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Thiamine Suppresses Thermal Hyperalgesia, Inhibits Hyperexcitability, and Lessens Alterations of Sodium Currents in Injured, Dorsal Root Ganglion Neurons in Rats
Abstract
B vitamins can effectively attenuate inflammatory and neuropathic pain in experimental animals, while their efficacy in treating clinical pain syndromes remains unclear. To understand possible mechanisms underlying B vitamin-induced analgesia and provide further evidence that may support the clinical utility of B vitamins in chronic pain treatment, this study investigated effects of thiamine (B1) on the excitability and Na currents of dorsal root ganglion (DRG) neurons that have been altered by nerve injury.
Nerve injury was mimicked by chronic compression of DRG in rats. Neuropathic pain was evidenced by the presence of thermal hyperalgesia. Intracellular and patch-clamp recordings were made in vitro from intact and dissociated DRG neurons, respectively.
(1) In vivo intraperitoneal administration of B1 (66 mg/kg/day, 10-14 doses) significantly inhibited DRG compression-induced neural hyperexcitability, in addition to suppressing thermal hyperalgesia. (2) In vitro perfusion of B1 (0.1, 1 and 10 mM) resulted in a dose-dependent inhibition of DRG neuron hyperexcitability. In addition, the DRG neurons exhibited size-dependent sensitivity to B1 treatment, i.e., the small and the medium-sized neurons, compared to the large neurons, were significantly more sensitive. (3) Both in vitro (1 mM) and in vivo application of B1 significantly reversed DRG compression-induced down-regulation of tetrodotoxin-resistant but not tetrodotoxin-sensitive Na current density in the small neurons. B1 at 1 mM also reversed the compression-induced hyperpolarizing shift of the inactivation curve of the tetrodotoxin-resistant currents and the upregulated ramp currents in small DRG neurons.
Thiamine can reduce hyperexcitability and lessen alterations of Na currents in injured DRG neurons, in addition to suppressing thermal hyperalgesia.
... Vitamin B1, B6, and B12 belong to the hydrosoluble group of vitamins. They are vital to axonal transport, neuron excitability, and the synthesis of neurotransmitters [10][11][12][13][14][15][16]. Vitamin B1, B6, and B12 are also important for nucleic acid and proteins synthesis, as well as for phosphatidylcholine synthesis [17][18][19]. ...
... Several experimental animals and in vitro models have shown that B vitamins (including thiamine, pyridoxine, riboflavin and cobalamin) produce antinociceptive, anti-hyperalgesic, and anti-inflammatory effects and reduce mechanic allodynia [12,[27][28][29][30][31]. Similarly, it has been described that B vitamins can enhance the therapeutic effects of analgesics [32][33][34][35][36][37][38][39][40][41][42][43][44][45][46][47][48]. ...
... Furthermore, DRG neurons showed differential sensitivity to B1 treatment, depending on their size (smaller neurons were more sensitive). Authors concluded that thiamine could modulate Na + currents, and reduce hyperexcitability and thermal hyperalgesia in harmed DRG neurons [12]. ...
Pain is a complex sensory and emotional experience with nociceptive, nociplastic, and neuropathic components. An involvement of neurotropic B vitamins (B1 - thiamine, B6 - pyridoxine, and B12 - cyanocobalamin) as modulators of inflammation and pain has been long discussed. New evidence suggests their therapeutic potential in different pain conditions. In this review, we discuss the main role of neurotropic B vitamins on different nociceptive pathways in the nervous system and to describe their analgesic action mechanisms. The performed literature review showed that, through different mechanisms, these vitamins regulate several inflammatory and neural mediators in nociceptive and neuropathic pain. Some of these processes include aiming the activation of the descending pain modulatory system and in specific intracellular pathways, anti-inflammatory, antioxidative and nerve regenerative effects. Moreover, recent data shows the antinociceptive, antiallodynic, and anti-hyperalgesic effects of the combination of these vitamins, as well as their synergistic effects with known analgesics. Understanding how vitamins B1, B6, and B12 affect several nociceptive mechanisms can therefore be of significance in the treatment of various pain conditions.
... The same effects were observed in patients suffering of several types of neuropathies (Eckert and Schejbal, 1992;Kluzer and Lampo, 1972;Levin and Moseĭkin, 2009). Furthermore, there is mounting evidence that B vitamins can control different aspects of neuropathic pain in various animal models Caram-Salas et al., 2006;Jolivalt et al., 2009;Mixcoatl-Zecuatl et al., 2008;Song et al., 2009;Wang et al., 2005;Yu et al., 2014). ...
... However, single injections of each one of the B vitamins failed to modify the heat latency of nerve-injured animals. In contrast, a single systemic injection of vitamins B1, B6 and B12, alone or in combination, resulted in alleviation of hind paw heat hyperalgesia induced by spinal ganglia compression or by loose ligation of the sciatic nerve in rats (Song et al., 2009;Wang et al., 2005). ...
... The mechanisms underlying the inhibition of neuropathic pain by B vitamins are currently unknown and a limited number of studies have sought to investigate this issue. It has been proposed that the antihyperalgesic mechanisms of B vitamins include its ability to increase afferent inhibitory control of nociceptive neurons at the spinal cord (Fu et al., 1998), to improve sensory nerve conduction velocity (Jolivalt et al., 2009) and to reduce neuronal hyperexcitability by altering sodium currents in injured dorsal root ganglia (Song et al., 2009). More recently, it was demonstrated that repeated systemic administration of a vitamin B complex reduced the ischemia injuryinduced thermal hyperalgesia and the increased expression of TRPV1 receptors in rats (Yu et al., 2014). ...
Vitamins of the B complex attenuate some neuropathic pain sensory aspects in various animal models and in patients, but the mechanisms underlying their effects remain to be elucidated. Herein it was investigated if the treatment with a vitamin B complex (VBC) reduces heat hyperalgesia in rats submitted to infraorbital nerve constriction and the possibility that TRPV1 receptors represent a target for B vitamins. In the present study, the VBC refers to a combination of vitamins B1, B6 and B12 at low- (18, 18 and 1.8mg/kg, respectively) or high- (180, 180 and 18mg/kg, respectively) doses. Acute treatment of rats with either the low- or the high-doses combination reduced heat hyperalgesia after nerve injury, but the high-doses combination resulted in a long-lasting effect. Repeated treatment with the low-dose combination reduced heat hyperalgesia on day four after nerve injury and showed a synergist effect with a single injection of carbamazepine (3 or 10mg/kg), which per se failed to modify the heat threshold. In naïve rats, acute treatment with the high-dose of VBC or B1 and B12 vitamins independently reduced heat hyperalgesia evoked by capsaicin (3µg into the upper lip). Moreover, the VBC, as well as, each one of the B vitamins independently reduced the capsaicin-induced calcium responses in HEK 293 cells transiently transfected with the human TRPV1 channels. Altogether, these results indicate that B vitamins can be useful to control heat hyperalgesia associated with trigeminal neuropathic pain and that modulation of TRPV1 receptors may contribute to their anti-hyperalgesic effects.
Copyright © 2015. Published by Elsevier B.V.
... Allodynia depends in part on peripheral sensitization, which involves neuronal hyperexcitability. It is well known that Neuro2a/DRG cells extend neurites and display inward Na + /Ca 2+ currents in response to treatment with the differentiating agent RA and NGF [18,35,36,[63][64][65]. Our results demonstrated that, in both RAtreated Neuro2a cells and NGF-treated DRGNs, Panx1 was required for neurite extension and robust expression of cellular excitability. ...
... Generally, smaller diameter DRG cells are nociceptors and thermoreceptors, and larger high threshold mechanoreceptors become recruited into activity in pain sensitization. In this study, it was also observed that electrophysiology of small-diameter DRGNs was improved after Panx1 deletion, indicating that the Panx1 channels particularly impacted nociceptive C-and Aβ-fiber cells that mediate pain sensitization [33,35,65]. ...
Background
The channel-forming protein Pannexin1 (Panx1) has been implicated in both human studies and animal models of chronic pain, but the underlying mechanisms remain incompletely understood.
Methods
Wild-type (WT, n = 24), global Panx1 KO (n = 24), neuron-specific Panx1 KO (n = 20), and glia-specific Panx1 KO (n = 20) mice were used in this study at Albert Einstein College of Medicine. The von Frey test was used to quantify pain sensitivity in these mice following complete Freund’s adjuvant (CFA) injection (7, 14, and 21 d). The qRT-PCR was employed to measure mRNA levels of Panx1, Panx2, Panx3, Cx43, Calhm1, and β-catenin. Laser scanning confocal microscopy imaging, Sholl analysis, and electrophysiology were utilized to evaluate the impact of Panx1 on neuronal excitability and morphology in Neuro2a and dorsal root ganglion neurons (DRGNs) in which Panx1 expression or function was manipulated. Ethidium bromide (EtBr) dye uptake assay and calcium imaging were employed to investigate the role of Panx1 in adenosine triphosphate (ATP) sensitivity. β-galactosidase (β-gal) staining was applied to determine the relative cellular expression levels of Panx1 in trigeminal ganglia (TG) and DRG of transgenic mice.
Results
Global or neuron-specific Panx1 deletion markedly decreased pain thresholds after CFA stimuli (7, 14, and 21 d; P < 0.01 vs. WT group), indicating that Panx1 was positively correlated with pain sensitivity. In Neuro2a, global Panx1 deletion dramatically reduced neurite extension and inward currents compared to the WT group (P < 0.05), revealing that Panx1 enhanced neurogenesis and excitability. Similarly, global Panx1 deletion significantly suppressed Wnt/β-catenin dependent DRG neurogenesis following 5 d of nerve growth factor (NGF) treatment (P < 0.01 vs. WT group). Moreover, Panx1 channels enhanced DRG neuron response to ATP after CFA injection (P < 0.01 vs. Panx1 KO group). Furthermore, ATP release increased Ca²⁺ responses in DRGNs and satellite glial cells surrounding them following 7 d of CFA treatment (P < 0.01 vs. Panx1 KO group), suggesting that Panx1 in glia also impacts exaggerated neuronal excitability. Interestingly, neuron-specific Panx1 deletion was found to markedly reduce differentiation in cultured DRGNs, as evidenced by stunted neurite outgrowth (P < 0.05 vs. Panx1 KO group; P < 0.01 vs. WT group or GFAP-Cre group), blunted activation of Wnt/β-catenin signaling (P < 0.01 vs. WT, Panx1 KO and GFAP-Cre groups), and diminished cell excitability (P < 0.01 vs. GFAP-Cre group) and response to ATP stimulation (P < 0.01 vs. WT group). Analysis of β-gal staining showed that cellular expression levels of Panx1 in neurons are significantly higher (2.5-fold increase) in the DRG than in the TG.
Conclusions
The present study revealed that neuronal Panx1 is a prominent driver of peripheral sensitivity in the setting of inflammatory pain through cell-autonomous effects on neuronal excitability. This hyperexcitability dependence on neuronal Panx1 contrasts with inflammatory orofacial pain, where similar studies revealed a prominent role for glial Panx1. The apparent differences in Panx1 expression in neuronal and non-neuronal TG and DRG cells are likely responsible for the distinct impact of these cell types in the two pain models.
Supplementary Information
The online version contains supplementary material available at 10.1186/s40779-024-00525-8.
... Despite these efforts over the past decades, the specific cellular and molecular mechanisms underlying DNP pathogenesis remain elusive, and clinical approaches for DNP treatment are limited. e B vitamins, thiamine (B1), pyridoxine (B6), and cyanocobalamin (B12), have been reported to be effective in treating certain chronic painful disorders, such as neuropathic pain [19,20], trigeminal neuralgia [21], diabetic neuropathy [22,23], and rheumatoid arthritis [24]. It has also been reported that chronic exposure to thiamine, pyridoxine, and cyanocobalamin protects neurons from glutamate or NMDA-mediated excitotoxicity in vitro [25,26]. ...
... VBC was injected daily for 7 consecutive days from day 36 to day 42 after STZ injection. e doses of VBC were used based on our previous studies [19,20,27]. ...
Background:
Treatment of diabetic neuropathic pain (DNP) continues to be a major challenge, and underlying mechanisms of DNP remain elusive. We investigated treatment effects of B vitamins on DPN- and DNP-associated alterations of neurochemical signaling in the nociceptive dorsal root ganglion (DRG) neurons and the spinal cord in rats.
Methods:
DNP was produced in male, adult, Sprague Dawley rats by single i.p. streptozotocin (STZ). Western blot analysis and immunohistochemistry were used to analyze protein expressions in DRG and ELISA to measure the proinflammatory cytokines in the spinal cord. Behaviorally expressed DNP was determined by measuring the sensitivity of hindpaw skin to mechanical and thermal stimulation.
Results:
There were 87.5% (77/88) rats which developed high blood glucose within 1-2 weeks following STZ injection. Of which, 70.13% (n = 54/77) animals exhibited DNP manifested as mechanical allodynia and/or thermal hyperalgesia. Intraperitoneal administration of vitamins B1/B6/B12 (100/100/2 mg/kg, one or multiple doses) significantly attenuated DNP without affecting the blood glucose. Expressions of P2X3 and TRPV1 in CGRP-positive and IB4-positive DRG neurons as well as the interleukin-1β, tumor necrosis factor-α, and nerve growth factor in the lumbar spinal cord were greatly increased in DNP rats. Such DNP-associated neurochemical alterations were also greatly suppressed by the B-vitamin treatment.
Conclusions:
B-vitamin treatment can greatly suppress chronic DNP and DNP-associated increased activities of P2X3 and TRPV1 in DRG and the spinal proinflammatory cytokines, which may contribute to the pathogenesis of DNP. Systematic administration of B vitamins can be a strategy for DNP management in clinic.
... On the other hand, inflammation, oxidative stress, autophagy, and endoplasmic reticulum stress leading to neurodegeneration, are known to be induced by thiamine deficiency (24)(25)(26)(27), and we have recently reported that a high dose of thiamine results in a long-term optimization of the amino acid metabolism (28), potentially contributing to beneficial influence of thiamine on brain pathologies (29). It is also known that thiamine exerts analgesic and anti-inflammatory effects in different rat models including nerve injuries (30)(31)(32)(33). The aim of this work is to estimate long-term changes in the NO • -related compounds in the cerebral cortex after SCI, and their potential normalization by thiamine treatment. ...
... After surgery, the rats were placed into the individual cages with heating pad. Previous protocols (35)(36)(37) were adapted to this study involving postoperative administration of thiamine, which is known for analgesic and anti-inflammatory effects (30)(31)(32)(33). Within the first 3 days after the operation, antibiotic (gentamicin, 40 mg/kg) was injected subcutaneously (s.q.) once per day to rats. ...
Severe spinal cord injuries (SCIs) result in chronic neuroinflammation in the brain, associated with the development of cognitive and behavioral impairments. Nitric oxide (NO•) is a gaseous messenger involved in neuronal signaling and inflammation, contributing to nitrosative stress under dysregulated production of reactive nitrogen species. In this work, biochemical changes induced in the cerebral cortex of rats 8 weeks after SCI are assessed by quantification of the levels of amino acids participating in the NO• and glutathione metabolism. The contribution of the injury-induced neurodegeneration is revealed by comparison of the SCI- and laminectomy (LE)-subjected animals. Effects of the operative interventions are assessed by comparison of the operated (LE/SCI) and non-operated animals. Lower ratios of citrulline (Cit) to arginine (Arg) or Cit to ornithine and a more profound decrease in the ratio of lysine to glycine distinguish SCI animals from those after LE. The data suggest decreased NO• production from both Arg and homoarginine in the cortex 8 weeks after SCI. Both LE and SCI groups show a strong decrease in the level of cortex glutathione. The neurotropic, anti-inflammatory, and antioxidant actions of thiamine (vitamin B1) prompted us to study the thiamine effects on the SCI-induced changes in the NO• and glutathione metabolism. A thiamine injection (400 mg/kg intraperitoneally) within 24 h after SCI abrogates the changes in the cerebral cortex amino acids related to NO•. Thiamine-induced normalization of the brain glutathione levels after LE and SCI may involve increased supply of glutamate for glutathione biosynthesis. Thus, thiamine protects from sequelae of SCI on NO•-related amino acids and glutathione in cerebral cortex.
... In nerve membrane conduction, thiamine triphosphate is thought to activate ion transport, in particular, chlorine but also participation in nerve impulse transmission via sodium channel regulation and release of acetylcholine. It has been reported that thiamine administration suppresses thermal hyperalgesia by reducing hyperexcitability and lessening alterations of sodium currents in injured dorsal root ganglion neurons in rats [9]. Therefore, thiamine administration can help in nerve axons regeneration, reduce pain and aid in balancing sodium currents. ...
... Pyridostigmine is a synthetic quaternary ammonium agent which increases the concentration of endogenous acetylcholine by inhibiting acetylcholinesterase in the neuromuscular junction which in turn increases muscle strength [9]. Pyridostigmine has been used for vincristinerelated neuropathy as a reduction of gastrointestinal motility, which is one of the major symptoms commonly found. ...
Ptosis is a rare side effect of vincristine chemotherapy in patients treated for cancer. We report a case of a child with common B-cell acute lymphoblastic leukemia who developed bilateral moderate ptosis following the chemotherapy protocol of the United Kingdom Acute Lymphoblastic Leukemia (ALL) regimen A. The patient showed dramatic clinical improvement after a combination of oral pyridoxine and thiamine treatment. We provide a literature review of this uncommon presentation.
... nels. American Journal of Physiology and Cell Physiology, 297, C823eC834, (B) Modified from Sun, G. C., Werkman, T. R., & Wadman, W. J. (2006). Kinetic changes and modulation by carbamazepine on voltage-gated sodium channels in rat CA1 neurons after epilepsy. Acta Pharmacological Sinica, 12, 1537e1546, (Ci) Modified from Song, X. S., Huang, Z. J., & Song, X. J. (2009). Thiamine suppresses thermal hyperalgesia, inhibits hyperexcitability, and lessens alterations of sodium currents in injured, dorsal root ganglion neurons in rats. Anesthesiology, 110, 387e400, and (Ciii) Modified from Song, Y., Li, H. M., Xie, R. G., Yue, Z. F., Song, X. J., Hu, S. J., & Xing, J.L. (2012). Evoked bursting in injured Ab ...
... To model tactile allodynia, a phenomenon linked to hyperexcitable DRG neurons, chronic compression of DRG neurons [chronic crush damage (CCD)] has been used (Song et al., 2009(Song et al., , 2012. CCD yields bursting discharges associated with STOs in response to peripheral stimulation (see Fig. 2C). ...
Sick excitable cells (ie, Nav channel–expressing cells injured by trauma, ischemia, inflammatory, and other conditions) typically exhibit “acquired sodium channelopathies” which, we argue, reflect bleb-damaged membranes rendering their Nav channels “leaky.” The situation is excitotoxic because untreated Nav leak exacerbates bleb damage. Fast Nav inactivation (a voltage-independent process) is so tightly coupled, kinetically speaking, to the inherently voltage-dependent process of fast activation that when bleb damage accelerates and thus left-shifts macroscopic fast activation, fast inactivation accelerates to the same extent. The coupled g(V) and availability(V) processes and their window conductance regions consequently left-shift by the same number of millivolts. These damage-induced hyperpolarizing shifts, whose magnitude increases with damage intensity, are called coupled left shift (CLS). Based on past work and modeling, we discuss how to test for Nav-CLS, emphasizing the virtue of sawtooth ramp clamp. We explain that it is the inherent mechanosensitivity of Nav activation that underlies Nav-CLS. Using modeling of excitability, we show the known process of Nav-CLS is sufficient to predict a wide variety of “sick excitable cell” phenomena, from hyperexcitability through to depolarizing block. When living cells are mimicked by inclusion of pumps, mild Nav-CLS produces a wide array of burst phenomena and subthreshold oscillations. Dynamical analysis of mild damage scenarios shows how these phenomena reflect changes in spike thresholds as the pumps try to counteract the leaky Nav channels. Smart Nav inhibitors designed for sick excitable cells would target bleb-damaged membrane, buying time for cell-mediated removal or repair of Nav-bearing membrane that has become bleb-damaged (ie, detached from the cytoskeleton).
... The protocol was the same as that we have described previously. 30,32,37 Under deep anesthesia, a laminectomy was performed, and the L4 and/or L5 DRG with attached sciatic nerve and the dorsal roots were removed and placed in 35-mm petri dishes containing ice-cold oxygenated ACSF consisting of (in mM) 140 NaCl, 3. To test excitability of the nociceptive DRG neurons, whole-cell current-clamp and voltage-clamp recordings were made with an Axopatch-200B amplifier (Molecular Devices, Union city, CA) in the small DRG neurons (soma diameter: 15-30 mm) from the intact ganglion preparations. These neurons largely correspond to neurons with C-fiber conduction velocities. ...
... The protocols were similar to that we have previously described. 32,37 Glass electrodes were fabricated with a Flaming/Brown micropipette puller (P-97, Sutter instruments, Novato, CA). Electrode impedance was 3 to 5 MV when filled with saline containing (in mM) 120 K 1 -gluconate, 20 KCl, 1 CaCl 2 , 2 MgCl 2 , 11 ethylene glycol-bis-(b-aminoethyl-ether) N,N,N9,N9,-tetraacetic acid, 2 Mg-ATP, and 10 HEPES-K (pH 7.2, osmolarity 290-300 mOsm). ...
Treating neuropathic pain continues to be a major clinical challenge and underlying mechanisms of neuropathic pain remain elusive. We have recently demonstrated that Wnt signaling, which is important in developmental processes of the nervous systems, plays critical roles in the development of neuropathic pain through the β-catenin-dependent pathway in the spinal cord and the β-catenin-independent pathway in primary sensory neurons after nerve injury. Here, we report that Wnt signaling may contribute to neuropathic pain through the atypical Wnt/Ryk signaling pathway in rats. Sciatic nerve injury causes a rapid-onset and long-lasting expression of Wnt3a, Wnt5b and Ryk receptors in primary sensory neurons, and dorsal horn neurons and astrocytes. Spinal blocking of the Wnt/Ryk receptor signaling inhibits the induction and persistence of neuropathic pain without affecting normal pain sensitivity and locomotor activity. Blocking activation of the Ryk receptor with anti-Ryk antibody, in vivo or in vitro, greatly suppresses nerve injury-induced increased intracellular Ca and hyperexcitability of the sensory neurons, as well as the enhanced plasticity of synapses between afferent C-fibers and the dorsal horn neurons, and activation of the NR2B receptor and the subsequent Ca-dependent signals CaMKII, Src, ERK, PKCγ, and CREB in sensory neurons and the spinal cord. These findings indicate a critical mechanism underlying the pathogenesis of neuropathic pain and suggest that targeting the Wnt/Ryk signaling may be an effective approach for treating neuropathic pain.
... Thiamine, in the form of thiamine pyrophosphate (TPP) and as an important cofactor, participates in carbohydrate metabolism and the synthesis of neurotransmitters such as acetylcholine (ACH) (Paez-Hurtado et al. 2023). Based on experimental studies, the mechanisms and features by which thiamine functions as an antiallodynic agent are as follows: -Regulation of neuronal excitability in the dorsal root ganglion (DRG) neurons and the prolongation of reaction time in a dose-dependent manner by blocking voltage-gated Na+ channels conductance and, thereby, modulating Na+ currents (Song et al. 2009;Moalem et al. 2008). ...
Diabetes-induced hyperglycemia leads to excessive production of oxygen free radicals, inflammatory cytokines, and oxidative stress, which initiates diabetic peripheral neuropathy (DPN). Currently, this condition affects 20% of adults with diabetes. Despite significant advances in the treatment of diabetes, the incidence of its complications, including DPN, is still high. Thus, there is a growing research interest in developing more effective and treatment approaches with less side effects for diabetes and its complications. Nigellasativa L. (NS) has received much research attention as an antioxidant, anti-yperglycemic factor, and anti-inflammatory agent. This natural compound demonstrates its antidiabetic neuropathy effect through various pathways, including the reduction of lipid peroxidation, the enhancement of catalase and superoxide dismutase enzyme activity, and the decrease in inflammatory cytokine levels. The present review focuses on the bioactive and nutraceutical components of black cumin (Nigella sativa L.) and their effects on DPN. In addition, we have also summarized the findings obtained from several experimental and clinical studies regarding the antidiabetic neuropathy effect of NS in animal models and human subjects.
... Thiamin (B1) can modify sodium channel conductance to reduce hyperexcitability and thermal hyperalgesia after dorsal root ganglion injury. The active form of B6, pyridoxal phosphate, serves as a coenzyme for γ-aminobutyric acid (GABA) synthesis, making B6 bioavailability essential for maintaining inhibitory neurotransmission in pain-related pathways [49,96]. The injection of a vitamin B complex (i.e., B1, B6, and B12) at the time of ischemic injury and up to 2 weeks later significantly reduced thermal hyperalgesia, although it had no effect on mechanical allodynia [49]. ...
Spinal cord injury (SCI) is a common neurological disease worldwide, often resulting in a substantial decrease in quality of life, disability, and in severe cases, even death. Unfortunately, there is currently no effective treatment for this disease. Nevertheless, current basic and clinical evidence suggests that vitamins, with their antioxidant properties and biological functions, may play a valuable role in improving the quality of life for individuals with SCI. They can promote overall health and facilitate the healing process. In this review, we discuss the mechanisms and therapeutic potential of vitamins in the treatment of SCI.
... VB, a group of water-soluble nutrients essential for many metabolic pathways [27], has been studied frequently among scientists in relation to controlling DNP. Reports had shown that VB could be effective against several chronic painful conditions, including DNP [28][29][30][31][32]. One recent study mainly focused on the effects of systematic administration of VBC containing B1, B6, and B12 on STZ-induced rats with DNP by measuring the behavioural and biochemical alterations of P2 × 3 and TRPV1 expression [33]. ...
Diabetic neuropathic pain (DNP) is one of the common and severe late-stage complications of diabetes mellitus, which could greatly influence the patients’ quality of life. Patients with DNP often experience spontaneous pain and evoked pain such as mechanical allodynia and thermal hyperalgesia, meaning that their physical and psychological health are severely impaired. Unfortunately, the mechanisms of DNP remain highly elusive, so substantial breakthrough in effective DNP targeted treatments is still clinically challenging. This article will hence summarise the main mechanisms currently known to underlie DNP pathogenesis, along with describing some of the current and potential treatment methods against diabetic neuropathic pain.
... В эксперименте на мышах было выявлено, что тиамина гидрохлорид дозозависимо уменьшает острую и хроническую невропатическую и воспалительную боль [22]. В другом эксперименте тиамина гидрохлорид дозозависимо уменьшал, вызванную компрессией дорзального ганглия, температурную гипералгезию и гипервозбудимость нейронов дорзального ганглия преимущественно в нейронах малого размера, нормализуя в них ток ионов натрия [26]. Можно предполагать, что антиноцицептивное действие тиамина гидрохлорида реализуется через снижение активности различных изоформ протеинкиназы С. ...
Diagnostics of neuropathy pain is presented in the article, where most essential are methods of clinical estimation with the use of questionnaires and scales for verification and quantitative estimation of pain. The neurological inspection of patients with suspicion on neuropathy pain must plug in itself of the motive, sensory and vegetative phenomena with the purpose of authentication of all signs of neurological dysfunction. If on a background immunotherapy it is not succeeded fully a pain syndrome preparations of the first row, setting of combined pharmacotherapy allows to promote efficiency of treatment at the less dosages of preparations and reduce the risk of development of by-effects.
... This is the reason why it has been extensively used in clinical pain conditions. Although multiple mechanisms have been suggested to explain the analgesic and anti-inflammatory effects of B-complex vitamins (Hurt et al., 2012;Song et al., 2009;Thériault et al., 2014;Erfanparast et al., 2017;Hosseinzadeh et al., 2012), few investigations have been reported on the effects of B-complex vitamins on analgesia. Fewer studies have investigated their effects on the different aspects of the inflammatory pain response, and the exact pain reduction mechanism caused by B vitamins remains unknown. ...
B-vitamins have been evaluated as a useful adjuvant therapy to treat pain. In spite of clinical and experimental
evidence indicating the analgesic effect of B-vitamins, few studies have investigated their effect on aspects of the
inflammatory pain response. In the present study, we investigated the analgesic effect of chronic application of Bcomplex vitamins (Neurobion) using an inflammatory experimental pain model in rats. Nociceptive behavioral
responses were evaluated in male Wistar rats after plantar injection of formalin, comparing the treatment group
(TG) with Neurobion pretreatment to the control group (CG) without the pretreatment. In addition, neuronal
activity in the central pain pathway was evaluated using c-Fos immunohistochemical reactivity and NADPHd histochemistry. A highly significant reduction of painful behaviors such as licking and flinching were
observed in TG, especially during the secondary phase of the formalin test compared to CG. Results suggest that
long-term pre-treatment using Neurobion can have a beneficial effect in reducing the chronic phase of pain. In
addition, we observed a downregulation of c-Fos and NADPH-d in dorsal spinal neurons, suggesting that the
antinociceptive effect induced by Neurobion could be due to a suppression of nociceptive transmission at the
spinal level, particularly in the afferent regions of the dorsal spinal horn, which these neurons utilizing nitric
oxide at least as one of their pain neurotransmitters.
... 86 Cobalamin, an endogenous neuroprotectant and neurotrophic agent, targets protein synthesis in the distal axonal cytoskeleton 87 and scavenges superoxide 88 making it a beneficial treatment for neuropathic pain. 89 According to several clinical studies, the injection of methylcobalamin locally has shown promising results in treating ZAP and PHN, with an overall effectiveness rate of over 80%. [90][91][92][93][94][95] Additionally, locally injected thiamine has been found to have a significant antipruritic effect. ...
Background
Herpes zoster (HZ) is a skin disease that can also cause virus-infectious peripheral neuropathies. Despite this, there is limited information on patient preferences for seeking medical attention for HZ and zoster-associated pain (ZAP). Our study aimed to evaluate how frequently patients with ZAP choose to visit neurologists for their symptoms.
Methods
This study conducted a retrospective review of electronic health records in three general hospitals from January 2017 to June 2022. Using association rule mining, the study analyzed referral behaviors.
Results
We identified 33,633 patients with 111,488 outpatient visits over 5.5 years. The study found that the majority of patients (74.77–91.22%) visited dermatologists during their first outpatient visit, while only a small percentage (0.86–1.47%) preferred to consult a neurologist. The proportion of patients referred to a specialist during their medical visit varied significantly between different specialties within the same hospital (p <0.05) and even within the same specialty (p<0.05). There was a weak association (Lift:1.00–1.17) of referral behaviors between dermatology and neurology. Across the three hospitals, the average number of visits to a neurologist for ZAP was 1.42–2.49, with an average electronic health record duration of 11–15 days per patient. After consulting with a neurologist, some patients were referred to other specialists.
Conclusion
It was observed that patients with HZ and ZAP tended to visit a variety of specialists, with only a small number seeking the assistance of neurologists. However, from the perspective of neuroprotection, it is the duty of neurologists to provide more means.
... The use of vitamins B1, B6, and B12 in the treatment of mixed pain has been discussed for quite a while, due to their involvement in the physiopathology of several pain mechanisms. Antinociceptive activity, regulation of inflammatory mediators in various inflammatory pain models, and a role in neuron regeneration have been described, to name a few [45][46][47][48][49][50][51][52][53] . The role of vitamin B1, B6, and B12 in pain relief either given alone or as an adjuvant to other drugs for analgesia was therefore also reviewed for this consensus meeting. ...
Objectives:
The term "mixed pain" has been established when a mixture of different pain components (e.g. nociceptive, neuropathic, and nociplastic) are present. It has gained more and more acceptance amongst pain experts worldwide, but many questions around the concept of mixed pain are still unsolved. The sensation of pain is very personal. Cultural, social, personal experiences, idiomatic, and taxonomic differences should be taken into account during pain assessment. Therefore, a Latin American consensus committee was formed to further elaborate the essentials of mixed pain, focusing on the specific characteristics of the Latin American population.
Methods:
The current approach was based on a systematic literature search and review carried out in Medline. Eight topics about the definition, diagnosis, and treatment of mixed pain were discussed and voted for by a Latin American consensus committee and recommendations were expressed.
Results:
At the end of the meeting a total of 14 voting sheets were collected. Full consensus was obtained for 21 of 25 recommendations (15 strong agreement and 6 unanimous agreement) formulated for above described 8 topics (7 of the 8 topics had for all questions at least a strong agreement - 1 topic had no agreement for all 4 questions).
Conclusion:
In a subject as complex as mixed pain, a consensus has been reached among Latin American specialists on points related to the definition and essence of this pain, its diagnosis and treatment. Recommendations for diagnosis and treatment of mixed pain in Latin America were raised.
... In neuropathic pain models including CCD, the distribution, expression and activation voltage of Na + channels are altered among DRG neurons. [30][31][32][33] After DRG/nerve injury, TTXinsensitive Na + channels expression was downregulated, whereas TTX-sensitive Na + channels expression was upregulated. 34 So the expression of T-type Ca 2+ channels may upregulate or downregulate in conjunction with Na + channels to enhance neuronal excitability. ...
A subgroup of low-threshold dorsal root ganglia (DRG) neurons discharge action potentials (APs) with an afterdepolarizing potential (ADP). The ADP is formed by T-type Ca2+ currents. It is known that T-type Ca2+ currents contribute to neuropathic pain. However, the change in ADP-firing of injured DRG neurons has not been widely studied yet. Here we applied patch clamp to record ADP-firing and T-type Ca2+ currents in intact and chronically compressed DRG (CCD) neurons and examined T-type Ca2+ channel proteins expression with western blotting. After CCD injury, the incidences of both ADP firing and non-ADP burst firing increased, and T-type Ca2+ channels contributed to both of these firing patterns. The neurons discharging large-amplitude-ADP firing were TTX-insensitive, implying that high-density T-type Ca2+ channels might cooperate with TTX-insensitive Na+ channels to reduce the AP threshold. By contrast, the neurons displaying non-ADP burst firing were TTX-sensitive, implying that low density T-type Ca2+ channels may cooperate with TTX-sensitive Na+ channels to increase AP number. In DRG neurons, T-type Ca2+ currents density varied widely, ranging between 100 pA/pF and 5 pA/pF. After injury, the proportion of DRG neurons with large T-type Ca2+ currents increased in parallel with the increase in the incidence of large-amplitude-ADP firing. And in addition to Cav3.2, Cav3.3 channels are also likely to contribute to low-threshold firing. The data revealed that T-type Ca2+ channels may play a dual role in modulating the injured neurons' high excitability through a cooperative process with Na+ channels, thereby contributing to neuropathic pain.
... Manipulating the brain glutathione redox status by specific OGDH-directed inhibitors, we not only have reproduced the increased anxiety in the animal model but demonstrated the causal link between the OGDHC function and glutathione redox state. Our results on the biochemical and physiological effects of the brain OGDHC inhibition unravel molecular mechanisms underlying the known benefits of therapeutic applications of a physiological OGDHC activator, thiamine, and its pharmacological derivatives, in patients with Alzheimer's disease [72,73], in animal models of neurodegeneration [74][75][76][77], brain and spinal cord injuries [20,21], enhanced stress [78][79][80], and other neurological conditions [81][82][83][84][85][86][87]. ...
Specific inhibitors of mitochondrial 2-oxoglutarate dehydrogenase (OGDH) are administered to animals to model the downregulation of the enzyme as observed in neurodegenerative diseases. Comparison of the effects of succinyl phosphonate (SP, 0.02 mmol/kg) and its uncharged precursor, triethyl succinyl phosphonate (TESP, 0.02 and 0.1 mmol/kg) reveals a biphasic response of the rat brain metabolism and physiology to increasing perturbation of OGDH function. At the low (TE)SP dose, glutamate, NAD+, and the activities of dehydrogenases of 2-oxoglutarate and malate increase, followed by their decreases at the high TESP dose. The complementary changes, i.e., an initial decrease followed by growth, are demonstrated by activities of pyruvate dehydrogenase and glutamine synthetase, and levels of oxidized glutathione and citrulline. While most of these indicators return to control levels at the high TESP dose, OGDH activity decreases and oxidized glutathione increases, compared to their control values. The first phase of metabolic perturbations does not cause significant physiological changes, but in the second phase, the ECG parameters and behavior reveal decreased adaptability and increased anxiety. Thus, lower levels of OGDH inhibition are compensated by the rearranged metabolic network, while the increased levels induce a metabolic switch to a lower redox state of the brain, associated with elevated stress of the animals.
... роль ВитаМиноВ группы В В лечении боли В спине В течение почти 30 лет изучались обезболивающие эффекты тиамина (витамин B 1 ), пиридоксина (витамин B 6 ) и цианокобаламина (витамин B 12 ) в терапевтических дозах, а также их комбинаций с НПВП [20][21][22]. Обезболивающий эффект сочетания всех трех витаминов группы В объясняется множеством механизмов действия, включая противовоспалительный и антиоксидантный, активацию аденозиновых рецепторов, модуляцию потенциалзависимых натриевых каналов (тиамин), блокирование рецепторов P2X с помощью АТФ (пиридоксин), ГАМКергическое и серотонинергическое воздействие (цианокобаламин и пиридоксин), а также воздействие на другие системы нейротрансмиттеров [23][24][25][26][27][28][29]. Усиление антиноцицептивных эффектов морфина витаминами группы B можно объяснить внутриклеточными путями, связанными с толерантностью к морфину и иммуномодулирующими эффектами в спинном мозге [30]. ...
Back pain is one of the most common pain syndromes affecting significantly working capacity and quality of life. In the future, back pain is predicted to grow due to a higher rate of comorbidities and conditions (i.e., obesity, smoking, sedentary lifestyle) and population aging. Therefore, back pain relief is an essential issue for various specialists. However, despite a growing body of studies and published data, the issue of the management of patients with back pain is far from being resolved. This paper discusses the efficacy and safety of various therapeutic strategies for back pain treatment, focusing on B vitamins. Analgesic properties plus the enhancement of painkiller effects and lower risk of pain chronicity (as a result of reduced peripheral and central sensitization) favor including B vitamins into treatment regimens for back pain. The authors also address non-pharmacological approaches to back pain and emphasize that a long-lasting effect of analgesics cannot be achieved without switching from reducing acute pain to preventing future exacerbations. KEYWORDS: back pain, B vitamins, biopsychosocial model, adjuvant treatment, manual therapy. FOR CITATION: Kurushina O.V., Barulin A.E. Back pain: easy is the new difficult? Russian Medical Inquiry. 2021;5(10):642–647 (in Russ.). DOI: 10.32364/2587-6821-2021-5-10-642-647.
... В течение почти 30 лет изучались обезболивающие эффекты тиамина (витамин B 1 ), пиридоксина (витамин B 6 ) и цианокобаламина (витамин B 12 ) в терапевтических дозах в качестве монотерапии, а также в комбинации с НПВП (особенно с диклофенаком) у пациентов с БНЧС [63][64][65]. Обезболивающий эффект комплекса тиамин + пиридоксин + цианокобаламин объясняется множеством механизмов действия, включая противовоспалительный и антиоксидантный эффекты, активацию аденозиновых рецепторов, модуляцию потенциалзависимых натриевых каналов (тиамин), блокирование рецепторов P2X с помощью АТФ (пиридоксин), а также наличием ГАМКергического и серотонинергического эффектов (цианокобаламин и пиридоксин) [66][67][68][69][70][71][72][73][74][75]. Противовоспалительные эффекты витаминов группы B были описаны на животных моделях боли, таких как механическая аллодиния и невропатическая боль [76,77]. ...
Low back pain (LBP) is one of the most common pathologies of the musculoskeletal system worldwide. The article presents data on the main causes of LBP (mechanical, non-mechanical and visceral), the importance of differential diagnosis concerning possible causal factors, taking into account the presence of so-called red and yellow flags. The article also notes the fact of increased pain in the lower back and neck revealed in a number of studies in the conditions of COVID-19 and lists the main possible causes of this phenomenon. The expediency of an integrated approach to patient management with acute and chronic LBP, given the principles of evidence-based medicine, is substantiated. Drug therapy means are characterized, and data are presented indicating complex drugs’ efficacy, including those based on NSAIDs with a proven analgesic effect (diclofenac) and B vitamins. The importance of maintaining the physical activity of patients with both acute and chronic LBP and the ability of some non-pharmacological pain therapy methods (manual therapy, Kinesio taping, etc.) to reduce pain and fear of movement are noted. KEYWORDS: low back pain, red flags, differential diagnosis, treatment, NSAIDs, B vitamins. FOR CITATION: Pizova N.V. Modern patient management with low back pain. Russian Medical Inquiry. 2021;5(10):659–667 (in Russ.). DOI: 10.32364/2587-6821-2021-5-10-659-667.
... In this case, the promising neurodevelopmental response to thiamine (vitamin B1) and biotin (vitamin B7) is encouraging for further clinical research for their role in autoimmune encephalitis. Although we acknowledge the limited evidence of a case report, thiamine has many different roles in the nervous system, such as anti-inflammatory, anti-oxidant, neuroprotective, neuro-conduction, and neuro-recovery effect [14,15]. Biotin has an important role in inflammatory and immune regulation, myelin regeneration, and reducing axonal hypoxia [16,17]. ...
Anti-N-methyl-D-aspartate receptor encephalitis (anti-NMDARE) is the most common cause of autoimmune encephalitis in children with a wide spectrum of clinical presentation and MRI findings. A high index of suspicion is required to avoid a delay in treatment and long-term morbidity. We present a healthy two-year-old male who developed fever and viral prodrome symptoms that rapidly progressed to acute encephalopathy, status epilepticus, quadriparesis, and abnormal movements. Brain MRI showed symmetric involvement of bilateral insula, posterior part of basal ganglia, and thalami. The patient survived the acute phase with supportive therapy but ended up with a devastating neurologic sequela, including developmental delay, inability to communicate, dysphagia, quadriparesis, and cortical visual impairment. Anti-N-methyl-D-aspartate (anti-NMDA) immunoglobulin G (IgG) antibodies were negative in serum and cerebrospinal fluid (CSF). The patient underwent an extensive inflammatory, infectious, metabolic, and genetic workup, including a whole-exome sequence (WES) and mitochondrial panel, which was unremarkable. CSF studies were unremarkable. Repeated anti-NMDA IgG antibodies were positive in serum a year after the presentation. This presentation highlights the crucial role of early immunotherapy in suspected autoimmune encephalitis (AE) cases, even at a young age, to prevent devastating neurologic outcomes. Moreover, clinicians should not rely on antibody results to treat a suspected case of AE due to possible false-negative test results, and the majority of AE cases remain without known antibodies.
... Moreover, Song et al. found that vitamin B1 positively influenced nerve excitability of rat neurons after chronic compression of dorsal roots, i.e., it led to improved signal transmission and at the same time reduced hyperexcitability [33], indicating a regenerative effect. These results are supported by an in vitro study from Geng et al., demonstrating that vitamin B1 promoted survival of cultured rat brain neurons in high-density cell culture [34]. ...
Damage and regeneration naturally occur in the peripheral nervous system. The neurotropic B vitamins thiamine (B1), pyridoxine (B6), and cobalamin (B12) are key players, which maintain the neuronal viability in different ways. Firstly, they constantly protect nerves against damaging environmental influences. While vitamin B1 acts as a site-directed antioxidant, vitamin B6 balances nerve metabolism, and vitamin B12 maintains myelin sheaths. However, nerve injury occurs at times, because of an imbalance between protective factors and accumulating stress and noxae. This will result in the so-called Wallerian degeneration process. The presence of vitamins B1, B6, and B12 paves the way out to the following important regeneration by supporting the development of new cell structures. Furthermore, vitamin B1 facilitates the usage of carbohydrates for energy production, whereas vitamin B12 promotes nerve cell survival and remyelination. Absence of these vitamins will favor permanent nerve degeneration and pain, eventually leading to peripheral neuropathy.
... Комплекс витаминов В 1 , В 6 , В 12 тормозит прохождение болевых импульсов не только на уровне заднего рога, но и в таламусе. Во многих исследованиях подтверждено, что как комбинация, так и отдельное назначение витаминов B 1 , В 6 и В 12 имеет собственный анальгетический потенциал [15,16]. Это связано с тем, что витамины группы В обладают схожими с НПВП механизмами, например блокируют действия медиаторов воспаления [17], ингибируют синтез простагландинов [18], а также замедляют метаболизм НПВП через ингибирование каталитической активности цитохрома С450 3А4 [19]. ...
Objective of the Review: To present, for internists and general practitioners, two sets of multidisciplinary consensus recommendations for the management of patients with back pain. Key Points: The paper includes short diagnostic protocols, red flag screening protocols, and criteria for involving specialists from related fields, starting physiotherapy, and using a battery of psychological tools. Also covered are criteria for optimal treatment with medications, including fast-acting analgesics (particularly non-steroidal anti-inflammatory drugs) and prolonged-action structure-modifying drugs. Conclusion: The management of patients with non-specific back pain is dealt with by internists or general practitioners. It requires a clear, structured approach to identifying red flags and bringing in specialists from related fields; lifestyle and diet modifications; exercise and physical therapy; a battery of psychological tools; and, without question, optimal treatment with medications, including fast-acting analgesics and prolonged-action structure-modifying drugs. Keywords: non-steroidal anti-inflammatory drugs, back pain, treatment protocol, neurotropic B vitamins, prolonged-action structuremodifying drugs.
... Вітаміни групи В відіграють роль у ноцицепції, завдяки чому можуть зменшувати прояви болю й гіпералгезії. Зокрема, знеболюючий ефект вітаміну В 1 пов'язаний із блокуванням метаболічного ушкодження нервів, також останній відіграє роль модуляції нейронального збудження [48]. Тіамін може зменшувати прояви болю через такі механізми, як трансактивація кетолази (забезпечуючи перехід глюкози на пентозофосфатний шунт), протеїнкіназа B опосередковано потенціює ангіогенез й гальмує апоптоз [49], а також протидіє церебральному окислювальному стресу [50]. ...
В статье дана клиническая характеристика полинейропатий при различных заболеваниях и патологических состояниях, представлен перечень обследований для диагностического поиска причин полинейропатии, алгоритм проведения дифференциальной диагностики полинейропатий. Рассмотрено место витаминов группы В в комплексной терапии полинейропатий.
... Diversas investigaciones han estudiado la e cacia de los antin amatorios no esteroideos (AINE), opioides y corticoides, empleados en monoterapia o en combinaciones 5 ; sin embargo, al utilizarse en combinaciones aumentan sus efectos analgésicos y antin amatorios, pero también incrementan la incidencia de efectos adversos, lo que limita su uso. Debido a esto, las vitaminas del complejo B (B 1 , B 6 y B 12 ) aparecen como una buena alternativa para asociarse con AINE (diclofenaco) o corticoides (dexametasona), proporcionando ventajas como un mayor efecto analgésico, antihiperalgésico y antinociceptivo sin aumentar la incidencia de efectos adversos 6,7 . las condiciones del estudio. ...
Objetivo:
Evaluar el efecto antinflamatorio de la administración preoperatoria de la asociación de dexametasona con vitaminas B en cirugías de tercer molar mandibular.
Materiales y métodos:
Estudio experimental conformado por 54 pacientes de 18-25 años, que se asignaron en dos grupos: al grupo control se le administró 4 mg de dexametasona y al grupo experimental la asociación de 4 mg de dexametasona con vitaminas B1, B6 y B12; ambos por vía intramuscular antes de la cirugía. El efecto antinflamatorio se determinó por la evaluación del dolor y la tumefacción. El dolor se evaluó mediante la escala visual análoga, el tiempo para analgesia de rescate y el consumo total de analgésicos. La tumefacción se evaluó mediante mediciones del contorno facial.
Resultados:
Se demostró que la intensidad máxima de dolor apareció a las 24 horas, siendo este significativamente menor en el grupo experimental (4,0 vs. 5,8 cm), p < 0,05; luego los valores fueron disminuyendo progresivamente a las 48 horas, siendo significativamente menor el valor en el grupo experimental (3,3 vs. 5,4 cm), p < 0,05. El grupo experimental demostró un mayor tiempo para analgesia de rescate (2,48 vs. 2,08 h), p > 0,05; y menor consumo de analgésicos (8,5 vs. 9,4 tab), p < 0,05. La tumefacción facial se incrementó progresivamente hasta el tercer día, sin diferencia significativa entre los grupos (45,4 vs. 46 cm), p > 0,05.
Conclusiones:
Se evidenció una significativa mayor actividad analgésica y un significativo menor consumo total de analgésicos en el grupo experimental en comparación con el grupo control. No se evidenció diferencia significativa en la tumefacción.
... Diversas investigaciones han estudiado la eficacia de los antinflamatorios no esteroideos (AINE), opioides y corticoides, empleados en monoterapia o en combinaciones 5 ; sin embargo, al utilizarse en combinaciones aumentan sus efectos analgésicos y antinflamatorios, pero también incrementan la incidencia de efectos adversos, lo que limita su uso. Debido a esto, las vitaminas del complejo B (B 1 , B 6 y B 12 ) aparecen como una buena alternativa para asociarse con AINE (diclofenaco) o corticoides (dexametasona), proporcionando ventajas como un mayor efecto analgésico, antihiperalgésico y antinociceptivo sin aumentar la incidencia de efectos adversos 6,7 . ...
... VBC has received a lot of attention due to the probable action in treat painful conditions (Yu et al., 2014), showing important roles in various biological events such as promote nerve regeneration (Sun et al., 2012), relieves thermal hyperalgesia (Yu et al., 2014), alleviate indices of neuropathic pain in diabetic rats (Jolivalt et al., 2009) and presents anti-hyperalgesic results in diverse kinds of neuropathies and pain conditions (Song et al., 2009;Kopruszinski et al., 2012;Yu et al., 2014). VBC therapy shows promise in helping nociception control, it appears to be safe and there are no reports of adverse side effects due the long-term exposure. ...
Chronic constriction injury (CCI) of infraorbital nerve (IoN) results in whisker pad mechanical allodynia in rats and activation glial cells contributing to the development of orofacial pain. Whisker pad mechanical allodynia (von Frey stimuli) was tested pre and postoperatively and conducted during the treatment time. Photobiomodulation (PBM) and vitamins B complex (VBC) has been demonstrated therapeutic efficacy in ameliorate neuropathic pain. The aim of this study was to evaluate the antinociceptive effect of PBM, VBC or the combined treatment VBC + PBM on orofacial pain due to CCI-IoN. Behavioral and molecular approaches were used to analyses nociception, cellular and neurochemical alterations. CCI-IoN caused mechanical allodynia and cellular alterations including increased expression of glial fibrillary acid protein (GFAP) and ionized calcium binding adaptor molecule 1 (Iba-1), administration of VBC (B1/B6/B12 at 180/180/1.8 mg/kg, s.c., 5 times all long 10 sessions) and PBM therapy (904 nm, power of 75Wpico, average power of 0.0434 W, pulse frequency of 9500 Hz, area of the beam 0.13 cm², 18 s duration, energy density 6 J/cm², with an energy per point of 0.78 J for 10 sessions) or their combination presented improvement of the nociceptive behavior and decreased expression of GFAP and Iba-1. Additionally, CCI-IoN rats exhibited an upregulation of IL1β, IL6 and TNF-α expression and all treatments prevented this upregulation and also increased IL10 expression. Overall, the present results highlight the pain reliever effect of VBC or PBM alone or in combination, through the modulation of glial cells and cytokines expression in the spinal trigeminal nucleus of rats.
... For nearly 30 years, the analgesic effects of thiamine (vitamin B1), pyridoxine (vitamin B6), and cyanocobalamin (vitamin B12; TPC) have been studied at therapeutic doses (far higher than nutritional ones), as well as in combination with NSAIDs (particularly diclofenac), in patients with LBP [15][16][17]. The analgesic effect of TPC has been explained by multiple mechanisms of action, including an anti-inflammatory and antioxidant effect, the activation of adenosine receptors, the modulation of voltage-gated sodium channels (thiamine), blocking of P2X receptors by ATP (pyridoxine), and a GABAergic and serotoninergic effect (cyanocobalamin and pyridoxine), as well as other neurotransmitter systems [18][19][20][21][22][23][24][25][26][27]. Recent evidence indicates that potentiation of antinociceptive effects of morphine by B vitamins could be explained through intracellular pathways related to morphine tolerance (p-NR1 and p-PKC) and immunomodulatory effects in the spinal cord (IBA1 and IL-1b) [28]. ...
Background:
Cumulative evidence suggests an analgesic effect of thiamine, pyridoxine, and cyanocobalamin (TPC) in monotherapy, and also when combined with nonsteroidal anti-inflammatory drugs (NSAIDs), particularly diclofenac, in a synergistic manner. The aim of this review was to determine the effects of diclofenac combined with TPC compared with diclofenac monotherapy for low back pain (LBP) management.
Methods:
We searched for randomized clinical trials on the MEDLINE, EMBASE, LILACS, and Cochrane databases of records of clinical trials, among other sources. We evaluated the risk of bias regarding randomization, allocation concealment, blinding, incomplete outcome data, selective reporting, and other biases. A random-effects meta-analysis to examine patients with acute LBP (N = 1,108 adults) was performed, along with a subsequent sensitivity analysis.
Results:
Five studies in patients with LBP were included in the qualitative synthesis. Four of these studies in acute LBP were included in the first meta-analysis. A sensitivity test based on risk of bias (three moderate- to high-quality studies) found that the combination therapy of diclofenac plus TPC was associated with a significant reduction in the duration of treatment (around 50%) compared with diclofenac monotherapy (odds ratio = 2.23, 95% confidence interval = 1.59 to 3.13, P < 0.00001). We found no differences in the safety profile and patient satisfaction.
Conclusions:
This meta-analysis demonstrated that combination therapy of diclofenac with TPC might have an analgesic superiority compared with diclofenac monotherapy in acute LBP. However, there is not enough evidence to recommend this therapy in other types of pain due to the scarcity of high-quality studies.
... Diversas investigaciones han estudiado la eficacia de los antinflamatorios no esteroideos (AINE), opioides y corticoides, empleados en monoterapia o en combinaciones 5 ; sin embargo, al utilizarse en combinaciones aumentan sus efectos analgésicos y antinflamatorios, pero también incrementan la incidencia de efectos adversos, lo que limita su uso. Debido a esto, las vitaminas del complejo B (B 1 , B 6 y B 12 ) aparecen como una buena alternativa para asociarse con AINE (diclofenaco) o corticoides (dexametasona), proporcionando ventajas como un mayor efecto analgésico, antihiperalgésico y antinociceptivo sin aumentar la incidencia de efectos adversos 6,7 . ...
... Их повторное введение вызывает стойкое уменьшение температурной гипералгезии, а комбинация витаминов группы В дает синергический эффект на различных моделях нейропатической боли. В эксперименте с тактильной аллодинией (лигатура, наложенная на спинальный корешок) показано, что тиамин, пиридоксин, цианокобаламин значительно уменьшают аллодинию [9]. Одновременное введение с дексаметазоном тиамина или цианокобаламина значительно увеличивает антиаллодинический эффект [10]. ...
Combined vitamin preparations in therapeutic doses are used, along with simple analgesics, nonsteroidal anti-inflammatory drugs (NSAIDs), muscle and epidural blockade, for the relief of acute pain. It is recommended to use the B vitamin preparation neuromultivit. The tablet form of this preparation contains vitamin thiamine hydrochloride (100 mg), pyridoxine hydrochloride (200 mg), cyanocobalamin (0.2 mg), and injectable form includes thiamine hydrochloride (100mg), pyridoxine hydrochloride (100 mg), cyanocobalamin (1 mg). The efficacy of neuromultivit in a two stage scheme (intramuscular injections of 2 ml daily for 5—10 days with further injections 2—3 times a week for 2—3 weeks at the initial stage and 1 tablet 3 times a day for 4 weeks at the second stage) was shown.
... The suggested mechanisms of action by which vitamin B1 may exert an effect in pain relief include a blockade of metabolic damage pathways, including the advanced glycation end-product formation pathway, the diacylglycerol protein kinase C pathway, and the hexamine pathway [65,71,72]. Vitamin B1 also plays a role in modulation of neural excitability and Na+ currents in injured DRG neurons, with a partial reversal of injury-induced density alterations and inactivation properties of tetrodotoxin-resistant and tetrodotoxinsensitive Na+ currents and ramp currents in small DRG neurons [73]. Thiamine has also been suggested to mediate pain via its roles in trans ketolase activation (providing a shift for glucose to the pentose phosphate shunt) [74]; protein kinase B/Akt-mediated potentiation of angiogenesis and inhibition of apoptosis [75]; as well as antagonism of cerebral oxidative stress [76]. ...
Vitamins B1, B6 and B12 are members of a group of water-soluble organic vitamins with important structural and functional roles in the human body. This updated literature review examines the physiological and biochemical properties of these B vitamins.
... The B vitamins, especially thiamine (B1), pyridoxine (B6), and cyanocobalamin (B12), have been demonstrated to be clinically useful in treating some chronic painful disorders such as neuropathic pain [20,21], trigeminal neuralgia [22], diabetic neuropathy [23,24], and rheumatoid arthritis [25]. Morphine tolerance shares a similar pathobiological mechanism with chronic pain. ...
Objectives. :
Opiate analgesics are the most effective treatments for severe pain, but their clinical utility is often hampered by the development of analgesic tolerance. There are striking similarities between morphine actions and neuropathic pain. We have demonstrated that B vitamins can attenuate neuropathic pain after peripheral nerve injury, sensory neuron inflammation/compression, and transient spinal cord ischemia. Given this similarity, the present study investigated whether B vitamins might be able to modify the antinociceptive effect of morphine as well as morphine tolerance in mice.
Methods. :
Cell signaling was assayed by Western blot and immunohistochemistry. Antinociception was assessed in ICR mice using the tail flick. The effects of B vitamins on acute morphine-induced antinociception and chronic morphine tolerance were studied.
Results. :
1) Co-administration of B vitamins with morphine potentiates acute morphine antinociception. 2) B vitamins attenuate the development of antinociceptive tolerance to chronic morphine administration and inhibit morphine-induced p-NR1, p-PKC in the spinal cord. 3) Morphine induces microglial activation, as evidenced by increased p38 MAPK phosphorylation, IBA1, and IL-1β in the spinal cord, and these changes are inhibited by B vitamins. 4) Treatment of B vitamins alone shows no notable effects on pain threshold and activity of microglia in vivo.
Conclusions. :
B vitamins potentiate acute morphine antinociception and attenuate chronic morphine tolerance.
... The protocols were similar to that we have previously described. [28][29][30] Dorsal root ganglion cells were visualized under differential interference contrast in the microscope, and the cell soma was classified visually by the diameter of its soma as small (≤ 30 μm), medium (31-49 μm), or large (≥ 50 μm). In this study, we recorded only the small DRG neurons, which are recognized as the nociceptive neurons. ...
Objectives:
The purpose of this study was to investigate roles of the anti-inflammatory cytokine interleukin (IL) 10 and the proinflammatory cytokines IL-1β and tumor necrosis factor α (TNF-α) in spinal manipulation-induced analgesic effects of neuropathic and postoperative pain.
Methods:
Neuropathic and postoperative pain were mimicked by chronic compression of dorsal root ganglion (DRG) (CCD) and decompression (de-CCD) in adult, male, Sprague-Dawley rats. Behavioral pain after CCD and de-CCD was determined by the increased thermal and mechanical hypersensitivity of the affected hindpaw. Hematoxylin and eosin staining, whole-cell patch clamp electrophysiological recordings, immunohistochemistry, and enzyme-linked immunosorbent assay were used to examine the neural inflammation, neural excitability, and expression of c-Fos and PKC as well as levels of IL-1β, TNF-α, and IL-10 in blood plasma, DRG, or the spinal cord. We used the activator adjusting instrument, a chiropractic spinal manipulative therapy tool, to deliver force to the spinous processes of L5 and L6.
Results:
After CCD and de-CCD treatments, the animals exhibited behavioral and neurochemical signs of neuropathic pain manifested as mechanical allodynia and thermal hyperalgesia, DRG inflammation, DRG neuron hyperexcitability, induction of c-Fos, and the increased expression of PKCγ in the spinal cord as well as increased level of IL-1β and TNF-α in DRG and the spinal cord. Repetitive Activator-assisted spinal manipulative therapy significantly reduced simulated neuropathic and postoperative pain, inhibited or reversed the neurochemical alterations, and increased the anti-inflammatory IL-10 in the spinal cord.
Conclusion:
These findings show that spinal manipulation may activate the endogenous anti-inflammatory cytokine IL-10 in the spinal cord and thus has the potential to alleviate neuropathic and postoperative pain.
... Several studies have reported that thiamine, pyridoxine and cyanocobalamin have an important role for the adequate function of the central nervous system, the myelin cover and other cell structures, it is essential for nutrition, axonal transport, neural excitability and neurotransmitter synthesis, and combined with diclofenac they present a synergic action in ostheomuscular diseases and pain management [3,15,16]. The mechanisms are currently unknown, it has been proposed that the antihyperalgesic mechanisms of B vitamins include its ability to increase afferent inhibitory control of nociceptive neurons at the spinal cord [17], to improve sensory nerve conduction velocity [18] and to reduce neuronal hyperexcitability by altering sodium currents in injured dorsal root ganglia [19]. Moreover, the individual administration of thiamine and pyridoxine produce antinociception in acetic acid-induced pain or pain induced by supramaximal electrical stimulation of afferent C fibers, in the last years it has been postulated that B vitamins induced antinociception could result from activation of opioid receptors or nitric oxide release [20]. ...
Objective: the goal of this paper is to perform a systematic review on the use of diclofenac/B complex indicated for acute low back pain, compared to other available therapies for low back pain. Material and Methods: The systematic review was performed on the following databases: Medline/Pubmed, Cochrane Library (CENTRAL), EMBASE, Imbiomed,LILACS, Artemisa and Nieto Editores, up until February 14th, 2015. A manual searchwas also performed on Google search. Key words were used under the MeSH terminology (Medical Subject Headings): low back pain, lumbago, diclofenac/vitamin B, non-steroidal anti-inflammatory, diclofenac, ibuprofen, naproxen, treatment. Study: Selection was performed by two investigators experts on the subject, selecting those studies with relevant information for the goal of this review. Results: We found 261 studies with potential interest. Finally, 2 studies were selected, 1 clinical trial and a systematic review. The systematic review by Roelofs et al. (2011), which was done with Cochrane Collaboration and had as a goal to evaluate the effects of NDAIS´s and COX-2 inhibitors on non-specific low back pain treatment and to evaluate which NSAID´s was the most effective. The other selected study was a clinical trial performed by Mibielli et al. in 2009, a randomized study, double-blinded,with parallel groups, that included patients that received diclofenac and B complex andthe other arm received only diclofenac. Conclusion: Diclofenac/B complex has a pain relief effect, anti-inflammatory and synergic neuro-regenerative effect, and this efficiency has been evaluated in several clinical studies where the administration of diclofenac plus vitamins B1, B6 and B12 decreases pain quicker, apart from being a safe drug.
... Thiamine, pyridoxine or cyanocobalamin and their combination inhibit thermal hyperalgesia, but not mechanical allodynia, in rats subjected to spinal ganglia compression or CCI [171]. The antihyperalgesic effect induced by thiamine is associated with inhibition of rat dorsal root ganglia neuronal hyperexcitability due to nerve injury [172]. On the other hand, the B vitamin cocktail thiamine/pyridoxine/cyanocobalamin induces an antiallodynic effect in a rat model of diabetic neuropathy [173]. ...
The number of approved new molecular entity drugs has been decreasing as the pharmaceutical company investment in research and development is increasing. As we face this painful crisis, called an innovation gap, there is increasing awareness that development of new uses of existing drugs may be a powerful tool to help overcome this obstacle because it takes too long, costs too much and can be risky to release drugs developed de novo. Consequently, drug repositioning is emerging in different therapeutic areas, including the pain research area. Worldwide, pain is the main reason for seeking healthcare, and pain relief represents an unmet global clinical need. Therefore, development of analgesics with better efficacy, safety and cost effectiveness is of paramount importance. Despite the remarkable advancement in research on cellular and molecular mechanisms underlying pain pathophysiology over the past three decades, target-based therapeutic opportunities have not been pursued to the same extent. Phenotypic screening remains a more powerful tool for drug development than target-based screening so far. It sounds somewhat heretical, but some multi-action drugs, rather than very selective ones, have been developed intentionally. In the present review, we first critically discuss the utility of drug repositioning for analgesic drug development and then show examples of 'old' drugs that have been successfully repositioned or that are under investigation for their analgesic actions. We conclude that drug repositioning should be more strongly encouraged to help build a bridge between basic research and pain relief worldwide.
Tendon injury produces intractable pain and disability in movement, but the medications for analgesia and restoring functional integrity of tendon are still limited. In this study, we report that proteinase-activated receptor 2 (PAR2) activation in dorsal root ganglion (DRG) neurons contributes to chronic pain and tendon histopathological changes produced by Achilles tendon partial transection injury (TTI). Tendon partial transection injury increases the expression of PAR2 protein in both somata of DRG neurons and their peripheral terminals within the injured Achilles tendon. Activation of PAR2 promotes the primary sensory neuron plasticity by activating downstream cAMP-PKA pathway, phosphorylation of PKC, CaMKII, and CREB. Blocking PAR2 signaling by PAR2 small-interference RNA or antagonistic peptide PIP delays the onset of TTI-induced pain, reverses the ongoing pain, as well as inhibits sensory nerve sprouting, and promotes structural remodeling of the injured tendon. Vitamin B complex (VBC), containing thiamine (B1), pyridoxine (B6), and cyanocobalamin (B12), is effective to ameliorate TTI-induced pain, inhibit ectopic nerve sprouting, and accelerate tendon repair, through suppressing PAR2 activation. These findings reveal a critical role of PAR2 signaling in the development of chronic pain and histopathological alterations of injured tendon following Achilles tendon injury. This study suggests that the pharmaceuticals targeting PAR2, such as VBC, may be an effective approach for the treatment of tendon injury-induced pain and promoting tendon repair.
Objetivo: Comparar la efectividad de la administración de paracetamol solo, y en combinación con las vitaminas del complejo B sobre el dolor ortodóntico, después de la colocación de separadores elásticos. Material y método: El estudio incluyó 3 grupos de 30 alumnos de 21-25 años de edad. Al primer grupo se le administró paracetamol, al segundo grupo se le administró paracetamol más complejo B y al tercer grupo se le administró un placebo. La intensidad de dolor fue evaluada mediante la escala visual análoga en diferentes intervalos de tiempo, a las 0 h, 3 h, 10 h, 48 h, día 3, día 4 y día 7; asimismo al acostarse y al despertar a partir de las 48 h y hasta cumplir 7 días. Resultados: Se observó un mejor efecto analgésico en la sinergia (paracetamol más complejo B) en comparación con el paracetamol, con diferencia estadísticamente significativa al acostarse. Conclusiones: Las vitaminas del complejo B + el paracetamol tienen efecto analgésico sinérgico sobre el dolor en pacientes tratados ortodónticamente, en comparación con el paracetamol solo. Este estudio es pionero en el ámbito de la especialidad de ortodoncia, para controlar el dolor causado por separadores ortodónticos. Palabras Clave: Dolor ortodóntico, efecto sinérgico, paracetamol, complejo B vitamínico.
B-vitamins have been evaluated as a useful adjuvant therapy to treat pain. In spite of clinical and experimental evidence indicating the analgesic effect of B-vitamins, few studies have investigated their effect on aspects of the inflammatory pain response. In the present study, we investigated the analgesic effect of chronic application of B-complex vitamins (Neurobion) using an inflammatory experimental pain model in rats. Nociceptive behavioral responses were evaluated in male Wistar rats after plantar injection of formalin, comparing groups with (TG) and without (CG) Neurobion pretreatment. In addition, neuronal activity in the central pain pathway was evaluated using c-Fos immunohistochemical reactivity and NADPH-d histochemistry. A highly significant reduction of painful behaviors such as licking and flinching were observed in TG, especially during the secondary phase of the formalin test compared to CG. Results suggest that long-term pre-treatment using Neurobion can have a beneficial effect in reducing the chronic phase of pain. In addition, we observed a downregulation of c-Fos and NADPH-d in dorsal spinal neurons, suggesting that the antinociceptive effect induced by Neurobion could be due to a suppression of nociceptive transmission at the spinal level, particularly in the afferent regions of the dorsal spinal horn, which these neurons utilizing nitric oxide at least as one of their pain neurotransmitters.
Pain syndrome accompanies the vast majority of diseases; therefore, the issues of adequate pain relief remain topical not only for urgent conditions, but also for everyday medical practice. Modern and changed in recent years approaches to the appointment of anesthetic therapy should take into account not only the pathogenetic mechanisms of the development of pain syndrome in a particular patient, but also the need to use drug combinations. This allows for the potentiation of the analgesic effect, reduction of effective dosages of individual drugs and minimization of side effects. In case of severe pain syndrome in the presence of signs of impaired nociception, neuropathic and muscle-fascial pain syndromes, the use of non-steroidal anti-inflammatory drugs in conjunction with group B vitamins is justified. The article considers the pathogenetic details of such a combination therapy, reveals the mechanisms of the cooperative action of the proposed combination of drugs.
Resumen
El dolor lumbar, así como otras alteraciones musculoesqueléticas (cervicalgia, artrosis, etc.), son causa muy frecuente de consulta tanto en atención primaria como en otras especialidades hospitalarias y suelen asociarse con una alta discapacidad funcional y laboral. La lumbalgia aguda puede presentar diferentes componentes nociceptivos, neuropáticos y nociplásticos, lo que lleva a considerarlo como un dolor de tipo mixto. La importancia del concepto de dolor mixto obedece a que el alivio sintomático de dichas patologías requiere un enfoque terapéutico multimodal a diversas dianas farmacológicas. Desde hace varias décadas se reconoce el papel antinociceptivo del complejo de vitaminas B, específicamente de la combinación de tiamina, piridoxina y cianocobalamina (TPC). Asimismo, hay evidencia acumulada que indica una acción analgésica adyuvante en el dolor lumbar. El objetivo de la presente revisión es presentar la evidencia existente y los últimos hallazgos sobre los efectos terapéuticos de la combinación TPC en el dolor lumbar. Asimismo, se analizan algunos de los mecanismos de acción más relevantes implicados que pueden explicar dichos efectos. La evidencia revisada indica que el uso combinado de TPC tiene un efecto adyuvante analgésico en el dolor mixto, específicamente en el dolor lumbar y otras alteraciones musculoesqueléticas con componentes nociceptivos y neuropáticos. Dicho efecto puede ser explicado por una acción antiinflamatoria, antinociceptiva, neuroprotectora y neuromoduladora de la combinación TPC sobre el sistema descendente del dolor.
Pain syndrome accompanies absolute majority of diseases, therefore problems of adequate anesthesia remain acute not only for urgent conditions but also for everyday medical practice. Modern approaches of anesthetic therapy should consider not only pathogenic mechanisms of evolving pain syndrome by a certain patient but also necessity to administer drug combinations. It allows potentiating an analgesic effect, to decrease effective dosages of individual drugs and minimize adverse effects. The administration of non-steroidal anti-inflammatory drugs together with B vitamins and tolperisone is justified in a marked pain syndrome with a spastic component and/or spasms of skeletal muscles, muscle contractures, myofascial pain syndromes, as well in rehabilitation therapy after orthopedic and traumatology surgeries. The article considers pathogenic details of such combined therapy, discloses mechanism of synergic action of the proposed drug combination.
Objectives
The ophthalmic branch of the trigeminal nerve is one of the most frequently involved sites of postherpetic neuralgia (PHN). A single‐center randomized controlled study was conducted to evaluate the efficacy of local methylcobalamin injection for subacute ophthalmic herpetic neuralgia (SOHN).
Methods
One hundred and five patients with a pain score of 4 or greater were randomized to receive a combination of methylcobalamin and lidocaine via local injection (LM, N=35), intramuscular methylcobalamin and local lidocaine injection (IM, N=35), and oral methylcobalamin tablet and lidocaine local injection (OM, N=35) for four weeks. Multilevel mixed modeling was employed to examine treatment responses.
Results
Pain scores were reduced in all groups but this reduction was significantly greater in patients who received local methylcobalamin (6.7 at baseline vs 2.8 at endpoint) when compared with systemic administration (intramuscular 6.8 vs 4.9, oral 6.7 vs 5.1). Clinically relevant reduction of pain (>30%) was seen in 91% of patients in the local methylcobalamin group, a significantly greater proportion than in the systemic groups (66% intramuscular, 57% oral). Analgesic use reduced significantly in the local group (94% at baseline vs 6% at endpoint) but not in systemic groups (intramuscular 97% vs 86%, oral 94% vs 80%). Health‐related Quality of Life was higher in the local group than in the systemic groups. In mixed modelling, increased age was associated with a lower response to methylcobalamin.
Conclusions
This study indicates that the local injection of methylcobalamin produces significant pain relief from SOHN and is superior to the systemic administration.
EphrinB-EphB receptor tyrosine kinases have been demonstrated to play important roles in pain processing after peripheral nerve injury. We have previously reported that ephrinB-EphB receptor signaling can regulate excitability and plasticity of neurons in spinal dorsal horn, and thus contribute to spinal central sensitization in neuropathic pain. How EphB receptor activation influences excitability of primary neurons in dorsal root ganglion (DRG), however, remains unknown. Here we report that EphB receptor activation facilitates calcium influx through NMDA receptor dependent and independent manners. In cultured DRG cells from adult rats, EphB1 and EphB2 receptors were expressed in neurons, but not the glial cells. Bath application of EphB receptor agonist ephrinB2-Fc induced NMDA-independent Ca influx, which was from the extracellular space rather than endoplasmic reticulum. EphB receptor activation also greatly enhanced NMDA-dependent Ca influx and NR2B phosphorylation, which was prevented by pre-treatment of Src kinase inhibitor PP2. In nerve-injured DRG neurons, elevated expression and activation of EphB1 and EphB2 receptors contributed to the increased intracellular Ca concentration and NMDA-induced Ca influx. Repetitive intrathecal administration of EphB2-Fc inhibited the increased phosphorylation of NR2B and Ca-dependent subsequent signals Src, ERK, and CaMKII as well as behaviorally expressed pain after nerve injury. These findings demonstrate that activation of EphB receptors can modulate DRG neuron excitability by facilitating Ca influx directly or through Src kinase activation-mediated NMDA receptor phosphorylation and that EphB receptor activation is critical to DRG neuron hyperexcitability, which has been considered critical to the subsequent spinal central sensitization and neuropathic pain.
Low back pain is a common cause of chronic pain and disability. It is modeled in rodents by chronically compressing the lumbar dorsal root ganglia (DRG) with small metal rods, resulting in ipsilateral mechanical and cold hypersensitivity, and hyperexcitability of sensory neurons. Sodium channels are implicated in this hyperexcitability, but the responsible isoforms are unknown. In this study, we used siRNA-mediated knockdown of the pore-forming NaV1.6 and regulatory NaVβ4 sodium channel isoforms that have been previously implicated in a different model of low back pain caused by locally inflaming the L5 DRG. Knockdown of either subunit markedly reduced spontaneous pain and mechanical and cold hypersensitivity induced by DRG compression, and reduced spontaneous activity and hyperexcitability of sensory neurons with action potentials <1.5 msec (predominately cells with myelinated axons, based on conduction velocities measured in a subset of cells) 4 days after DRG compression. These results were similar to those previously obtained in the DRG inflammation model and some neuropathic pain models, in which sensory neurons other than nociceptors seem to play key roles. The cytokine profiles induced by DRG compression and DRG inflammation were also very similar, with upregulation of several type 1 pro-inflammatory cytokines and downregulation of type 2 anti-inflammatory cytokines. Surprisingly, the cytokine profile was largely unaffected by NaVβ4 knockdown in either model. The NaV1.6 channel, and the NaVβ4 subunit that can regulate NaV1.6 to enhance repetitive firing, play key roles in both models of low back pain; targeting the abnormal spontaneous activity they generate may have therapeutic value.
Background:
The effects induced by thiamine and riboflavin, isolated or in association with corticosteroids, in models of chronic inflammation are not known. Thus, we evaluated the effect induced by these B vitamins, isolated or in association with dexamethasone, on the mechanical allodynia, paw edema and cytokine production induced by complete Freund's adjuvant (CFA) in rats.
Methods:
Chronic inflammation was induced by two injections of CFA. Nociceptive threshold, paw volume and body temperature were evaluated for 21days. Tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) contents were determined in paw tissue. Riboflavin (125, 250 or 500mg/kg) or thiamine (150, 300 or 600mg/kg) were administered per os (po), twice daily. Dexamethasone (0.5mg/kgday, po) was administered every three days.
Results:
CFA induced long lasting mechanical allodynia and paw edema. Elevation of body temperature was observed for a short period. Riboflavin reduced neither paw edema nor mechanical allodynia. Thiamine did not change paw edema, but partially inhibited mechanical allodynia. Riboflavin (500mg/kg) and thiamine (600mg/kg) exacerbated the anti-inflammatory activity of dexamethasone. Riboflavin, thiamine and dexamethasone reduced TNF-α and IL-6 production. The association of dexamethasone with thiamine induced greater inhibition of IL-6 production when compared with that induced by dexamethasone.
Conclusions:
Riboflavin and thiamine exacerbate the anti-inflammatory activity of dexamethasone and reduce production of TNF-α and IL-6.
The objective of this study was to develop rat model of second-degree burn pain and test analgesic efficacy of local thiamine administration. Automatic temperature-controlled hot plate was set at 85 ± 0.1°C with a filter paper on the top. Rats were thrust on hot plate landing on plantar surface for 4 to 7 and 10 seconds, respectively. Burnt skin was observed. Hematoxylin and eosin staining and Masson staining were used to monitor burn degree. Gait analysis detected change of locomotion. Allodynia and hyperalgesia in the burnt area were evaluated with von Frey test and Hargreaves Test, and ongoing pain was detected with conditional place preference test. Markers for the activity of microglia (Iba1), astrocytes (GFAP), and neurons (c-fos) were detected with immunofluorescence. Finally, thiamine was injected into blisters to observe its effect on burn pain. Blisters on burnt skin, space between dermal and epidermal layers in hematoxylin and eosin staining and burn injury limiting in dermal layer in Masson stain all indicated that burn injury lasting for 7 seconds matched second-degree burn. Behavioral tests revealed allodynia, ongoing pain, and increased expression of c-fos, GFAP, and Iba1, as well as the absence of hyperalgesia in Burn7s. Burn injury reduced distance of second and fourth digits. MK801 could relieve allodynia in Burn7s. Local administration of 1, 2, and 4 mg of thiamine had no effect on the allodynia, but 2 and 4 mg of thiamine also could induce CCP in Burn7s. A rat model of second-degree burn pain was developed and local administration of thiamine provided relief from pain.
Objective:
The thiamin is often used in the treatment of neuropathy, and pregabalin is often used to treat neuropathic pain. Our study examined the influence of thiamin on the efficacy of pregabalin in a rat model of spinal nerve ligation (SNL)-induced neuropathic pain.
Methods:
Sprague-Dawley male rats were randomly divided into six groups. The neuropathic pain-relieving properties were measured by plantar test, cold plate test, and hot plate test after administration of pregabalin (i.v) and/or thiamin (i.p) in SNL rats 14 days after operation.
Results:
In the therapy period, pregabalin, or thiamin alone all produced antinociceptive effects in rats with neuropathic pain. And combination treatment of thiamin and pregabalin resulted in an enhanced pain relief compared to the administration of pregabalin or thiamin alone.
Conclusion:
Combination of thiamin and pregabalin produces an additive antinociceptive effect in neuropathic pain rats, this drug combination may offer a beneficial treatment option for neuropathic pain.
Vitamins are crucial components in the diet of animals and many other living organisms. One of these essential nutrients, thiamin, is known to be involved in several cell-functions, including energy-metabolism and the degradation of sugars and carbon skeletons. Other roles that are connected to this vitamin are neuronal communication, immune system activation, signaling and maintenance processes in cells and tissues and cell-membrane dynamics. Because of the key functions thiamin has, uptake and transport through the body are crucial. Its uptake route is relatively complex encompassing a variety of protein families, including the solute carrier (SLC) anion transporters, the alkaline phosphatase (ALP) transport system and the human extraneuronal monoamine transporter (hEMT) family, some of which are multi-specific proteins. There are two known structures of protein (subunits) involved in thiamin uptake in prokaryotes. Binding of thiamin to these proteins is strongly guided by electrostatic interactions. The lack of structural information on thiamin binding proteins for higher organisms remains a bottleneck for understanding the uptake process of thiamin in atomic detail. This review includes recent data on thiamin metabolism, related deficiencies and pathologies, and the latest findings on thiamin binding transporters.
Clinical and experimental studies have shown that spinal sensory neurons become hyperexcitable after axonal injury, and electrophysiological changes have suggested that this may be attributable to changes in sodium current expression. We have demonstrated previously that sodium channel alpha-III mRNA levels are elevated and sodium channel alpha-SNS mRNA levels are reduced in rat spinal sensory neurons after axotomy. In this study we show that small (C-type) rat spinal sensory neurons express sodium currents with dramatically different kinetics after axotomy produced by sciatic nerve ligation. Uninjured C-type neurons express both slowly inactivating tetrodotoxin-resistant (TTX-R) sodium current and a fast-inactivating tetrodotoxin-sensitive (TTX-S) current that reprimes (recovers from inactivation) slowly. After axotomy, the TTX-R current density was greatly reduced. No difference was observed in the density of TTX-S currents after axotomy, and their voltage dependence was not different from controls. However, TTX-S currents in axotomized neurons reprimed four times faster than control TTX-S currents. These data indicate that axotomy of spinal neurons is followed by downregulation of TTX-R current and by the emergence of a rapidly repriming TTX-S current and suggest that this may be attributable to the upregulation of a sodium channel isoform that was unexpressed previously in these cells. These axotomy-induced changes in sodium currents are expected to alter excitability substantially and could underlie the molecular pathogenesis of some chronic pain syndromes associated with injury to the axons of spinal sensory neurons.
Pain and hyperalgesia can occur when the dorsal root ganglion (DRG) and its roots are deformed mechanically in association with injuries or diseases of the spine. To evaluate the electrophysiological changes that contribute to this sensory pathology, intracellular recordings were obtained in vitro from DRGs that had received a chronic mechanical compression [chronic compression of DRG (CCD)]. The compression was produced by inserting L-shaped rods ipsilaterally into the intervertebral foramina, one at L(4) and the other at L(5) in rats 1-14 days before the recording. Control rats received a sham operation. Postoperatively, the threshold force applied by punctate stimulation of the plantar surface of the hind paw decreased significantly on the foot ipsilateral to the CCD (mechanical hyperalgesia) but changed little on the contralateral foot or on either foot for control rats. DRG somata were viewed through a microscope during recording and classified as small, medium, and large according to their diameters. CCD cells in each size category were more excitable than those of comparable size from control rats as judged by the significantly lowered threshold currents and action potential voltage thresholds. Spontaneous activity was recorded in 11% of all the CCD cells tested. The spontaneous activity and/or changes in both the threshold currents and action potential thresholds were observed as early as one day after injury. The association of cutaneous hyperalgesia with changes in the electrophysiological properties of DRG cells suggests a possible role for intrinsic alterations in the membrane properties of compressed DRG cells in the production and persistence of chronic pain after certain spinal injuries or pathologies of the spine.
Chronic compression of the dorsal root ganglion (CCD) was produced in adult rats by implanting a stainless steel rod unilaterally into the intervertebral foramen, one rod at L(4) and another at L(5). Two additional groups of rats received either a sham surgery or an acute injury consisting of a transient compression of the ganglion. Withdrawal of the hindpaw was used as evidence of a nocifensive response to mechanical and thermal stimulation of the plantar surface. In addition, extracellular electrophysiological recordings of spontaneous discharges were obtained from dorsal root fibers of formerly compressed ganglia using an in vitro nerve-DRG-dorsal root preparation. The mean threshold force of punctate indentation and the mean threshold temperature of heating required to elicit a 50% incidence of foot withdrawal ipsilateral to the CCD were significantly lower than preoperative values throughout the 35 days of postoperative testing. The number of foot withdrawals ipsilateral to the CCD during a 20-min contact with a temperature-controlled floor was significantly increased over preoperative values throughout postoperative testing when the floor was 4 degrees C (hyperalgesia) and, to a lesser extent, when it was 30 degrees C (spontaneous pain). Stroking the foot with a cotton wisp never elicited a reflex withdrawal before surgery but did so in most rats tested ipsilateral to the CCD during the first 2 postoperative weeks. In contrast, the CCD produced no changes in responses to mechanical or thermal stimuli on the contralateral foot. The sham operation and acute injury produced no change in behavior other than slight, mechanical hyperalgesia for approximately 1 day, ipsilateral to the acute injury. Ectopic spontaneous discharges generated within the chronically compressed ganglion and, occurring in the absence of blood-borne chemicals and without an intact sympathetic nervous system, were recorded from neurons with intact, conducting, myelinated or unmyelinated peripheral nerve fibers. The incidence of spontaneously active myelinated fibers was 8.61% for CCD rats versus 0.96% for previously nonsurgical rats. We hypothesize that a chronic compression of the dorsal root ganglion after certain injuries or diseases of the spine may produce, in neurons with intact axons, abnormal ectopic discharges that originate from the ganglion and potentially contribute to low back pain, sciatica, hyperalgesia, and tactile allodynia.
The rat L(5) dorsal root ganglion (DRG) was chronically compressed by inserting a hollow perforated rod into the intervertebral foramen. The DRG was constantly perfused through the hollow rod with either lidocaine or normal saline delivered by a subcutaneous osmotic pump. Behavioral evidence for neuropathic pain after DRG compression involved measuring the incidence of hindlimb withdrawals to both punctate indentations of the hind paw with mechanical probes exerting different bending forces (hyperalgesia) and to light stroking of the hind paw with a cotton wisp (tactile allodynia). Behavioral results showed that for saline-treated control rats: the withdrawal thresholds for the ipsilateral and contralateral paws to mechanical stimuli decreased significantly after surgery and the incidence of foot withdrawal to light stroking significantly increased on both ipsilateral and contralateral hind paws. Local perfusion of the compressed DRG with 2% lidocaine for 7 days at a low flow-rate (1 microl/h), or for 1 day at a high flow-rate (8 microl/h) partially reduced the decrease in the withdrawal thresholds on the ipsilateral foot but did not affect the contralateral foot. The incidence of foot withdrawal in response to light stroking with a cotton wisp decreased significantly on the ipsilateral foot and was completely abolished on the contralateral foot in the lidocaine treatment groups. This study demonstrated that compression of the L(5) DRG induced a central pain syndrome that included bilateral mechanical hyperalgesia and tactile allodynia. Results also suggest that a lidocaine block, or a reduction in abnormal activity from the compressed ganglia to the spinal cord, could partially reduce mechanical hyperalgesia and tactile allodynia.
The effect of some B vitamins in chemical and thermal models of nociception in mice was investigated. The association thiamine/pyridoxine/cyanocobalamin (TPC, 20-200 mg/kg, i.p. or per os), thiamine, pyridoxine (50-200 mg/kg, i.p.) or riboflavin (3-100 mg/kg, i.p) induced an antinociceptive effect, not changed by naloxone (10 mg/kg, i.p.), in the acetic acid writhing model. Treatment for 7 days with thiamine/pyridoxine/cyanocobalamin (100 or 200 mg/kg, i.p.), thiamine (50 or 100 mg/kg) or pyridoxine (50 or 100 mg/kg) or acute treatment with riboflavin (6 or 12 mg/kg, i.p) inhibited the nociceptive response induced by formaldehyde. The B vitamins did not inhibit the nociceptive response in the hot-plate model. Both 7-day thiamine/pyridoxine/cyanocobalamin (100 mg/kg, i.p.) or acute riboflavin (25 or 50 mg/kg, i.p.) treatment partially reduced formaldehyde-induced hindpaw oedema. The B vitamins antinociceptive effect may involve inhibition of the synthesis and/or action of inflammatory mediators since it was not observed in the hot-plate model, was not reversed by naloxone, only the second phase of the formaldehyde-induced nociceptive response was inhibited, and formaldehyde-induced hindpaw oedema was reduced.
Phenotypic modification of dorsal root ganglion (DRG) neurons represents an important mechanism underlying neuropathic pain. However, the nerve injury-induced molecular changes are not fully identified. To determine the molecular alterations in a broader way, we have carried out cDNA array on the genes mainly made from the cDNA libraries of lumbar DRGs of normal rats and of rats 14 days after peripheral axotomy. Of the 7,523 examined genes and expressed sequence tags (ESTs), the expression of 122 genes and 51 expressed sequence tags is strongly changed. These genes encompass a large number of members of distinct families, including neuropeptides, receptors, ion channels, signal transduction molecules, synaptic vesicle proteins, and others. Of particular interest is the up-regulation of gamma-aminobutyric acid(A) receptor alpha5 subunit, peripheral benzodiazepine receptor, nicotinic acetylcholine receptor alpha7 subunit, P2Y1 purinoceptor, Na(+) channel beta2 subunit, and L-type Ca(2+) channel alpha2delta-1 subunit. Our findings therefore reveal dynamic and complex changes in molecular diversity among DRG neurons after axotomy. Sequences reported in this paper have been deposited in the GenBank database (accession numbers BG 662484-BG 673712)
Section of rat sciatic nerve (axotomy) increases the excitability of neurons in the L(4)-L(5) dorsal root ganglia (DRG). These changes are more pronounced in animals that exhibit a self-mutilatory behavior known as autotomy. We used whole cell recording to examine changes in the tetrodotoxin-sensitive (TTX-S) and the tetrodotoxin-resistant (TTX-R) components of sodium channel currents (I(Na)) that may contribute to axotomy-induced increases in excitability. Cells were initially divided on the basis of size into "large," "medium," and "small" groups. TTX-S I(Na) predominated in "large" cells, whereas TTX-R I(Na) predominated in some, but not all "small cells." "Small" cells were therefore subdivided into "small-slow" cells, which predominantly exhibited TTX-R I(Na) and "small fast" cells that exhibited more TTX-S I(Na). In contrast to results obtained in other laboratories, where slightly different experimental procedures were used, we found that axotomy increased TTX-R and/or TTX-S I(Na) and slowed inactivation. The effects were greatest in "small-slow" cells and least in "large" cells. The changes promoted by axotomy were expressed more clearly in animals that exhibited autotomy. Also, the presence of autotomy correlated with a shift in the properties of I(Na) in "large" rather than "small-slow," putative nociceptive cells. These trends parallel previous observations on axotomy-induced increases in excitability, spike height, and spike width that are also greatest in "small" cells and least in "large" cells. In addition, the presence of autotomy correlates with an increase in excitability of "large" rather than "small" cells. Increases in TTX-R and TTX-S I(Na) thus coincide with axotomy-induced increases in excitability and alterations in spike shape across the whole population of sensory neurons. Injury-induced changes of this type are likely associated with the onset of chronic pain in humans.
Numerous studies have implicated the cAMP-protein kinase A (PKA) pathway in producing hyperexcitability of dorsal root ganglia (DRG) sensory neurons under conditions associated with pain. Evidence is presented for roles of both the cAMP-PKA and cGMP-protein kinase G (PKG) pathways in maintaining neuronal hyperexcitability and behavioral hyperalgesia in a neuropathic pain model: chronic compression of the DRG (CCD treatment). Lumbar DRGs were compressed by a steel rod inserted into the intervertebral foramen. Thermal hyperalgesia was revealed by shortened latencies of foot withdrawal to radiant heat. Intracellular recordings were obtained in vitro from lumbar ganglia after in vivo DRG compression. Activators of the cAMP-PKA pathway, 8-Br-cAMP and Sp-cAMPS, and of the cGMP-PKG pathway, 8-Br-cGMP and Sp-cGMPS, increased the hyperexcitability of DRG neurons already produced by CCD treatment, as shown by further decreases in action potential threshold and increased repetitive discharge during depolarization. The adenylate cyclase inhibitor, SQ22536, the PKA antagonist, Rp-cAMPS, the guanylate cyclase inhibitor, ODQ, and the PKG inhibitor, Rp-8-pCPT-cGMPS, reduced the hyperexcitability of CCD DRG neurons. In vivo application of PKA and PKG antagonists transiently depressed behavioral hyperalgesia induced by CCD treatment. Unexpectedly, application of these agonists and antagonists to ganglia of naïve, uninjured animals had little effect on electrophysiological properties of DRG neurons and no effect on foot withdrawal, suggesting that sensitizing actions of these pathways in the DRG are enabled by prior injury or stress. The only effect observed in uncompressed ganglia was modest depolarization of DRG neurons by PKA and PKG agonists. CCD treatment also depolarized DRG neurons, but CCD-induced depolarization was not affected by agonists or antagonists of these pathways.
A chronic compression of the dorsal root ganglion (CCD) produces ipsilateral cutaneous hyperalgesia that is associated with an increased excitability of neuronal somata in the compressed ganglion, as evidenced by spontaneous activity and a lower rheobase. We searched for differences in the properties of voltage-gated Na+ and K+ currents between somata of CCD- and control (unoperated) rats. CCD was produced in adult rats by inserting two rods through the intervertebral foramina, one compressing the L4, and the other, the ipsilateral, L5 dorsal root ganglion (DRG). After 5-9 days, DRG somata were dissociated and placed in culture for 16-26 h. Cutaneous neurons of medium size (35-45 microm), Fluorogold-labeled from the hindpaw, were selected for whole cell patch-clamp recording of action potentials and ion currents. In comparison with control neurons, CCD neurons had steady-state activation curves for TTX-sensitive (TTX-S) Na+ currents that were shifted in the hyperpolarizing direction, and CCD neurons had enhanced TTX-resistant (TTX-R) current. CCD neurons also had smaller, fast-inactivating K+ currents (Ka) at voltages from -30 to 50 mV. The reduction in Ka, the hyperpolarizing shift in TTX-S Na+ current activation, and the enhanced TTX-R Na+ current may all contribute to the enhanced neuronal excitability and thus to the pain and hyperalgesia associated with CCD.
Treatment of neuropathic pain is an area of largely unmet medical need. Therefore, this pain may require the development of novel drug entities. In the search for alternatives, B vitamins have been found to be a clinically useful pharmacological tool for patients with neuropathic pain. However, preclinical studies supporting this use are lacking. In this study, we assessed the possible antiallodynic effects of thiamine, pyridoxine, and cyanocobalamin as well as dexamethasone and their combination on spinal nerve ligation induced allodynia. Sub cutaneous administration of thiamine (75-600 mg/kg), pyridoxine (75-600 mg/kg), cyanocobalamin(0.75-6 mg/kg), and dexamethasone (4-32 mg/kg) significantly reduced tactile allodynia in rats. Maximal antiallodynic effects were reached with 600 mg/kg of thiamine (approximately 58%), 600 mg/kg of pyridoxine (approximately 22%), 6 mg/kg of cyanocobalamin (approximately 73%), and 32 mg/kg of dexamethasone (approximately 68%). Since a small antiallodynic effect was observed with pyridoxine, this drug was not further analyzed in the combinations. Coadministration of thiamine or cyanocobalamin and dexamethasone remarkably reduced spinal nerve ligation induced allodynia (approximately 90%), showing a synergistic interaction between either thiamine or cyanocobalamin and dexamethasone. Our data indicate that thiamine and pyridoxine as well as the combination of B vitamins and dexamethasone are able to reduce tactile allodynia in rats and suggest the possible clinical use of these drugs in the treatment of neuropathic pain in human beings.
Traumatic spinal cord injury (SCI) results not only in motor impairment, but also in chronic central neuropathic pain, which often is refractory to conventional treatment approaches. Upregulated expression of sodium channel Nav1.3 has been observed within the spinal dorsal horn neurons after SCI, and appears to contribute to neuronal hyperresponsiveness and pain-related behaviors. In this study we characterized the changes in sodium current properties within dorsal horn neurons after contusive SCI. Four weeks after adult male Sprague-Dawley rats underwent T9 spinal cord contusion injury, when behavioral nociceptive thresholds were decreased to both mechanical and thermal stimuli, whole-cell patch-clamp recordings were performed on acutely dissociated lumbar dorsal horn neurons. The cells demonstrated characteristic fast-activating and fast-inactivating sodium currents. SCI led to a shift of the steady-state activation and inactivation of the sodium current towards more depolarized potentials. The shifted steady-state inactivation shows similarities to that obtained from axotomized dorsal root ganglions, which were shown to upregulate Nav1.3. Small slow depolarizations below action potential threshold produced ramp currents, which were markedly enhanced by SCI (from 182 +/- 41 to 338 +/- 55 pA). The density of the noninactivating persistent sodium current was also significantly enhanced in neurons from SCI animals (from 17.4 +/- 3.2 to 27.7 +/- 4.4 pA/pF at 50-70 ms of depolarization). The increased persistent sodium current and ramp current, which are consistent with upregulation of Nav1.3 within dorsal horn neurons, suggest a basis for the hyperresponsiveness of these neurons following SCI.
Voltage-gated sodium channel (Na(v)1) beta2 subunits modulate channel gating, assembly, and cell-surface expression in CNS neurons in vitro and in vivo. beta2 expression increases in sensory neurons after nerve injury, and development of mechanical allodynia in the spared nerve injury model is attenuated in beta2-null mice. Thus, we hypothesized that beta2 modulates electrical excitability in dorsal root ganglion (DRG) neurons in vivo. We compared sodium currents (I(Na)) in small DRG neurons from beta2+/+ and beta2-/- mice to determine the effects of beta2 on tetrodotoxin-sensitive (TTX-S) and tetrodotoxin-resistant (TTX-R) Na(v)1 in vivo. Small-fast DRG neurons acutely isolated from beta2-/- mice showed significant decreases in TTX-S I(Na) compared with beta2+/+ neurons. This decrease included a 51% reduction in maximal sodium conductance with no detectable changes in the voltage dependence of activation or inactivation. TTX-S, but not TTX-R, I(Na) activation and inactivation kinetics in these cells were slower in beta2(-/-) mice compared with controls. The selective regulation of TTX-S I(Na) was supported by reductions in transcript and protein levels of TTX-S Na(v)1s, particularly Na(v)1.7. Low-threshold mechanical sensitivity was preserved in beta2-/- mice, but they were more sensitive to noxious thermal stimuli than wild type whereas their response during the late phase of the formalin test was attenuated. Our results suggest that beta2 modulates TTX-S Na(v)1 mRNA and protein expression resulting in increased TTX-S I(Na) and increases the rates of TTX-S Na(v)1 activation and inactivation in small-fast DRG neurons in vivo. TTX-R I(Na) were not significantly modulated by beta2.
Injury or inflammation affecting sensory neurons in dorsal root ganglia (DRG) causes hyperexcitability of DRG neurons that can lead to spontaneous firing and neuropathic pain. Recent results indicate that after chronic compression of DRG (CCD treatment), both hyperexcitability of neurons in intact DRG and behaviorally expressed hyperalgesia are maintained by concurrent activity in cAMP-protein kinase A (PKA) and cGMP-protein kinase G (PKG) signaling pathways. We report here that when tested under identical conditions, dissociation produces a pattern of hyperexcitability in small DRG neurons similar to that produced by CCD treatment, manifest as decreased action potential (AP) current threshold, increased AP duration, increased repetitive firing to depolarizing pulses, increased spontaneous firing and resting depolarization. A novel feature of this hyperexcitability is its early expression-as soon as testing can be conducted after dissociation (approximately 2 h). Both forms of injury increase the electrophysiological responsiveness of the neurons to activation of cAMP-PKA and cGMP-PKG pathways as indicated by enhancement of hyperexcitability by agonists of these pathways in dissociated or CCD-treated neurons but not in control neurons. Although inflammatory signals are known to activate cAMP-PKA pathways, dissociation-induced hyperexcitability is unlikely to be triggered by signals released from inflammatory cells recruited to the DRG because of insufficient time for recruitment during the dissociation procedure. Inhibition by specific antagonists indicates that continuing activation of cAMP-PKA and cGMP-PKG pathways is required to maintain hyperexcitability after dissociation. The reduction of hyperexcitability by blockers of adenylyl cyclase and soluble guanylyl cyclase after dissociation suggests a continuing release of autocrine and/or paracrine factors from dissociated neurons and/or satellite cells, which activate both cyclases and help to maintain acute, injury-induced hyperexcitability of DRG neurons.
Some chronic pain conditions are maintained or enhanced by sympathetic activity. In animal models of pathological pain, abnormal sprouting of sympathetic fibers around large- and medium-sized sensory neurons is observed in dorsal root ganglia (DRGs). Large- and medium-sized cells are also more likely to be spontaneously active, suggesting that sprouting may be related to neuron activity. We previously showed that sprouting could be reduced by systemic or locally applied lidocaine. In the complete sciatic nerve transection model in rats, spontaneous activity initially originates in the injury site; later, the DRGs become the major source of spontaneous activity. In this study, spontaneous activity reaching the DRG soma was reduced by early nerve blockade (local perfusion of the transected nerve with TTX for the 1st 7 days after injury). This significantly reduced sympathetic sprouting. Conversely, increasing spontaneous activity by local nerve perfusion with K(+) channel blockers increased sprouting. The hyperexcitability and spontaneous activity of DRG neurons observed in this model were also significantly reduced by early nerve blockade. These effects of early nerve blockade on sprouting, excitability, and spontaneous activity were all observed 4-5 wk after the end of early nerve blockade, indicating that the early period of spontaneous activity in the injured nerve is critical for establishing the more long-lasting pathologies observed in the DRG. Individual spontaneously active neurons, labeled with fluorescent dye, were five to six times more likely than quiescent cells to be co-localized with sympathetic fibers, suggesting a highly localized correlation of activity and sprouting.
Inherited erythromelalgia/erythermalgia (IEM) is a neuropathy characterized by pain and redness of the extremities that is triggered by warmth. IEM has been associated with missense mutations of the voltage-gated sodium channel Na(V)1.7, which is preferentially expressed in most nociceptive dorsal root ganglia (DRGs) and sympathetic ganglion neurons. Several mutations occur in cytoplasmic linkers of Na(V)1.7, with only two mutations in segment 4 (S4) and S6 of domain I. We report here a simplex case with an alanine 863 substitution by proline (A863P) in S5 of domain II of Na(V)1.7. The functional effect of A863P was investigated by voltage-clamp analysis in human embryonic kidney 293 cells and by current-clamp analysis to determine the effects of A863P on firing properties of small DRG neurons. Activation of mutant channels was shifted by -8 mV, whereas steady-state fast inactivation was shifted by +10 mV, compared with wild-type (WT) channels. There was a marked decrease in the rate of deactivation of mutant channels, and currents elicited by slow ramp depolarizations were 12 times larger than for WT. These results suggested that A863P could render DRG neurons hyperexcitable. We tested this hypothesis by studying properties of rat DRG neurons transfected with either A863P or WT channels. A863P depolarized resting potential of DRG neurons by +6 mV compared with WT channels, reduced the threshold for triggering single action potentials to 63% of that for WT channels, and increased firing frequency of neurons when stimulated with suprathreshold stimuli. Thus, A863P mutant channels produce hyperexcitability in DRG neurons, which contributes to the pathophysiology of IEM.
The aim of this investigation was to quantitate the effects of a dietary
restriction in Vitamin B-6 during gestation or gestation and lactation
on neurogenesis, neuron longevity and neuron differentiation in the
neocortex of rats. Sprague Dawley female rats were fed, ad libitum, a
Vitamin B-6 free diet (AIN 76) supplemented with 0.0 or 0.6 mg
pyridoxine (PN)/kg diet during gestation followed by a control level of
7.0 mg PN/kg diet during lactation, or were fed the Vitamin B-6 free
diet supplemented with 0.6 or 7.0 mg PN/kg diet throughout gestation and
lactation. The neocortex of progeny of these animals were examined at 30
days of age employing light and electron microscopy. Analyses of
neurogenesis, neuron longevity and differentiation of neurons (size of
somata, dendritic arborization and spine density in Golgi Cox
preparations, and synaptic density in E.M. preparations) were conducted.
Each of the Vitamin B-6 restricted treatments adversely affected
neurogenesis, neuron longevity and neuron differentiation. The degree of
adverse effects paralleled the severity (dose or duration) of the
restriction imposed. Expressed as percentage reduction from control
values, the findings indicated that neuron longevity and differentiation
of neurons in the neocortex were more severely affected than
neurogenesis by a maternal dietary restriction in Vitamin B-6.
Additive analgesic effects of long-term application of a combination of the vitamins B1 B6B12 (thiamine diphosphate 100 mg, pyridoxsine-HCl 200 mg, cyanocobalamin 20 µg, p.o.) on a single dose of the nonsteroidal anti-inflammatory drug (NSAID) diclofenac (diclofenac-Na, 50 mg, p.o.) were investigated with a noninflammatory experimental pain model in 38 healthy volunteers. B-vitamins were given with 3 dosages/day for 1 week. Then experimental sessions of 3 h followed to test the analgesic efficacy of the NSAID. In these sessions, phasic pain was induced by intracutaneously applied brief electrical pulses (20 ms). Measured were the pain ratings, the cerebral potentials and the EEG δ power in responses to the stimuli as target variables for the analgesic test. Unspecifïc effects upon the vigilance system were evaluated by spontaneous EEG, auditory-evoked potentials and reaction times. The investigation was performed as a placebo-controlled, double-blind cross-over study. Blood samples were taken to monitor the plasma concentrations of the active agents. Whereas in the first block of stimuli (40–60 min after diclofenac medication) no analgesic effects of diclofenac could be observed, either given alone or after pretreatment with the B-vitamins, in the second stimulus block (100–120 min after medication) significant effects appeared in all target variables describing analgesia. Pain ratings were decreased by about 5%, late cerebral potentials by about 9% and stimulus-induced δ power of the EEG by about 14%. These effects were significant (p 6 by 700%, for vitamin B1by 70% and for vitamin B12 by 50%. All B-vitamin concentrations were independent of each other.
The effects of vitamin B12 are compared to those of aspirin and 0.9% saline in three different experimental pain models in rats and mice; an electric shock test, the hotplate test, and the phenylbenzoquinone writhing test. Neither cyanocobalamin nor hydroxocobalamin showed any antinociceptive activity in any of the three tests at any of the doses used, whether the drug was administered as a single injection or as a series of daily injections lasting 7 days. These results run counter to those of clinical trials in man, though close scrutiny of the experimental procedures used in these trials often reveals a lack of rigor which casts doubts on their validity. This consideration, together with the negative findings reported here, suggests that the clinical use of vitamin B12 as an analgesic may be inappropriate.
Neuropathic pain is induced by injury or disease of the nervous system. Studies aimed at understanding the molecular pathophysiology of neuropathic pain have so far focused on a few known molecules and signaling pathways in neurons. However, the pathophysiology of neuropathic pain appears to be very complex and remains poorly understood. A global understanding of the molecular mechanisms involved in neuropathic pain is needed for a better understanding of the pathophysiology and treatment of neuropathic pain. Towards this end, we examined global gene expression changes as well as the pathobiology at the cellular level in a spinal nerve ligation neuropathic pain model using DNA microarray, quantitative real-time PCR and immunohistochemistry. We found that the behavioral hypersensitivity that is manifested in the persistent pain state is accompanied by previously undescribed changes in gene expression. In the DRG, we found regulation of: (1) immediate early genes; (2) genes such as ion channels and signaling molecules that contribute to the excitability of neurons; and (3) genes that are indicative of secondary events such as neuroinflammation. In addition, we studied gene regulation in both injured and uninjured DRG by quantitative PCR, and observed differential gene regulation in these two populations of DRGs. Furthermore, we demonstrated unexpected co-regulation of many genes, especially the activation of neuroinflammation markers in both the PNS and CNS. The results of our study provide a new picture of the molecular mechanisms that underlie the complexity of neuropathic pain and suggest that chronic pain shares common pathobiology with progressive neurodegenerative disease.
This review deals with physiological and biological mechanisms of neuropathic pain, that is, pain induced by injury or disease of the nervous system. Animal models of neuropathic pain mostly use injury to a peripheral nerve, therefore, our focus is on results from nerve injury models. To make sure that the nerve injury models are related to pain, the behavior was assessed of animals following nerve injury, i.e. partial/total nerve transection/ligation or chronic nerve constriction. The following behaviors observed in such animals are considered to indicate pain: (a) autotomy, i.e. self-attack, assessed by counting the number of wounds implied, (b) hyperalgesia, i.e. strong withdrawal responses to a moderate heat stimulus, (c) allodynia, i.e. withdrawal in response to non-noxious tactile or cold stimuli. These behavioral parameters have been exploited to study the pharmacology and modulation of neuropathic pain. Nerve fibers develop abnormal ectopic excitability at or near the site of nerve injury. The
Following repeated oral administration for 7 days thiamine (thiamine nitrate, CAS 532-43-4), pyridoxine (pyridoxol hydrochloride, CAS 58-56-0), and cyanocobalamin (CAS 68-19-9) exhibited at high dose levels alone or in combination dose-related antinociceptive properties in the writhing test in the mouse. Cyanocobalamin exerted a potentiating effect in the combination of the 3 vitamins.
Nociceptive activity was elicited in neurones of the thalamus by supramaximal electrical stimulation of afferent C fibres in the sural nerve of rats under urethane anesthesia. The fixed combination of vitamin B1, B6, and B12 (Neurobion) as well as of vitamin B6 administered by i.p. injection dose-dependently reduced the evoked nociceptive activity. The ED50 of Neurobion is 4.6 ml/kg (at 100 min after injection) and that of vitamin B6 is 189 mg/kg (at 90 min after injection). The minimum effective doses of Neurobion and vitamin B6 are 0.5 ml/kg and 40 mg/kg, respectively. When Neurobion or vitamin B6 were given at their minimum effective doses, and the minimum effective doses of morphine (0.025 mg/kg) or paracetamol (5 mg/kg) were injected i.v. 80 min later, i.e., when the maximum effect of higher doses of Neurobion or vitamin B6 was about to develop, no supraadditive effect developed. It is concluded that the antinociceptive effect caused by a single injection of Neurobion is largely due to vitamin B6. Vitamin B12 may contribute to this effect, whereas vitamin B1 alone exhibited only a slight effect on nociception. Moreover, it appears that Neurobion produces its antinociceptive effect after a single injection and after repeated administration during several days by different mechanisms so that the effect of analgesic agents is not enhanced following a single injection of Neurobion but may be enhanced after repeated administration of the compound.
Many conditions in clinical neurology may be responsive to pyridoxine as a therapeutic agent. The current difficulty is in trying to isolate the conditions that are most likely to respond. Treating seizures is a major part of a neurologic practice. Our current therapeutic agents are only partially successful and limited by multiple side effects. One problem is that patients often have to take these agents for an entire lifetime, further raising the risk of toxicity. If pyridoxine supplementation can improve the efficacy of currently used medications, it will be gladly accepted into our therapeutic arsenal. Headache, chronic pain, and depression all appear to run together in many of our patients. The observations that serotonin deficiency is a common thread between them and that pyridoxine can raise serotonin levels open a wide range of therapeutic options. Small studies have been carried out with mixed success. Comparison with amitriptyline in the treatment of headache appears to show about equal efficacy, although side effects would be expected to be more of a problem with the amitriptyline. Behavioral disorders are relatively common and continue to be a major problem, disrupting the lives of the patients and their families. Current treatments are not acceptable to most people because of the risk of side effects with long-term usage. If, as Dr. Feingold suggests, many of these problems are caused by "toxic" exposures to chemicals that are pyridoxine antagonists, supplementation at early ages may reduce the incidence of hyperactivity and aggressive behavior. This raises the question of safety. Is pyridoxine safe for long-term use in large segments of the population, including children? The studies on children with Down's syndrome and autism, utilizing much higher doses than are used for other therapeutic purposes, seem to indicate relative safety if carefully monitored. Studies involving large population groups with carpal tunnel syndrome, all adults, using 100-150 mg/day have shown minimal or no toxicity in five- to 10-year studies. Women self-medicating for PMS taking 500 to 5000 mg/day have shown peripheral neuropathy within one to three years. It would appear from this retrospective analysis that pyridoxine is safe at doses of 100 mg/day or less in adults. In children there is not enough data to make any sort of suggestion. Because the major neurologic complication is a peripheral neuropathy and the causes of this condition are myriad, pyridoxine may cause neuropathy only in patients with a pre-existing susceptibility to this condition.
B-vitamins possess antinociceptive and antiinflammatory activity. The rat tail pressure test was used to examine whether a mixture of the vitamins B1, B6, and B12, clinically used as Neurobion, has antinociceptive activity itself or potentiates the effect of the non-steroidal antiinflammatory drug (NSAID) diclofenac on carrageenin-induced hyperalgesia. Only the highest dose of the vitamin mixture (667 mg/kg B1 and B6, 6.7 mg/kg B12 p.o.) exhibited antinociceptive activity. Nevertheless, lower doses which alone were lacking in activity (100-250 mg/kg B1 and B6, 1-2.5 mg/kg B12 p.o.) dose-dependently potentiated the antinociceptive of diclofenac. This result supports the clinical experience of a reduced need for diclofenac when B-vitamins are administered concomitantly.
A peripheral mononeuropathy was produced in adult rats by placing loosely constrictive ligatures around the common sciatic nerve. The postoperative behavior of these rats indicated that hyperalgesia, allodynia and, possibly, spontaneous pain (or dysesthesia) were produced. Hyperalgesic responses to noxious radiant heat were evident on the second postoperative day and lasted for over 2 months. Hyperalgesic responses to chemogenic pain were also present. The presence of allodynia was inferred from the nocifensive responses evoked by standing on an innocuous, chilled metal floor or by innocuous mechanical stimulation, and by the rats' persistence in holding the hind paw in a guarded position. The presence of spontaneous pain was suggested by a suppression of appetite and by the frequent occurrence of apparently spontaneous nocifensive responses. The affected hind paw was abnormally warm or cool in about one-third of the rats. About one-half of the rats developed grossly overgrown claws on the affected side. Experiments with this animal model may advance our understanding of the neural mechanisms of neuropathic pain disorders in humans.
66 female inpatients with dysfunction pain syndrome, chronic cephalgia and facial pain participated in a randomized, placebo-controlled double-blind study, half the patients receiving a multivitamin preparation for 12 days and the other half a placebo. The biochemically determined vitamin status at the start of the study revealed gaps in the coverage of the vitamin supply, particularly with regard to the vitamins thiamin, riboflavin and folic acid. 65% of the patients showed a subclinical vitamin deficiency of two or more vitamins. With regard to the development of pain during the study no statistically significant differences could be determined, however, between the active-treatment and placebo groups. Nevertheless, a clear reduction in pain was more frequently observed in the active-treatment group, and a deterioration of pain more frequently in the placebo group. A reduction in pain was reported more often by patients in whom the values of alpha-ETK, alpha-EGOT, folic acid and cyanocobalamin improved in the course of the study. Vitamin administration in physiological doses evidently have only weak effects on the behavior of pain; analgesic vitamin effects may be presumed in the case of correspondingly high therapeutic doses for a prolonged period.
To explore the role of vitamin B in neural mechanisms of analgesia, we investigated the effect of a compound of vitamins B1, B6 and B12 (Neurobion, E. Merck) on the nociceptive responses of single neurons in the spinal cord dorsal horn in anesthetized cats. Intrathecal superfusion of Neurobion, using a small pool placed on the spinal surface, produced a significant dose-dependent depression in the responses evoked by noxious skin heating (50 or 52 degrees C, 10 s) of hindfoot skin, but not of spontaneous activity in dorsal horn neurons. These results indicate that the therapeutic effect of vitamin B compounds in the clinical management of pain may involve a suppression of nociceptive transmission at the spinal level.
Influence of the time of maternal restriction in dietary vitamin B-6 on vitamer concentrations and morphological development of neocortex was examined. Rats were fed ad libitum a vitamin B-6-free diet supplemented with 0.0 or 0.6 mg pyridoxine X hydrochloride (PN X HCl)/kg diet during gestation followed by a control diet (7.0 mg PN X HCl/kg) during lactation or were supplemented with 0.6 or 7.0 mg PN X HCl/kg diet throughout gestation and lactation. During postweaning offspring received the maternal diets fed during lactation. Neocortices of offspring were examined at 30 d of age by liquid chromatography and light microscopy. Vitamin restriction during gestation and 30 d postnatal was the only vitamin B-6-restricted treatment of the three administered that altered B-6 vitamer levels in neocortex; all vitamers were depressed equally. Brain weight and volume of neocortex were not changed significantly by the maternal restrictions imposed. However, each restriction adversely affected neurogenesis and neuron longevity of the neocortex and when expressed as percent reduction from control, neuron longevity was affected more severely than neurogenesis.
In a double-blind, randomized, controlled study, the effectiveness of treatment with a combination of Benfotiamine (an Allithiamine, a lipid-soluble derivative of vitamin B1 with high bioavailability) plus vitamin B6/B12 on objective parameters of neuropathy was studied over a period of 12 weeks on 24 diabetic patients with diabetic polyneuropathy. The results showed a significant improvement (p = 0.006) of nerve conduction velocity in the peroneal nerve and a statistical trend toward improvement of the vibration perception threshold. Long-term observation of 9 patients with verum over a period of 9 months support the results. Therapy-specific adverse effects were not seen. The results of this double-blind investigation, of the long-term observation and of the reports in the literature support the contention that the neurotropic benfotiamine-vitamin B combination represents a starting point in the treatment of diabetic polyneuropathy.
We have been investigating the relationship between learning and thiamine. Electrical stimulation of mesencephalic periaqueductal gray matter (PAG) is known to have an aversive effect and elicits spontaneous instrumental escape behavior. We taught rats to press a lever to escape from the pain of electrical stimulation by learning to turn a switch off. Then we examined the relationship between learning and the thiamine concentration in various portions of the brain.
(1) One group of rats was given a normal diet and another group was given a thiamine-deficient diet which contained half of the amount of thiamine present in the normal diet. We measured the response time required for each rat to react by moving after an electrical impulse was applied, and the running time during which the rat was moving from the starting point to the end point to press a lever. The rats that were fed the thiamine-deficient diet showed a slower response time and a longer running time than the rats fed the normal diet.
(2) We divided the rats fed the normal diet into two groups, one group trained to switch off a lever and the other group not trained for such a task. We found that the thiamine concentration in the blood of the rats in the trained group was significantly higher than that in the group without training.
The tetrodotoxin-resistant (TTX-R) voltage-gated sodium channel SNS/PN3 and the newly discovered NaN/SNS2 are expressed in sensory neurones, particularly in nociceptors. Using specific antibodies, we have studied, for the first time in humans, the presence of SNS/PN3 and NaN/SNS2 in peripheral nerves, including tissues from patients with chronic neurogenic pain. In brachial plexus injury patients, there was an acute decrease of SNS/PN3- and NaN/SNS2-like immunoreactivity in sensory cell bodies of cervical dorsal root ganglia (DRG) whose central axons had been avulsed from spinal cord, with gradual return of the immunoreactivity to control levels over months. In contrast, there was increased intensity of immunoreactivity to both channels in some peripheral nerve fibers just proximal to the site of injury in brachial plexus trunks, and in neuromas. These