vivo and graded motor imaging). If psychosocial comorbidities exist, patients should be appropriately treated and supported. Invasive methods should only be used in specialised centres and in carefully evaluated cases. Considering these fundamentals, CRPS often remains a chronic pain disorder but the devastating cases should become rare.

Neuropathic symptoms of the ocular surface: dryness, pain, and itch.

This review aims to describe the recent findings on epidemiology, pathophysiology, and management of neuropathic symptoms of the ocular surface, with a focus on potential similarities between sensations of dry eye, pain and itch. A narrative review of the literature was undertaken. Key references from research in dry eye, neuropathic symptoms of the ocular surface, ocular pain and itch, as well as general references on itch and pain neurobiology were included. Recent findings suggest aspects of dry eye, chronic ocular pain and itch symptomatology are driven by neuropathic pain mechanisms involving peripheral and central sensitization processes. Ocular dryness, pain, and itch are prevalent complaints with several of shared features. Multiple lines of evidence suggest that peripheral and central neuronal sensitization processes are involved in generating and maintaining ocular sensory symptoms. Research is warranted on the epidemiology of ocular sensations, molecular mechanisms involved in nociception and pruriception in the eye, electrophysiological alterations in animal models of eye conditions, and therapeutic modalities that can alleviate unpleasant ocular sensations.

Laser-evoked potentials in painful radiculopathy

ObjectiveThe aims of this exploratory study were (1) to develop a standardized objective electrophysiological technique with laser-evoked potentials to assess dorsal root damage quantitatively and (2) to correlate these LEP measures with clinical parameters and sensory abnormalities (QST) in the affected dermatome. MethodsThirty-eight patients with painful radiculopathy and 20 healthy subjects were investigated with LEP recorded from the affected dermatome and control areas as well as with quantitative sensory testing. Questionnaires evaluating severity and functionality were applied. ResultsOn average, LEP amplitudes and latencies from the affected dermatomes did not differ from the contralateral control side. In patients with left L5 radiculopathy (more severely affected) the N2 latency was longer and the amplitudes reduced. ConclusionsThe N2P2 amplitude correlated with pinprick evoked sensations in QST. The N2 latency from the affected dermatome correlates with pain intensity, chronicity, clinical severity and with a decrease of physical function. SignificanceAn increase in N2-latency indicates a more pronounced nerve root damage, which is associated with a decrease of function and an increase of severity and pain. LEP amplitudes are associated with the functional status of the nociceptive system and may distinguish between degeneration of neuronal systems and central sensitization processes.

Pathophysiology of Pain: Why Does Chronic Pain Hurt? The Multiple Hit Theory

Acute pain hurts and most often is the result of tissue injury. Chronic pain also hurts. Although those who suffer from chronic pain also tend to associate the onset with an injury, illness, or surgical procedure; the root cause is far more complex. Chronic pain most often does not follow dermatomal distributions associated with any injury, disease or surgical procedure. And more often than not, chronic pain sufferers also suffer from various forms of depression and/or anxiety. The process of central sensitization resulting from tissue injury has been elucidated, as has many of the molecular changes within the brain that perpetuate chronic pain. Genetics, epigenetics, environmental stressors, and emotional stressors all play roles to varying degrees in the development of the chronic pain state. This article explores how synaptic memories form in the brain as a result of both physical and emotional traumas (multiple hits) resulting in progression to chronic pain, because of failure of the brain’s descending modulatory mechanisms to prevent or control “the pain.” This review contains 15 figures, and 178 references. Key words: Epigenetics, memory, central sensitization, chronic pain

Nitroglycerin increases serotonin transporter expression in rat spinal cord but anandamide modulated this effect

Migraine is one of the most prevalent neurological diseases, which affects 16% of the total population. The exact pathomechanism of this disorder is still not well understood, but it seems that serotonin and its transporter have a crucial role in the pathogenesis.One of the animal models of migraine is the systemic administration of nitroglycerin (NTG), a nitric oxide (NO) donor. NO can initiate a central sensitization process in the trigeminal system, which is also present in migraineurs.Recent studies showed that the endocannabinoid system has a modulatory role on the trigeminal activation and sensitization.Our aim was to investigate the effect of an endogenous cannabinoid, anandamide (AEA) on the NTG-induced changes on serotonin transporter (5-HTT) expression in the upper cervical spinal cord (C1–C2) of the rat, where most of the trigeminal nociceptive afferents convey.The animals were divided into four groups. Rats in the first group, called placebo, received only the vehicle solution as treatment. In the second group, they were treated with an intraperitoneal (i.p.) injection of NTG (10mg/kg). Rats in the third and fourth groups received i.p. AEA (2×5mg/kg) half hour before and one hour after the placebo or NTG treatment. Four hours after placebo/NTG injection, the animals were perfused and the cervical spinal cords were removed for immunohistochemistry and Western blotting.Our results show that both NTG and AEA alone are able to increase 5-HTT expression in the C1–C2 segments. Combination of NTG and AEA has an opposing effect on this marker, nullifying the effects of non-combined administration, probably by negative feedback mechanisms.

Prevention and reversal of latent sensitization of dorsal horn neurons by glial blockers in a model of low back pain in male rats.

In an animal model of nonspecific low back pain, recordings from dorsal horn neurons were made to investigate the influence of glial cells in the central sensitization process. To induce a latent sensitization of the neurons, nerve growth factor (NGF) was injected into the multifidus muscle; the manifest sensitization to a second NGF injection 5 days later was used as a read-out. The sensitization manifested in increased resting activity and in an increased proportion of neurons responding to stimulation of deep somatic tissues. To block microglial activation, minocycline was continuously administered intrathecally starting 1 day before or 2 days after the first NGF injection. The glia inhibitor fluorocitrate that also blocks astrocyte activation was administrated 2 days after the first injection. Minocycline applied before the first NGF injection reduced the manifest sensitization after the second NGF injection to control values. The proportion of neurons responsive to stimulation of deep tissues was reduced from 50% to 17.7% (P < 0.01). No significant changes occurred when minocycline was applied after the first injection. In contrast, fluorocitrate administrated after the first NGF injection reduced significantly the proportion of neurons with deep input (15.8%, P < 0.01). A block of glia activation had no significant effect on the increased resting activity. The data suggest that blocking microglial activation prevented the NGF-induced latent spinal sensitization, whereas blocking astrocyte activation reversed it. The induction of spinal neuronal sensitization in this pain model appears to depend on microglia activation, whereas its maintenance is regulated by activated astrocytes.NEW & NOTEWORTHY Activated microglia and astrocytes mediate the latent sensitization induced by nerve growth factor in dorsal horn neurons that receive input from deep tissues of the low back. These processes may contribute to nonspecific low back pain.

Topical Phenytoin in Neuralgic Pain, Peripheral Modulation of Central Sensitization: Two Case Reports

We herewith describe a topical formulation of phenytoin with a clear analgesic effect in localized neuropathic pain: in post herpetic neuralgia and trigeminal neuralgia. Such topical analgesic effect for phenytoin has not yet been described in literature. We have developed various topical phenytoin formulations and identified a stable cream base in which we compounded a range of concentrations of phenytoin up to 10%. We will present two cases supporting the analgesic effect of phenytoin cream in neuralgic pain, and discuss the putative mechanism of action of phenytoin as a topical analgesic. The essence of both cases is that, apparently, it is possible to down-regulate central sensitization processes via the modulation (inhibition) of peripheral input. This hypothesis was brought forward in 2013 based on neurophysiological data, and our clinical data seem to also support this important chapter in pain treatment. Thus, topical analgesia, in our case based on phenytoin, can play an important role in multimodal therapy of chronic neuropathic pain, related to central sensitization states.