Advances in Study of Molecular and Cellular Mechanisms Underlying Pain and Itch

A special issue of Brain Sciences (ISSN 2076-3425). This special issue belongs to the section "Neural Control of Peripheral Function".

Deadline for manuscript submissions: closed (25 April 2023) | Viewed by 17468

Special Issue Editors

1. Department of Anesthesiology, Tianjin Medical University, Tianjin, China
2. Department of Anesthesiology, Tianjin Medical University General Hospital, Tianjin, China
Interests: inflammatory pain; neuropathic pain; bone cancer pain; fracture-associated pain; opi-oid-induced hyperalgesia; chemotherapy-induced peripheral neuropathy; acute itch; chronic itch; neuroinflammation; oxidative stress
Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Southern Medical University, Guangzhou, China
Interests: neuroimmune regulation of chronic pain; sex dimorphism in chronic pain; chemothera-py-induced neuropathic pain; central sensitization of the itch circuitry

Special Issue Information

Dear Colleagues,

Pain and itch are distinct peripheral sensory modalities. Whereas pain leads to withdrawal responses following noxious stimulation, itch (pruritus) leads to scratching. The treatment of pain and itch continues to be a major clinical challenge. Accumulating evidence emphasizes that neuroinflammation and oxidative insult drive the peripheral and central sensitization of nociceptive and itch circuitry, which governs multiple pain and itch perceptions after peripheral inflammation, nerve injury, chemotherapy and cancer. The specific molecular and cellular mechanisms underlying pain and itch development remain unclear and have attracted considerable attention.

The overall aim of this Special Issue is to share and discuss recent achievements to understand and/or augment the neuroinflammatory and neural circuits underlying the peripheral and central sensitization in pain and itch with different etiologies.

Although females are highly over-represented among patients with clinical pain syndromes, the majority of laboratory investigations in pain medicine have been conducted in male animals. Our Special Issue also aims to summarize the most recent insights into the pathogenesis of pain in females, to help inform clinical practice and to design new research addressing unanswered questions.

Original research and review papers covering topics ranging from basic to translational or clinical research in this field are encouraged.

Dr. Linlin Zhang
Prof. Dr. Xin Luo
Guest Editors

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Keywords

  • pain mechanism
  • itch pathogenesis
  • neuroinflammation
  • oxidative stress
  • peripheral sensitization
  • central sensitization
  • excitatory glutamate receptor
  • postsynaptic modulation
  • synaptic plasticity

Published Papers (8 papers)

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Research

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10 pages, 1739 KiB  
Article
Association between PDE4D rs966221 and the Risk of Ischemic Stroke in Regional Chinese Populations
by Chunyang Wang, Fenghe Zhang, Xiaojing Zhang, Chao Zhang and He Li
Brain Sci. 2023, 13(7), 1038; https://doi.org/10.3390/brainsci13071038 - 07 Jul 2023
Viewed by 705
Abstract
In published research that includes genome-wide association studies and meta-analyses, the phosphodiesterase 4D (PDE4D) rs966221 variant has been identified as a risk factor in ischemic stroke (IS) in the Caucasian population. Several studies have investigated the relationship between rs966221 and IS susceptibility in [...] Read more.
In published research that includes genome-wide association studies and meta-analyses, the phosphodiesterase 4D (PDE4D) rs966221 variant has been identified as a risk factor in ischemic stroke (IS) in the Caucasian population. Several studies have investigated the relationship between rs966221 and IS susceptibility in Chinese populations over the years but have not provided consistently conclusive results. Therefore, our team performed a new meta-analysis of 5973 IS patients and 6204 controls from qualified studies. We observed no significant link between the PDE4D rs966221 variant and IS in any of the regional Chinese populations. Thus, we performed a subgroup analysis by the geographical distribution of China. Notably, significant associations were observed between rs96622 and the susceptibility of IS in the Northeast Chinese populations (p = 1.00 × 10−4, odds ratio = 1.28, and 95% confidence interval = 1.13–1.44, I2 = 0%). However, rs966221 was not found to be correlated with IS risk in the populations of North, Central, South, and East China. Our meta-analysis demonstrated that the PDE4D rs966221 variant is significantly associated with IS risk in some regional Chinese populations. Full article
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16 pages, 3227 KiB  
Article
Glabridin Therapy Reduces Chronic Allodynia, Spinal Microgliosis, and Dendritic Spine Generation by Inhibiting Fractalkine-CX3CR1 Signaling in a Mouse Model of Tibial Fractures
by Juan Long, Hongbing Liu, Zhimin Qiu, Zhong Xiao and Zhongqiu Lu
Brain Sci. 2023, 13(5), 739; https://doi.org/10.3390/brainsci13050739 - 29 Apr 2023
Cited by 1 | Viewed by 1213
Abstract
Patients undergoing bone fractures frequently suffer from irritating chronic pain after orthopedic repairs. Chemokine-mediated interactions between neurons and microglia are important steps for neuroinflammation and excitatory synaptic plasticity during the spinal transmission of pathological pain. Recently, glabridin, the main bioactive component of licorice, [...] Read more.
Patients undergoing bone fractures frequently suffer from irritating chronic pain after orthopedic repairs. Chemokine-mediated interactions between neurons and microglia are important steps for neuroinflammation and excitatory synaptic plasticity during the spinal transmission of pathological pain. Recently, glabridin, the main bioactive component of licorice, has been shown to exhibit anti-nociceptive and neuroprotective properties for inflammatory pain. This present study evaluated the therapeutic potential of glabridin and its analgesic mechanisms using a mouse model of tibial fracture-associated chronic pain. Repetitive injections of glabridin were delivered spinally daily for 4 continuous days from days 3 to 6 after the fractures. Herein, we discovered that repeated administrations of glabridin (10 and 50 μg, but not 1 μg) could prevent prolonged cold allodynia and mechanical allodynia following bone fractures. A single intrathecal intervention with glabridin (50 μg) relieved an existing chronic allodynia two weeks following the fracture surgeries. Systemic therapies with glabridin (intraperitoneal; 50 mg kg−1) were protective against long-lasting allodynia caused by fractures. Furthermore, glabridin restricted the fracture-caused spinal overexpressions of the chemokine fractalkine and its receptor CX3CR1, as well as the elevated number of microglial cells and dendritic spines. Strikingly, glabridin induced the inhibition of pain behaviors, microgliosis, and spine generation, which were abolished with the co-administration of exogenous fractalkine. Meanwhile, the exogenous fractalkine-evoked acute pain was compensated after microglia inhibition. Additionally, spinal neutralization of fractalkine/CX3CR1 signaling alleviated the intensity of postoperative allodynia after tibial fractures. These key findings identify that glabridin therapies confer protection against inducing and sustaining fracture-elicited chronic allodynia by suppressing fractalkine/CX3CR1-dependent spinal microgliosis and spine morphogenesis, suggesting that glabridin is a promising candidate in the translational development of chronic fracture pain control. Full article
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15 pages, 3068 KiB  
Article
Resolvin D2 Reduces Chronic Neuropathic Pain and Bone Cancer Pain via Spinal Inhibition of IL-17 Secretion, CXCL1 Release and Astrocyte Activation in Mice
by Jun Pang, Pengfei Xin, Ying Kong, Zhe Wang and Xiaopeng Wang
Brain Sci. 2023, 13(1), 152; https://doi.org/10.3390/brainsci13010152 - 15 Jan 2023
Cited by 5 | Viewed by 1932
Abstract
Chronic pain burdens patients and healthcare systems worldwide. Pain control remains urgently required. IL-17 (interleukin-17)-mediated neuroinflammation is of unique importance in spinal nociceptive transduction in pathological pain development. Recently, resolvin D2 (RvD2), as a bioactive, specialized pro-resolving mediator derived from docosahexaenoic acid, exhibits [...] Read more.
Chronic pain burdens patients and healthcare systems worldwide. Pain control remains urgently required. IL-17 (interleukin-17)-mediated neuroinflammation is of unique importance in spinal nociceptive transduction in pathological pain development. Recently, resolvin D2 (RvD2), as a bioactive, specialized pro-resolving mediator derived from docosahexaenoic acid, exhibits potent resolution of inflammation in several neurological disorders. This preclinical study evaluates the therapeutic potential and underlying targets of RvD2 in two mouse models of chronic pain, including sciatic nerve ligation-caused neuropathic pain and sarcoma-caused bone cancer pain. Herein, we report that repetitive injections of RvD2 (intrathecal, 500 ng) reduce the initiation of mechanical allodynia and heat hyperalgesia following sciatic nerve damage and bone cancer. Single exposure to RvD2 (intrathecal, 500 ng) attenuates the established neuropathic pain and bone cancer pain. Furthermore, systemic RvD2 (intravenous, 5 μg) therapy is effective in attenuating chronic pain behaviors. Strikingly, RvD2 treatment suppresses spinal IL-17 overexpression, chemokine CXCL1 release and astrocyte activation in mice undergoing sciatic nerve trauma and bone cancer. Pharmacological neutralization of IL-17 ameliorates chronic neuropathic pain and persistent bone cancer pain, as well as reducing spinal CXCL1 release. Recombinant IL-17-evoked acute pain behaviors and spinal CXCL1 release are mitigated after RvD2 administration. In addition, RvD2 treatment dampens exogenous CXCL1-caused transient pain phenotypes. Overall, these current findings identify that RvD2 therapy is effective against the initiation and persistence of long-lasting neuropathic pain and bone cancer pain, which may be through spinal down-modulation of IL-17 secretion, CXCL1 release and astrocyte activation. Full article
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11 pages, 579 KiB  
Article
Multimodal Analgesia for Accelerated Rehabilitation after Total Knee Arthroplasty: A Randomized, Double-Blind, Controlled Trial on the Effect of the Co-Application of Local Infiltration Analgesia and Femoral Nerve Block Combined with Dexmedetomidine
by Chen Gao, Tingting Huang, Kerong Wu, Wei Zhang, Sheng Wang, Xiaoqing Chai, Yanhu Xie and Chaoliang Tang
Brain Sci. 2022, 12(12), 1652; https://doi.org/10.3390/brainsci12121652 - 02 Dec 2022
Cited by 6 | Viewed by 1336
Abstract
Background: Multimodal postoperative pain regimens are widely used following total knee arthroplasty (TKA). However, there are few studies on the rehabilitation of the co-application of local infiltration analgesia (LIA) and femoral nerve block (FNB) combined with dexmedetomidine (DEX) for patients undergoing TKA. This [...] Read more.
Background: Multimodal postoperative pain regimens are widely used following total knee arthroplasty (TKA). However, there are few studies on the rehabilitation of the co-application of local infiltration analgesia (LIA) and femoral nerve block (FNB) combined with dexmedetomidine (DEX) for patients undergoing TKA. This study aimed to investigate the effect of LIA plus FNB and co-application of perioperative DEX on TKA outcomes. Methods: 95 patients were randomized into two groups. Patients in group B (n = 48) received a single preoperative FNB and LIA. Patients in group A (n = 47) received FNB and LIA, as well as continuous intravenous injection of DEX starting from the induction of anesthesia to postoperative day 2. All patients were allowed patient-controlled analgesia postoperatively. Visual analog scale (VAS) scores, knee range of motion (ROM) degrees, narcotic consumption, length of hospital stay (LOS), complications, Hospital for Special Surgery (HSS) scores and Montreal Cognitive Assessment-Basic (MoCA-B) Scores were recorded. Results: In group A, the mean VAS scores at rest and during movement were lower, the amount of rescue analgesia was decreased, first time of ambulation was reduced, ROM was improved, MoCA-B Scores were increased, LOS was shorter, HSS scores were higher postoperatively compared with group B (all p < 0.05). Conclusion: Our study indicated multimodal analgesia involving a single FNB and LIA combined with DEX accelerates rehabilitation for patients undergoing TKA. Full article
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14 pages, 2282 KiB  
Article
Hydrogen-Rich Saline Attenuates Chronic Allodynia after Bone Fractures via Reducing Spinal CXCL1/CXCR2-Mediated Iron Accumulation in Mice
by Yanting Wang, Pei Wang, Cuicui Liu, Wei Chen, Pingping Wang and Lili Jiang
Brain Sci. 2022, 12(12), 1610; https://doi.org/10.3390/brainsci12121610 - 24 Nov 2022
Cited by 1 | Viewed by 1091
Abstract
Purpose: Neuroinflammation often initiates iron overload in the pathogenesis of neurological disorders. Chemokine-driven neuroinflammation is required for central sensitization and chronic allodynia following fractures, but specific molecular modulations are elusive. This present study explored whether hydrogen-rich saline, as one potent anti-inflammatory pharmaceutical, could [...] Read more.
Purpose: Neuroinflammation often initiates iron overload in the pathogenesis of neurological disorders. Chemokine-driven neuroinflammation is required for central sensitization and chronic allodynia following fractures, but specific molecular modulations are elusive. This present study explored whether hydrogen-rich saline, as one potent anti-inflammatory pharmaceutical, could alleviate fracture-caused allodynia by suppressing chemokine CXCL1 expression and iron overload. Methods: A mouse model of tibial fracture with intramedullary pinning was employed for establishing chronic allodynia. Three applications of hydrogen-rich saline (1, 5 or 10 mL/kg) were administrated intraperitoneally on a daily basis from days 4 to 6 following fractures. Spinal CXCL1 and its receptor CXCR2 levels, transferrin receptor 1 (TfR1) expression and iron concentration were examined. Recombinant CXCL1, a selective CXCR2 antagonist and an iron chelator were used for verification of mechanisms. Results: Repetitive injections of hydrogen-rich saline (5 and 10 mL/kg but not 1 mL/kg) prevent fracture-caused mechanical allodynia and cold allodynia in a dose-dependent manner. Single exposure to hydrogen-rich saline (10 mL/kg) on day 14 after orthopedic surgeries controls the established persistent fracture allodynia. Furthermore, hydrogen-rich saline therapy reduces spinal CXCL1/CXCR2 over-expression and TfR1-mediated iron accumulation in fracture mice. Spinal CXCR2 antagonism impairs allodynia and iron overload following fracture surgery. Intrathecal delivery of recombinant CXCL1 induces acute allodynia and spinal iron overload, which is reversed by hydrogen-rich saline. Moreover, iron chelation alleviates exogenous CXCL1-induced acute pain behaviors. Conclusions: These findings identify that hydrogen-rich saline confers protection against fracture-caused chronic allodynia via spinal down-modulation of CXCL1-dependent TfR1-mediated iron accumulation in mice. Full article
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12 pages, 3845 KiB  
Article
Pentraxin-3 in the Spinal Dorsal Horn Upregulates Nectin-1 Expression in Neuropathic Pain after Spinal Nerve Damage in Male Mice
by Min Zhu, Hongli Yu, Ying Sun and Wenli Yu
Brain Sci. 2022, 12(5), 648; https://doi.org/10.3390/brainsci12050648 - 15 May 2022
Viewed by 1698
Abstract
Purpose: Neuropathic pain often originates from nerve injury or diseases of the somatosensory nervous system. However, its specific pathogenesis remains unclear. The requirement for excitatory synaptic plasticity in pain-related syndromes has been demonstrated. A recent study reported that pentraxin-3 is important in glutamatergic [...] Read more.
Purpose: Neuropathic pain often originates from nerve injury or diseases of the somatosensory nervous system. However, its specific pathogenesis remains unclear. The requirement for excitatory synaptic plasticity in pain-related syndromes has been demonstrated. A recent study reported that pentraxin-3 is important in glutamatergic synaptic formation and function. Meanwhile, nectin-1 mediates synaptogenesis in neurological disorders. The present study aimed to evaluate whether pentraxin-3 and nectin-1 modulate spinal nerve damage-related neuropathic pain in male mice. Methods: L4 spinal nerve ligation (SNL) in male mice was performed to induce experimental neuropathic pain. Mechanical allodynia and heat hyperalgesia following SNL were based on paw withdrawal (PW) threshold and PW latency, respectively. Spinal pentraxin-3 levels and nectin-1 expression following SNL were examined. Pentraxin-3 and nectin-1 knockdown models were established by the shRNA method. These models were used with a recombinant pentraxin-3 cell model to investigate the underlying mechanisms of SNL. Results: The SNL operation generated persistent decreases in mechanical PW threshold and thermal PW latency, with subsequent long-lasting elevations in spinal pentraxin-3 and nectin-1 expression levels. Pentraxin-3 knockdown reduced SNL-associated neuropathic pain behaviors as well as nectin-1 amounts in the spinal dorsal horn. Nectin-1 deficiency impaired mechanical allodynia and thermal hyperalgesia following spinal nerve injury. The application of recombinant pentraxin-3 in the spinal cord triggered an acute nociception phenotype and induced spinal overexpression of nectin-1. The intrathecal knockdown of nectin-1 prevented exogenous pentraxin-3-evoked pain hypersensitivity. Conclusions: The findings suggest spinal pentraxin-3 is required for SNL-triggered neuropathic pain via nectin-1 upregulation in male mice. Full article
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11 pages, 1350 KiB  
Article
The Efficacy of an Ultrasound-Guided Improved Puncture Path Technique of Nerve Block/Pulsed Radiofrequency for Pudendal Neuralgia: A Retrospective Study
by Dan Zhu, Zhenzhen Fan, Fujun Cheng, Yuping Li, Xingyue Huo and Jian Cui
Brain Sci. 2022, 12(4), 510; https://doi.org/10.3390/brainsci12040510 - 18 Apr 2022
Cited by 1 | Viewed by 3783
Abstract
Objectives: To investigate the efficacy and safety of an improved ultrasound-guided pulsed radiofrequency (PRF) and nerve block (NB) for patients with pudendal neuralgia (PN). Methods: This retrospective analysis included 88 adults with PN treated in the Pain Department of Southwest Hospital from November [...] Read more.
Objectives: To investigate the efficacy and safety of an improved ultrasound-guided pulsed radiofrequency (PRF) and nerve block (NB) for patients with pudendal neuralgia (PN). Methods: This retrospective analysis included 88 adults with PN treated in the Pain Department of Southwest Hospital from November 2011 to June 2021, with treatment including NB (n = 40) and PRF (n = 48). The primary outcome variable was pain severity, measured by a standardized visual analog scale (VAS). VAS values were collected at 1, 3, 7, and 14 days and 1 and 3 months after patients were treated with NB or PRF. Results: Compared with patients treated with NB (n = 40) and those treated with PRF (n = 48), no significant difference in pain reduction was observed in the short term (p = 0.739 and 0.981, at 1 and 3 days, respectively); however, in the medium and long term (1 to 3 months), there were statistically significant improvements in the PRF group over the NB group (p < 0.001). Moreover, it was noted that the average pain severity of primary PN and PN due to sacral perineurial cyst was significantly reduced with PRF therapy in the medium and long term when compared to other secondary PNs, including surgery, trauma, and diabetes. Discussion: The ultrasound-guided, improved, and innovative PRF/NB puncture path technique allows for gentler stimulation and faster identification of the pudendal nerve. The PRF technique may provide better treatments for primary PN and sacral perineurial cyst causing secondary PN in the medium and long term. Full article
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Review

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20 pages, 1148 KiB  
Review
Chronic Pain after Bone Fracture: Current Insights into Molecular Mechanisms and Therapeutic Strategies
by Yuying Zhao, Haoyue Zhang, Nan Li, Jing Li and Linlin Zhang
Brain Sci. 2022, 12(8), 1056; https://doi.org/10.3390/brainsci12081056 - 09 Aug 2022
Cited by 7 | Viewed by 4426
Abstract
Bone fracture following traumatic injury or due to osteoporosis is characterized by severe pain and motor impairment and is a major cause of global mortality and disability. Fracture pain often originates from mechanical distortion of somatosensory nerve terminals innervating bones and muscles and [...] Read more.
Bone fracture following traumatic injury or due to osteoporosis is characterized by severe pain and motor impairment and is a major cause of global mortality and disability. Fracture pain often originates from mechanical distortion of somatosensory nerve terminals innervating bones and muscles and is maintained by central sensitization. Chronic fracture pain (CFP) after orthopedic repairs is considered one of the most critical contributors to interference with the physical rehabilitation and musculoskeletal functional recovery. Analgesics available for CFP in clinics not only have poor curative potency but also have considerable side effects; therefore, it is important to further explore the pathogenesis of CFP and identify safe and effective therapies. The typical physiopathological characteristics of CFP are a neuroinflammatory response and excitatory synaptic plasticity, but the specific molecular mechanisms involved remain poorly elucidated. Recent progress has deepened our understanding of the emerging properties of chemokine production, proinflammatory mediator secretion, caspase activation, neurotransmitter release, and neuron-glia interaction in initiating and sustaining synaptogenesis, synaptic strength, and signal transduction in central pain sensitization, indicating the possibility of targeting neuroinflammation to prevent and treat CFP. This review summarizes current literature on the excitatory synaptic plasticity, microgliosis, and microglial activation-associated signaling molecules and discusses the unconventional modulation of caspases and stimulator of interferon genes (STING) in the pathophysiology of CFP. We also review the mechanisms of action of analgesics in the clinic and their side effects as well as promising therapeutic candidates (e.g., specialized pro-resolving mediators, a caspase-6 inhibitor, and a STING agonist) for pain relief by the attenuation of neuroinflammation with the aim of better managing patients undergoing CFP in the clinical setting. Full article
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