Neuropathic Pain: Therapy and Mechanisms

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Neurobiology and Clinical Neuroscience".

Deadline for manuscript submissions: closed (31 July 2021) | Viewed by 82660

Special Issue Editors

Clinical and Regulatory Affairs, Arcellx, Gaithersburg, MD, USA
Interests: clinical research; clinical development (early and late); immunotherapy; melanoma; oxidative stress; type 2 diabetes and neuropathic pain
Special Issues, Collections and Topics in MDPI journals
Honorary Professor, Warwick University; Consultant, South Tees Hospitals NHS Foundation Trust, Middlesbrough, UK
Interests: clinical research; opioid withdrawal; spinal cord stimulation (SCS) and intrathecal drug delivery for pain and spasticity

Special Issue Information

Neuropathic pain, known to be originating from abnormal or damaged nerves, often manifests as shooting or burning pain. It is especially burdensome when it turns chronic, negatively impacting the well-being of patients, their social relationships, daily activities, as well as work productivity. The economic burden associated with chronic pain is estimated to exceed 500 billion USD per annum, which indicates the great impact of this condition. The treatment of chronic neuropathic pain includes physical and psychological therapies, as well as pharmacological, interventional, and surgical treatments. Opioids are often prescribed to patients who fail to achieve satisfactory pain relief with conventional treatment. However, evidence shows that opioids provide clinically meaningful pain relief in the short term, whereas their chronic use can result in tolerance as well as dependence. The use of opioids for the management of chronic pain has received significant attention in the recent decade, and several additional pharmacological and non-pharmacological treatments have been developed and approved for chronic pain management. This Special Issue on neuropathic pain intends to present the progress in the treatment of chronic pain and highlight the current understanding of pathophysiological and biochemical pathways involved in neuropathic pain. All article types related to neuropathic pain, pathophysiology, treatment (pharmacological as well as non-pharmacological), and biomarkers are considered within the scope of this Special Issue.

Dr. Anand Rotte
Prof. Sam Eldabe
Guest Editors

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Keywords

  • neuropathic pain
  • chronic pain
  • opioids
  • biomarkers
  • pain treatment

Published Papers (21 papers)

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Research

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25 pages, 4872 KiB  
Article
Fumagillin Attenuates Spinal Angiogenesis, Neuroinflammation, and Pain in Neuropathic Rats after Chronic Constriction Injury
by Zhi-Hong Wen, Shi-Ying Huang, Hsiao-Mei Kuo, Chao-Ting Chen, Nan-Fu Chen, Wu-Fu Chen, Kuan-Hao Tsui, Hsin-Tzu Liu and Chun-Sung Sung
Biomedicines 2021, 9(9), 1187; https://doi.org/10.3390/biomedicines9091187 - 10 Sep 2021
Cited by 12 | Viewed by 2556
Abstract
Introduction: Angiogenesis in the central nervous system is visible in animal models of neuroinflammation and bone cancer pain. However, whether spinal angiogenesis exists and contributes to central sensitization in neuropathic pain remains unclear. This study analyzes the impact of angiogenesis on spinal neuroinflammation [...] Read more.
Introduction: Angiogenesis in the central nervous system is visible in animal models of neuroinflammation and bone cancer pain. However, whether spinal angiogenesis exists and contributes to central sensitization in neuropathic pain remains unclear. This study analyzes the impact of angiogenesis on spinal neuroinflammation in neuropathic pain. Methods: Rats with chronic constriction injury (CCI) to the sciatic nerve underwent the implantation of an intrathecal catheter. Fumagillin or vascular endothelial growth factor-A antibody (anti-VEGF-A) was administered intrathecally. Nociceptive behaviors, cytokine immunoassay, Western blot, and immunohistochemical analysis assessed the effect of angiogenesis inhibition on CCI-induced neuropathic pain. Results: VEGF, cluster of differentiation 31 (CD31), and von Willebrand factor (vWF) expressions increased after CCI in the ipsilateral lumbar spinal cord compared to that in the contralateral side of CCI and control rats from post-operative day (POD) 7 to 28, with a peak at POD 14. Tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and IL-6 concentrations, but not IL-10 levels, also increased in the ipsilateral spinal cord after CCI. Fumagillin and anti-VEGF-A reduced CCI-induced thermal hyperalgesia from POD 5 to 14 and mechanical allodynia from POD 3 to 14. Fumagillin reduced CCI-upregulated expressions of angiogenic factors and astrocytes. Furthermore, fumagillin decreased TNF-α and IL-6 amounts and increased IL-10 levels at POD 7 and 14, but not IL-1β concentrations. Conclusions: Fumagillin significantly ameliorates CCI-induced nociceptive sensitization, spinal angiogenesis, and astrocyte activation. Our results suggest that angiogenesis inhibitor treatment suppresses peripheral neuropathy-induced central angiogenesis, neuroinflammation, astrocyte activation, and neuropathic pain. Full article
(This article belongs to the Special Issue Neuropathic Pain: Therapy and Mechanisms)
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11 pages, 632 KiB  
Article
Association between Neutrophil-Lymphocyte Ratio and Herpes Zoster Infection in 1688 Living Donor Liver Transplantation Recipients at a Large Single Center
by Ji-Hoon Sim, Young-Jin Moon, Sung-Hoon Kim, Kyoung-Sun Kim, Ju-Seung Lee, Jun-Gol Song and Gyu-Sam Hwang
Biomedicines 2021, 9(8), 963; https://doi.org/10.3390/biomedicines9080963 - 05 Aug 2021
Cited by 2 | Viewed by 1766
Abstract
Liver transplantation (LT) is closely associated with decreased immune function, a contributor to herpes zoster (HZ). However, risk factors for HZ in living donor LT (LDLT) remain unknown. Neutrophil-lymphocyte ratio (NLR) and immune system function are reportedly correlated. This study investigated the association [...] Read more.
Liver transplantation (LT) is closely associated with decreased immune function, a contributor to herpes zoster (HZ). However, risk factors for HZ in living donor LT (LDLT) remain unknown. Neutrophil-lymphocyte ratio (NLR) and immune system function are reportedly correlated. This study investigated the association between NLR and HZ in 1688 patients who underwent LDLT between January 2010 and July 2020 and evaluated risk factors for HZ and postherpetic neuralgia (PHN). The predictive power of NLR was assessed through the concordance index and an integrated discrimination improvement (IDI) analysis. Of the total cohort, 138 (8.2%) had HZ. The incidence of HZ after LT was 11.2 per 1000 person-years and 0.1%, 1.3%, 2.9%, and 13.5% at 1, 3, 5, and 10 years, respectively. In the Cox regression analysis, preoperative NLR was significantly associated with HZ (adjusted hazard ratio [HR], 1.05; 95% confidence interval [CI], 1.02–1.09; p = 0.005) and PHN (HR, 1.08; 95% CI, 1.03–1.13; p = 0.001). Age, sex, mycophenolate mofetil use, and hepatitis B virus infection were risk factors for HZ versus age and sex for PHN. In the IDI analysis, NLR was discriminative for HZ and PHN (p = 0.020 and p = 0.047, respectively). Preoperative NLR might predict HZ and PHN in LDLT recipients. Full article
(This article belongs to the Special Issue Neuropathic Pain: Therapy and Mechanisms)
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18 pages, 1083 KiB  
Article
Proof-of-Concept for the Analgesic Effect and Thermoregulatory Safety of Orally Administered Multi-Target Compound SZV 1287 in Mice: A Novel Drug Candidate for Neuropathic Pain
by Ádám István Horváth, Nikolett Szentes, Valéria Tékus, Maja Payrits, Éva Szőke, Emőke Oláh, András Garami, Eszter Fliszár-Nyúl, Miklós Poór, Cecília Sár, Tamás Kálai, Szilárd Pál, Krisztina Percze, Éva Nagyné Scholz, Tamás Mészáros, Blanka Tóth, Péter Mátyus and Zsuzsanna Helyes
Biomedicines 2021, 9(7), 749; https://doi.org/10.3390/biomedicines9070749 - 29 Jun 2021
Cited by 1 | Viewed by 2225
Abstract
SZV 1287 (3-(4,5-diphenyl-1,3-oxazol-2-yl)propanal oxime) is a novel multi-target candidate under preclinical development for neuropathic pain. It inhibits amine oxidase copper containing 3, transient receptor potential ankyrin 1 and vanilloid 1 (TRPV1) receptors. Mainly under acidic conditions, it is transformed to the cyclooxygenase inhibitor [...] Read more.
SZV 1287 (3-(4,5-diphenyl-1,3-oxazol-2-yl)propanal oxime) is a novel multi-target candidate under preclinical development for neuropathic pain. It inhibits amine oxidase copper containing 3, transient receptor potential ankyrin 1 and vanilloid 1 (TRPV1) receptors. Mainly under acidic conditions, it is transformed to the cyclooxygenase inhibitor oxaprozin, which is ineffective for neuropathy. Therefore, an enterosolvent capsule is suggested for oral formulation, which we investigated for nociception, basic kinetics, and thermoregulatory safety in mice. The antihyperalgesic effect of SZV 1287 (10, 20, 50, and 200 mg/kg, p.o.) was determined in partial sciatic nerve ligation-induced traumatic neuropathy by aesthesiometry, brain and plasma concentrations by HPLC, and deep body temperature by thermometry. Its effect on proton-induced TRPV1 activation involved in thermoregulation was assessed by microfluorimetry in cultured trigeminal neurons. The three higher SZV 1287 doses significantly, but not dose-dependently, reduced neuropathic hyperalgesia by 50% of its maximal effect. It was quickly absorbed; plasma concentration was stable for 2 h, and it entered into the brain. Although SZV 1287 significantly decreased the proton-induced TRPV1-mediated calcium-influx potentially leading to hyperthermia, it did not alter deep body temperature. Oral SZV 1287 inhibited neuropathic hyperalgesia and, despite TRPV1 antagonistic action and brain penetration, it did not influence thermoregulation, which makes it a promising analgesic candidate. Full article
(This article belongs to the Special Issue Neuropathic Pain: Therapy and Mechanisms)
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20 pages, 4451 KiB  
Article
Centromedian–Parafascicular and Somatosensory Thalamic Deep Brain Stimulation for Treatment of Chronic Neuropathic Pain: A Contemporary Series of 40 Patients
by Mahmoud Abdallat, Assel Saryyeva, Christian Blahak, Marc E. Wolf, Ralf Weigel, Thomas J. Loher, Joachim Runge, Hans E. Heissler, Thomas M. Kinfe and Joachim K. Krauss
Biomedicines 2021, 9(7), 731; https://doi.org/10.3390/biomedicines9070731 - 25 Jun 2021
Cited by 20 | Viewed by 2551
Abstract
Introduction: The treatment of neuropathic and central pain still remains a major challenge. Thalamic deep brain stimulation (DBS) involving various target structures is a therapeutic option which has received increased re-interest. Beneficial results have been reported in several more recent smaller studies, however, [...] Read more.
Introduction: The treatment of neuropathic and central pain still remains a major challenge. Thalamic deep brain stimulation (DBS) involving various target structures is a therapeutic option which has received increased re-interest. Beneficial results have been reported in several more recent smaller studies, however, there is a lack of prospective studies on larger series providing long term outcomes. Methods: Forty patients with refractory neuropathic and central pain syndromes underwent stereotactic bifocal implantation of DBS electrodes in the centromedian–parafascicular (CM–Pf) and the ventroposterolateral (VPL) or ventroposteromedial (VPM) nucleus contralateral to the side of pain. Electrodes were externalized for test stimulation for several days. Outcome was assessed with five specific VAS pain scores (maximum, minimum, average pain, pain at presentation, allodynia). Results: The mean age at surgery was 53.5 years, and the mean duration of pain was 8.2 years. During test stimulation significant reductions of all five pain scores was achieved with either CM–Pf or VPL/VPM stimulation. Pacemakers were implanted in 33/40 patients for chronic stimulation for whom a mean follow-up of 62.8 months (range 3–180 months) was available. Of these, 18 patients had a follow-up beyond four years. Hardware related complications requiring secondary surgeries occurred in 11/33 patients. The VAS maximum pain score was improved by ≥50% in 8/18, and by ≥30% in 11/18 on long term follow-up beyond four years, and the VAS average pain score by ≥50% in 10/18, and by ≥30% in 16/18. On a group level, changes in pain scores remained statistically significant over time, however, there was no difference when comparing the efficacy of CM–Pf versus VPL/VPM stimulation. The best results were achieved in patients with facial pain, poststroke/central pain (except thalamic pain), or brachial plexus injury, while patients with thalamic lesions had the least benefit. Conclusion: Thalamic DBS is a useful treatment option in selected patients with severe and medically refractory pain. Full article
(This article belongs to the Special Issue Neuropathic Pain: Therapy and Mechanisms)
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15 pages, 2039 KiB  
Article
Ammonium Glycyrrhizinate Prevents Apoptosis and Mitochondrial Dysfunction Induced by High Glucose in SH-SY5Y Cell Line and Counteracts Neuropathic Pain in Streptozotocin-Induced Diabetic Mice
by Laura Ciarlo, Francesca Marzoli, Paola Minosi, Paola Matarrese and Stefano Pieretti
Biomedicines 2021, 9(6), 608; https://doi.org/10.3390/biomedicines9060608 - 26 May 2021
Cited by 10 | Viewed by 3105
Abstract
Glycyrrhiza glabra, commonly known as liquorice, contains several bioactive compounds such as flavonoids, sterols, triterpene, and saponins; among which, glycyrrhizic acid, an oleanane-type saponin, is the most abundant component in liquorice root. Diabetic peripheral neuropathy is one of the major complications of diabetes [...] Read more.
Glycyrrhiza glabra, commonly known as liquorice, contains several bioactive compounds such as flavonoids, sterols, triterpene, and saponins; among which, glycyrrhizic acid, an oleanane-type saponin, is the most abundant component in liquorice root. Diabetic peripheral neuropathy is one of the major complications of diabetes mellitus, leading to painful condition as neuropathic pain. The pathogenetic mechanism of diabetic peripheral neuropathy is very complex, and its understanding could lead to a more suitable therapeutic strategy. In this work, we analyzed the effects of ammonium glycyrrhizinate, a derivate salt of glycyrrhizic acid, on an in vitro system, neuroblastoma cells line SH-SY5Y, and we observed that ammonium glycyrrhizinate was able to prevent cytotoxic effect and mitochondrial fragmentation after high-glucose administration. In an in vivo experiment, we found that a short-repeated treatment with ammonium glycyrrhizinate was able to attenuate neuropathic hyperalgesia in streptozotocin-induced diabetic mice. In conclusion, our results showed that ammonium glycyrrhizinate could ameliorate diabetic peripheral neuropathy, counteracting both in vitro and in vivo effects induced by high glucose, and might represent a complementary medicine for the clinical management of diabetic peripheral neuropathy. Full article
(This article belongs to the Special Issue Neuropathic Pain: Therapy and Mechanisms)
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10 pages, 1972 KiB  
Article
Possible Therapeutic Options for Complex Regional Pain Syndrome
by Myeounghoon Cha, Kyung Hee Lee, Minjee Kwon and Bae Hwan Lee
Biomedicines 2021, 9(6), 596; https://doi.org/10.3390/biomedicines9060596 - 24 May 2021
Cited by 4 | Viewed by 2798
Abstract
Complex regional pain syndrome (CRPS) describes an array of painful conditions that are characterized by continuing regional pain. CRPS comprises severe and inappropriate pain in cases of complete recovery after trauma. Research on the pharmacological treatment of CRPS, however, has not been well [...] Read more.
Complex regional pain syndrome (CRPS) describes an array of painful conditions that are characterized by continuing regional pain. CRPS comprises severe and inappropriate pain in cases of complete recovery after trauma. Research on the pharmacological treatment of CRPS, however, has not been well investigated. In this study, we compared the pain relief effects of different drugs (URB597, pyrrolidine dithiocarbamate, and hydralazine) in a rat model of chronic post-ischemic pain-induced CRPS. After drug injection, CRPS-induced mechanical allodynia was significantly recovered. After three repetitive drug injections, mechanical sensitivity generally improved as hyper-nociception subsided. Reduced Nav1.7 expression at dorsal root ganglions (DRGs) was observed in the drug treatment groups. Neural imaging analysis revealed decreased neural activity for each drug treatment, compared to vehicle. In addition, treatments significantly reduced IL-1β, IL-6, and TNFα expression in DRGs. These results indicated that drugs could reduce the expression of inflammatory factors and alleviate the symptoms of chronic post-ischemic pain-induced CRPS. Full article
(This article belongs to the Special Issue Neuropathic Pain: Therapy and Mechanisms)
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12 pages, 19553 KiB  
Article
Differential Modulation of Dorsal Horn Neurons by Various Spinal Cord Stimulation Strategies
by Kwan Yeop Lee, Dongchul Lee, Zachary B. Kagan, Dong Wang and Kerry Bradley
Biomedicines 2021, 9(5), 568; https://doi.org/10.3390/biomedicines9050568 - 18 May 2021
Cited by 13 | Viewed by 2871
Abstract
New strategies for spinal cord stimulation (SCS) for chronic pain have emerged in recent years, which may work better via different analgesic mechanisms than traditional low-frequency (e.g., 50 Hz) paresthesia-based SCS. To determine if 10 kHz and burst SCS waveforms might have a [...] Read more.
New strategies for spinal cord stimulation (SCS) for chronic pain have emerged in recent years, which may work better via different analgesic mechanisms than traditional low-frequency (e.g., 50 Hz) paresthesia-based SCS. To determine if 10 kHz and burst SCS waveforms might have a similar mechanistic basis, we examined whether these SCS strategies at intensities ostensibly below sensory thresholds would modulate spinal dorsal horn (DH) neuronal function in a neuron type-dependent manner. By using an in vivo electrophysiological approach in rodents, we found that low-intensity 10 kHz SCS, but not burst SCS, selectively activates inhibitory interneurons in the spinal DH. This study suggests that low-intensity 10 kHz SCS may inhibit pain-sensory processing in the spinal DH by activating inhibitory interneurons without activating DC fibers, resulting in paresthesia-free pain relief, whereas burst SCS likely operates via other mechanisms. Full article
(This article belongs to the Special Issue Neuropathic Pain: Therapy and Mechanisms)
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19 pages, 4616 KiB  
Article
Interactions between Autophagy, Proinflammatory Cytokines, and Apoptosis in Neuropathic Pain: Granulocyte Colony Stimulating Factor as a Multipotent Therapy in Rats with Chronic Constriction Injury
by Ming-Feng Liao, Shin-Rung Yeh, Kwok-Tung Lu, Jung-Lung Hsu, Po-Kuan Chao, Hui-Ching Hsu, Chi-Hao Peng, Yun-Lin Lee, Yu-Hui Hung and Long-Sun Ro
Biomedicines 2021, 9(5), 542; https://doi.org/10.3390/biomedicines9050542 - 12 May 2021
Cited by 8 | Viewed by 2440
Abstract
Our previous studies have shown that early systemic granulocyte colony-stimulating factor (G-CSF) treatment can attenuate neuropathic pain in rats with chronic constriction injury (CCI) by modulating expression of different proinflammatory cytokines, microRNAs, and proteins. Besides the modulation of inflammatory mediators’ expression, previous studies [...] Read more.
Our previous studies have shown that early systemic granulocyte colony-stimulating factor (G-CSF) treatment can attenuate neuropathic pain in rats with chronic constriction injury (CCI) by modulating expression of different proinflammatory cytokines, microRNAs, and proteins. Besides the modulation of inflammatory mediators’ expression, previous studies have also reported that G-CSF can modulate autophagic and apoptotic activity. Furthermore, both autophagy and apoptosis play important roles in chronic pain modulation. In this study, we evaluated the temporal interactions of autophagy, and apoptosis in the dorsal root ganglion (DRG) and injured sciatic nerve after G-CSF treatment in CCI rats. We studied the behaviors of CCI rats with or without G-CSF treatment and the various levels of autophagic, proinflammatory, and apoptotic proteins in injured sciatic nerves and DRG neurons at different time points using Western blot analysis and immunohistochemical methods. The results showed that G-CSF treatment upregulated autophagic protein expression in the early phase and suppressed apoptotic protein expression in the late phase after nerve injury. Thus, medication such as G-CSF can modulate autophagy, apoptosis, and different proinflammatory proteins in the injured sciatic nerve and DRG neurons, which have the potential to treat neuropathic pain. However, autophagy-mediated regulation of neuropathic pain is a time-dependent process. An increase in autophagic activity in the early phase before proinflammatory cytokines reach the threshold level to induce neuropathic pain can effectively alleviate further neuropathic pain development. Full article
(This article belongs to the Special Issue Neuropathic Pain: Therapy and Mechanisms)
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15 pages, 2705 KiB  
Article
Effects of Chronic Oral Probiotic Treatment in Paclitaxel-Induced Neuropathic Pain
by Mariarosaria Cuozzo, Vanessa Castelli, Carmen Avagliano, Annamaria Cimini, Michele d’Angelo, Claudia Cristiano and Roberto Russo
Biomedicines 2021, 9(4), 346; https://doi.org/10.3390/biomedicines9040346 - 30 Mar 2021
Cited by 32 | Viewed by 3667
Abstract
Chemotherapy-induced peripheral neuropathy (CIPN) represents one of the most prevalent and potentially disabling side effects due to the use of anticancer drugs, one of the primary neuropathies detected is peripheral neuropathy induced by administration of taxanes, including paclitaxel. It has been demonstrated that [...] Read more.
Chemotherapy-induced peripheral neuropathy (CIPN) represents one of the most prevalent and potentially disabling side effects due to the use of anticancer drugs, one of the primary neuropathies detected is peripheral neuropathy induced by administration of taxanes, including paclitaxel. It has been demonstrated that gut microbiota is crucial for the therapeutic effect of chemotherapeutic drugs for inhibiting tumor growth and contributed to the pathogenesis of the CIPN. The use of nutraceuticals has receiving growing attention from the research community due to their phytochemical, biological, and pharmacological properties. It has been demonstrated that probiotic formulations may both reduce inflammation and modulate the expression of pain receptors. Our studies tested the efficacy of a probiotic formulation, SLAB51, in preventing paclitaxel-induced neuropathy. Interestingly, our probiotic formulation was able to keep the gut integrity, preserving its functionality, in CIPN-mice, moreover, it prevented the mechanical and cold hypersensitivity induced in paclitaxel-mice. Additionally, ex-vivo analysis showed that in CIPN-mice the pro-biotic treatment increased the expression of opioid and cannabinoid receptors in spinal cord, it prevented in the reduction in nerve fiber damage in the paws and modulated the serum proinflammatory cytokines concentration. On basis of these data, the use of this specific probiotic formulation may represent a valid adjuvant agent to paclitaxel, useful and not toxic for long-lasting therapies. Full article
(This article belongs to the Special Issue Neuropathic Pain: Therapy and Mechanisms)
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17 pages, 3584 KiB  
Article
GPR171 Activation Modulates Nociceptor Functions, Alleviating Pathologic Pain
by Pyung Sun Cho, Han Kyu Lee, Young In Choi, Seung In Choi, Ji Yeon Lim, Minseok Kim, Hyun Kim, Sung Jun Jung and Sun Wook Hwang
Biomedicines 2021, 9(3), 256; https://doi.org/10.3390/biomedicines9030256 - 05 Mar 2021
Cited by 7 | Viewed by 3383
Abstract
Modulation of the function of somatosensory neurons is an important analgesic strategy, requiring the proposal of novel molecular targets. Many G-protein-coupled receptors (GPRs) have been deorphanized, but the receptor locations, outcomes due to their activations, and their signal transductions remain to be elucidated, [...] Read more.
Modulation of the function of somatosensory neurons is an important analgesic strategy, requiring the proposal of novel molecular targets. Many G-protein-coupled receptors (GPRs) have been deorphanized, but the receptor locations, outcomes due to their activations, and their signal transductions remain to be elucidated, regarding the somatosensory nociceptor function. Here we report that GPR171, expressed in a nociceptor subpopulation, attenuated pain signals via Gi/o-coupled modulation of the activities of nociceptive ion channels when activated by its newly found ligands. Administration of its natural peptide ligand and a synthetic chemical ligand alleviated nociceptor-mediated acute pain aggravations and also relieved pathologic pain at nanomolar and micromolar ranges. This study suggests that functional alteration of the nociceptor neurons by GPR171 signaling results in pain alleviation and indicates that GPR171 is a promising molecular target for peripheral pain modulation. Full article
(This article belongs to the Special Issue Neuropathic Pain: Therapy and Mechanisms)
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19 pages, 3682 KiB  
Article
Changes in Resurgent Sodium Current Contribute to the Hyperexcitability of Muscles in Patients with Paramyotonia Congenita
by Chiung-Wei Huang, Hsing-Jung Lai, Pi-Chen Lin and Ming-Jen Lee
Biomedicines 2021, 9(1), 51; https://doi.org/10.3390/biomedicines9010051 - 08 Jan 2021
Cited by 5 | Viewed by 2312
Abstract
Paramyotonia congenita (PMC) is a rare hereditary skeletal muscle disorder. The major symptom, muscle stiffness, is frequently induced by cold exposure and repetitive exercise. Mutations in human SCN4A gene, which encodes the α-subunit of Nav1.4 channel, are responsible for PMC. Mutation [...] Read more.
Paramyotonia congenita (PMC) is a rare hereditary skeletal muscle disorder. The major symptom, muscle stiffness, is frequently induced by cold exposure and repetitive exercise. Mutations in human SCN4A gene, which encodes the α-subunit of Nav1.4 channel, are responsible for PMC. Mutation screening of SCN4A gene from two PMC families identified two missense mutations, p.T1313M and p.R1448H. To elucidate the electrophysiological abnormalities caused by the mutations, the p.T1313M, p.R1448H, and wild-type (WT) SCN4A genes were transient expressed on Chinese hamster ovary (CHO-K1) cells. The detailed study on the gating defects of the mutant channels using the whole-cell patch clamping technique was performed. The mutant Nav1.4 channels impaired the basic gating properties with increasing sustained and window currents during membrane depolarization and facilitated the genesis of resurgent currents during repolarization. The mutations caused a hyperpolarization shift in the fast inactivation and slightly enhanced the slow inactivation with an increase in half-maximal inactivation voltage. No differences were found in the decay kinetics of the tail current between mutant and WT channels. In addition to generating the larger resurgent sodium current, the time to peak in the mutant channels was longer than that in the WT channels. In conclusion, our results demonstrated that the mutations p.T1313M and p.R1448H in Nav1.4 channels can enhance fast inactivation, slow inactivation, and resurgent current, revealing that subtle changes in gating processes can influence the clinical phenotype. Full article
(This article belongs to the Special Issue Neuropathic Pain: Therapy and Mechanisms)
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Review

Jump to: Research

14 pages, 748 KiB  
Review
A Review of the Clinical and Therapeutic Implications of Neuropathic Pain
by Eleonora Balzani, Andrea Fanelli, Valentina Malafoglia, Michael Tenti, Sara Ilari, Annette Corraro, Carolina Muscoli and William Raffaeli
Biomedicines 2021, 9(9), 1239; https://doi.org/10.3390/biomedicines9091239 - 16 Sep 2021
Cited by 13 | Viewed by 2734
Abstract
Understanding neuropathic pain presents several challenges, given the various mechanisms underlying its pathophysiological classification and the lack of suitable tools to assess its diagnosis. Furthermore, the response of this pathology to available drugs is still often unpredictable, leaving the treatment of neuropathic pain [...] Read more.
Understanding neuropathic pain presents several challenges, given the various mechanisms underlying its pathophysiological classification and the lack of suitable tools to assess its diagnosis. Furthermore, the response of this pathology to available drugs is still often unpredictable, leaving the treatment of neuropathic pain still questionable. In addition, the rise of personalized treatments further extends the ramified classification of neuropathic pain. While a few authors have focused on neuropathic pain clustering, by analyzing, for example, the presence of specific TRP channels, others have evaluated the presence of alterations in microRNAs to find tailored therapies. Thus, this review aims to synthesize the available evidence on the topic from a clinical perspective and provide a list of current demonstrations on the treatment of this disease. Full article
(This article belongs to the Special Issue Neuropathic Pain: Therapy and Mechanisms)
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14 pages, 1104 KiB  
Review
Melatonin Moderates the Triangle of Chronic Pain, Sleep Architecture and Immunometabolic Traffic
by Shafqat R. Chaudhry, Andreas Stadlbauer, Michael Buchfelder and Thomas M. Kinfe
Biomedicines 2021, 9(8), 984; https://doi.org/10.3390/biomedicines9080984 - 09 Aug 2021
Cited by 7 | Viewed by 7499
Abstract
Preclinical as well as human studies indicate that melatonin is essential for a physiological sleep state, promotes analgesia and is involved in immunometabolic signaling by regulating neuroinflammatory pathways. Experimental and clinical neuromodulation studies for chronic pain treatment suggest that neurostimulation therapies such as [...] Read more.
Preclinical as well as human studies indicate that melatonin is essential for a physiological sleep state, promotes analgesia and is involved in immunometabolic signaling by regulating neuroinflammatory pathways. Experimental and clinical neuromodulation studies for chronic pain treatment suggest that neurostimulation therapies such as spinal cord stimulation, vagus nerve stimulation and dorsal root ganglion stimulation have an impact on circulating inflammatory mediators in blood, cerebrospinal fluid and saliva. Herein, we provide an overview of current literature relevant for the shared pathways of sleep, pain and immunometabolism and elaborate the impact of melatonin on the crossroad of sleep, chronic pain and immunometabolism. Furthermore, we discuss the potential of melatonin as an adjunct to neurostimulation therapies. In this narrative review, we addressed these questions using the following search terms: melatonin, sleep, immunometabolism, obesity, chronic pain, neuromodulation, neurostimulation, neuroinflammation, molecular inflammatory phenotyping. So far, the majority of the published literature is derived from experimental studies and studies specifically assessing these relationships in context to neurostimulation are sparse. Thus, the adjunct potential of melatonin in clinical neurostimulation has not been evaluated under the umbrella of randomized-controlled trials and deserves increased attention as melatonin interacts and shares pathways relevant for noninvasive and invasive neurostimulation therapies. Full article
(This article belongs to the Special Issue Neuropathic Pain: Therapy and Mechanisms)
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17 pages, 723 KiB  
Review
Involvement of Serotonergic System in Oxaliplatin-Induced Neuropathic Pain
by Ji Hwan Lee and Woojin Kim
Biomedicines 2021, 9(8), 970; https://doi.org/10.3390/biomedicines9080970 - 06 Aug 2021
Cited by 8 | Viewed by 2292
Abstract
Oxaliplatin is a chemotherapeutic agent widely used against colorectal and breast cancers; however, it can also induce peripheral neuropathy that can rapidly occur even after a single infusion in up to 80–90% of treated patients. Numerous efforts have been made to understand the [...] Read more.
Oxaliplatin is a chemotherapeutic agent widely used against colorectal and breast cancers; however, it can also induce peripheral neuropathy that can rapidly occur even after a single infusion in up to 80–90% of treated patients. Numerous efforts have been made to understand the underlying mechanism and find an effective therapeutic agent that could diminish pain without damaging its anti-tumor effect. However, its mechanism is not yet clearly understood. The serotonergic system, as part of the descending pain inhibitory system, has been reported to be involved in different types of pain. The malfunction of serotonin (5-hydroxytryptamine; 5-HT) or its receptors has been associated with the development and maintenance of pain. However, its role in oxaliplatin-induced neuropathy has not been clearly elucidated. In this review, 16 in vivo studies focused on the role of the serotonergic system in oxaliplatin-induced neuropathic pain were analyzed. Five studies analyzed the involvement of 5-HT, while fourteen studies observed the role of its receptors in oxaliplatin-induced allodynia. The results show that 5-HT is not involved in the development of oxaliplatin-induced allodynia, but increasing the activity of the 5-HT1A, 5-HT2A, and 5-HT3 receptors and decreasing the action of 5-HT2C and 5-HT6 receptors may help inhibit pain. Full article
(This article belongs to the Special Issue Neuropathic Pain: Therapy and Mechanisms)
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12 pages, 655 KiB  
Review
Nutritional Supplements for the Treatment of Neuropathic Pain
by Khaled M. Abdelrahman and Kevin V. Hackshaw
Biomedicines 2021, 9(6), 674; https://doi.org/10.3390/biomedicines9060674 - 13 Jun 2021
Cited by 14 | Viewed by 6626
Abstract
Neuropathic pain affects 7–10% of the population and is often ineffectively and incompletely treated. Although the gold standard for treatment of neuropathic pain includes tricyclic antidepressants (TCAs), serotonin-noradrenaline reuptake inhibitors, and anticonvulsants, patients suffering from neuropathic pain are increasingly turning to nonpharmacologic treatments, [...] Read more.
Neuropathic pain affects 7–10% of the population and is often ineffectively and incompletely treated. Although the gold standard for treatment of neuropathic pain includes tricyclic antidepressants (TCAs), serotonin-noradrenaline reuptake inhibitors, and anticonvulsants, patients suffering from neuropathic pain are increasingly turning to nonpharmacologic treatments, including nutritional supplements for analgesia. So-called “nutraceuticals” have garnered significant interest among patients seeking to self-treat their neuropathic pain with readily available supplements. The supplements most often used by patients include vitamins such as vitamin B and vitamin D, trace minerals zinc and magnesium, and herbal remedies such as curcumin and St. John’s Wort. However, evidence surrounding the efficacy and mechanisms of these supplements in neuropathic pain is limited, and the scientific literature consists primarily of preclinical animal models, case studies, and small randomized controlled trials (RCTs). Further exploration into large randomized controlled trials is needed to fully inform patients and physicians on the utility of these supplements in neuropathic pain. In this review, we explore the basis behind using several nutritional supplements commonly used by patients with neuropathic pain seen in rheumatology clinics. Full article
(This article belongs to the Special Issue Neuropathic Pain: Therapy and Mechanisms)
15 pages, 331 KiB  
Review
Management of Chronic and Neuropathic Pain with 10 kHz Spinal Cord Stimulation Technology: Summary of Findings from Preclinical and Clinical Studies
by Vinicius Tieppo Francio, Keith F. Polston, Micheal T. Murphy, Jonathan M. Hagedorn and Dawood Sayed
Biomedicines 2021, 9(6), 644; https://doi.org/10.3390/biomedicines9060644 - 04 Jun 2021
Cited by 26 | Viewed by 4173
Abstract
Since the inception of spinal cord stimulation (SCS) in 1967, the technology has evolved dramatically with important advancements in waveforms and frequencies. One such advancement is Nevro’s Senza® SCS System for HF10, which received Food and Drug and Administration (FDA) approval in [...] Read more.
Since the inception of spinal cord stimulation (SCS) in 1967, the technology has evolved dramatically with important advancements in waveforms and frequencies. One such advancement is Nevro’s Senza® SCS System for HF10, which received Food and Drug and Administration (FDA) approval in 2015. Low-frequency SCS works by activating large-diameter Aβ fibers in the lateral discriminatory pathway (pain location, intensity, quality) at the dorsal column (DC), creating paresthesia-based stimulation at lower-frequencies (30–120 Hz), high-amplitude (3.5–8.5 mA), and longer-duration/pulse-width (100–500 μs). In contrast, high-frequency 10 kHz SCS works with a proposed different mechanism of action that is paresthesia-free with programming at a frequency of 10,000 Hz, low amplitude (1–5 mA), and short-duration/pulse-width (30 μS). This stimulation pattern selectively activates inhibitory interneurons in the dorsal horn (DH) at low stimulation intensities, which do not activate the dorsal column fibers. This ostensibly leads to suppression of hyperexcitable wide dynamic range neurons (WDR), which are sensitized and hyperactive in chronic pain states. It has also been reported to act on the medial pathway (drives attention and pain perception), in addition to the lateral pathways. Other theories include a reversible depolarization blockade, desynchronization of neural signals, membrane integration, glial–neuronal interaction, and induced temporal summation. The body of clinical evidence regarding 10 kHz SCS treatment for chronic back pain and neuropathic pain continues to grow. There is high-quality evidence supporting its use in patients with persistent back and radicular pain, particularly after spinal surgery. High-frequency 10 kHz SCS studies have demonstrated robust statistically and clinically significant superiority in pain control, compared to paresthesia-based SCS, supported by level I clinical evidence. Yet, as the field continues to grow with the technological advancements of multiple waveforms and programming stimulation algorithms, we encourage further research to focus on the ability to modulate pain with precision and efficacy, as the field of neuromodulation continues to adapt to the modern healthcare era. Full article
(This article belongs to the Special Issue Neuropathic Pain: Therapy and Mechanisms)
17 pages, 600 KiB  
Review
Neural Plasticity in the Brain during Neuropathic Pain
by Myeong Seong Bak, Haney Park and Sun Kwang Kim
Biomedicines 2021, 9(6), 624; https://doi.org/10.3390/biomedicines9060624 - 31 May 2021
Cited by 22 | Viewed by 5639
Abstract
Neuropathic pain is an intractable chronic pain, caused by damage to the somatosensory nervous system. To date, treatment for neuropathic pain has limited effects. For the development of efficient therapeutic methods, it is essential to fully understand the pathological mechanisms of neuropathic pain. [...] Read more.
Neuropathic pain is an intractable chronic pain, caused by damage to the somatosensory nervous system. To date, treatment for neuropathic pain has limited effects. For the development of efficient therapeutic methods, it is essential to fully understand the pathological mechanisms of neuropathic pain. Besides abnormal sensitization in the periphery and spinal cord, accumulating evidence suggests that neural plasticity in the brain is also critical for the development and maintenance of this pain. Recent technological advances in the measurement and manipulation of neuronal activity allow us to understand maladaptive plastic changes in the brain during neuropathic pain more precisely and modulate brain activity to reverse pain states at the preclinical and clinical levels. In this review paper, we discuss the current understanding of pathological neural plasticity in the four pain-related brain areas: the primary somatosensory cortex, the anterior cingulate cortex, the periaqueductal gray, and the basal ganglia. We also discuss potential treatments for neuropathic pain based on the modulation of neural plasticity in these brain areas. Full article
(This article belongs to the Special Issue Neuropathic Pain: Therapy and Mechanisms)
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18 pages, 266 KiB  
Review
Treatment of Painful Diabetic Neuropathy—A Narrative Review of Pharmacological and Interventional Approaches
by Mayank Gupta, Nebojsa Nick Knezevic, Alaa Abd-Elsayed, Mahoua Ray, Kiran Patel and Bhavika Chowdhury
Biomedicines 2021, 9(5), 573; https://doi.org/10.3390/biomedicines9050573 - 19 May 2021
Cited by 27 | Viewed by 5679
Abstract
Painful diabetic neuropathy (PDN) is a common complication of diabetes mellitus that is associated with a significant decline in quality of life. Like other painful neuropathic conditions, PDN is difficult to manage clinically, and a variety of pharmacological and non-pharmacological options are available [...] Read more.
Painful diabetic neuropathy (PDN) is a common complication of diabetes mellitus that is associated with a significant decline in quality of life. Like other painful neuropathic conditions, PDN is difficult to manage clinically, and a variety of pharmacological and non-pharmacological options are available for this condition. Recommended pharmacotherapies include anticonvulsive agents, antidepressant drugs, and topical capsaicin; and tapentadol, which combines opioid agonism and norepinephrine reuptake inhibition, has also recently been approved for use. Additionally, several neuromodulation therapies have been successfully used for pain relief in PDN, including intrathecal therapy, transcutaneous electrical nerve stimulation (TENS), and spinal cord stimulation (SCS). Recently, 10 kHz SCS has been shown to provide clinically meaningful pain relief for patients refractory to conventional medical management, with a subset of patients demonstrating improvement in neurological function. This literature review is intended to discuss the dosage and prospective data associated with pain management therapies for PDN. Full article
(This article belongs to the Special Issue Neuropathic Pain: Therapy and Mechanisms)
18 pages, 2535 KiB  
Review
Emerging Role of C5 Complement Pathway in Peripheral Neuropathies: Current Treatments and Future Perspectives
by Cristina Giorgio, Mara Zippoli, Pasquale Cocchiaro, Vanessa Castelli, Giustino Varrassi, Andrea Aramini, Marcello Allegretti, Laura Brandolini and Maria Candida Cesta
Biomedicines 2021, 9(4), 399; https://doi.org/10.3390/biomedicines9040399 - 07 Apr 2021
Cited by 17 | Viewed by 6970
Abstract
The complement system is a key component of innate immunity since it plays a critical role in inflammation and defense against common pathogens. However, an inappropriate activation of the complement system is involved in numerous disorders, including peripheral neuropathies. Current strategies for neuropathy-related [...] Read more.
The complement system is a key component of innate immunity since it plays a critical role in inflammation and defense against common pathogens. However, an inappropriate activation of the complement system is involved in numerous disorders, including peripheral neuropathies. Current strategies for neuropathy-related pain fail to achieve adequate pain relief, and although several therapies are used to alleviate symptoms, approved disease-modifying treatments are unavailable. This urgent medical need is driving the development of therapeutic agents for this condition, and special emphasis is given to complement-targeting approaches. Recent evidence has underscored the importance of complement component C5a and its receptor C5aR1 in inflammatory and neuropathic pain, indicating that C5a/C5aR1 axis activation triggers a cascade of events involved in pathophysiology of peripheral neuropathy and painful neuro-inflammatory states. However, the underlying pathophysiological mechanisms of this signaling in peripheral neuropathy are not fully known. Here, we provide an overview of complement pathways and major components associated with dysregulated complement activation in peripheral neuropathy, and of drugs under development targeting the C5 system. C5/C5aR1 axis modulators could represent a new strategy to treat complement-related peripheral neuropathies. Specifically, we describe novel C5aR allosteric modulators, which may potentially become new tools in the therapeutic armory against neuropathic pain. Full article
(This article belongs to the Special Issue Neuropathic Pain: Therapy and Mechanisms)
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21 pages, 470 KiB  
Review
Efficacy and Safety of 10 kHz Spinal Cord Stimulation for the Treatment of Chronic Pain: A Systematic Review and Narrative Synthesis of Real-World Retrospective Studies
by Ganesan Baranidharan, Deborah Edgar, Beatrice Bretherton, Tracey Crowther, Abdul-Ghaaliq Lalkhen, Ann-Katrin Fritz and Girish Vajramani
Biomedicines 2021, 9(2), 180; https://doi.org/10.3390/biomedicines9020180 - 11 Feb 2021
Cited by 16 | Viewed by 3496
Abstract
10 kHz spinal cord stimulation (SCS) is increasingly utilized globally to treat chronic pain syndromes. Real-world evidence complementing randomized controlled trials supporting its use, has accumulated over the last decade. This systematic review aims to summarize the retrospective literature with reference to the [...] Read more.
10 kHz spinal cord stimulation (SCS) is increasingly utilized globally to treat chronic pain syndromes. Real-world evidence complementing randomized controlled trials supporting its use, has accumulated over the last decade. This systematic review aims to summarize the retrospective literature with reference to the efficacy and safety of 10 kHz SCS. We performed a systematic literature search of PubMed between 1 January 2009 and 21 August 2020 for English-language retrospective studies of ≥3 human subjects implanted with a Senza® 10 kHz SCS system and followed-up for ≥3 months. Two independent reviewers screened titles/abstracts of 327 studies and 46 full-text manuscripts. In total, 16 articles were eligible for inclusion; 15 reported effectiveness outcomes and 11 presented safety outcomes. Follow-up duration ranged from 6–34 months. Mean pain relief was >50% in most studies, regardless of follow-up duration. Responder rates ranged from 67–100% at ≤12 months follow-up, and from 46–76% thereafter. 32–71% of patients decreased opioid or nonopioid analgesia intake. Complication incidence rates were consistent with other published SCS literature. Findings suggest 10 kHz SCS provides safe and durable pain relief in pragmatic populations of chronic pain patients. Furthermore, it may decrease opioid requirements, highlighting the key role 10 kHz SCS can play in the medium-term management of chronic pain. Full article
(This article belongs to the Special Issue Neuropathic Pain: Therapy and Mechanisms)
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12 pages, 840 KiB  
Review
The Role of Corticotropin-Releasing Hormone at Peripheral Nociceptors: Implications for Pain Modulation
by Haiyan Zheng, Ji Yeon Lim, Jae Young Seong and Sun Wook Hwang
Biomedicines 2020, 8(12), 623; https://doi.org/10.3390/biomedicines8120623 - 17 Dec 2020
Cited by 9 | Viewed by 5398
Abstract
Peripheral nociceptors and their synaptic partners utilize neuropeptides for signal transmission. Such communication tunes the excitatory and inhibitory function of nociceptor-based circuits, eventually contributing to pain modulation. Corticotropin-releasing hormone (CRH) is the initiator hormone for the conventional hypothalamic-pituitary-adrenal axis, preparing our body for [...] Read more.
Peripheral nociceptors and their synaptic partners utilize neuropeptides for signal transmission. Such communication tunes the excitatory and inhibitory function of nociceptor-based circuits, eventually contributing to pain modulation. Corticotropin-releasing hormone (CRH) is the initiator hormone for the conventional hypothalamic-pituitary-adrenal axis, preparing our body for stress insults. Although knowledge of the expression and functional profiles of CRH and its receptors and the outcomes of their interactions has been actively accumulating for many brain regions, those for nociceptors are still under gradual investigation. Currently, based on the evidence of their expressions in nociceptors and their neighboring components, several hypotheses for possible pain modulations are emerging. Here we overview the historical attention to CRH and its receptors on the peripheral nociception and the recent increases in information regarding their roles in tuning pain signals. We also briefly contemplate the possibility that the stress-response paradigm can be locally intrapolated into intercellular communication that is driven by nociceptor neurons. Such endeavors may contribute to a more precise view of local peptidergic mechanisms of peripheral pain modulation. Full article
(This article belongs to the Special Issue Neuropathic Pain: Therapy and Mechanisms)
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