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Neuro-Plastic Mechanisms of Pain and Addiction

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 March 2022) | Viewed by 28744

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Prof. Dr. Bae Hwan Lee

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Department of Physiology, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul 03722, Republic of Korea
Interests: mechanisms of pain; neural injury; functional recovery; higher order functions of the brain; science of emotion and sensibility
Special Issues, Collections and Topics in MDPI journals

Assoc. Prof. Dr. Hee Young Kim

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Department of Physiology, College of Korean Medicine, Daegu Haany University 136 Sincheondongro, Suseong-gu, Daegu 42158, Korea

Asst. Prof. Dr. Hee Kee Kim

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Department of Pain Medicine, the University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA

Special Issue Information

Dear Colleagues,

Over the last three decades, one of the most significant advancements in pain research is the discovery of neuro-plastic changes in the central nervous system (CNS) in chronic pain conditions. Central sensitization occurs when persistent nociceptive inputs enter the spinal cord. In this situation, the sensitized dorsal horn neurons show lowered stimulus thresholds and respond more vigorously to external stimuli. Central sensitization involves plastic changes and is believed to be the mechanism underlying chronic pain. Although central sensitization is best studied in the spinal cord, similar plastic changes likely occur at multiple sites along the neuraxis, from the periphery to the CNS. In chronic pain caused by nerve injury, these changes occur in both sensory systems and reward systems including the ventral tegmental area, nucleus accumbens, and forebrain areas. The processes resulting in central sensitization seem to be multiple and diverse. They include nociceptive neuronal hyper-excitability leading to hyperalgesia and allodynia.

In addition, changes in membrane receptors will determine changes in drug sensitivity. In the case of chronic pain, pain medications such as opioids are most commonly prescribed and used. However, the repeated administration of pain medications causes patients to experience drug dependence and addiction. Therefore, detailed studies to elucidate the precise mechanisms of central sensitization are required for a more effective addiction management and the development of analgesic treatment schemes with narcotics for chronic pain patients.

The purpose of this Special Issue is to bring together experts from the fields of pain and addiction to investigate the neuro-plastic mechanisms of these conditions. This Special Issue welcomes original research and review papers.

Topics of interest include but are not limited to:

Peripheral or central mechanisms of acute or chronic pain
Peripheral or central mechanisms of various types of addiction
Modulation of pain
Treatment of addiction
Interactions between pain, drug of abuse, and addiction

Prof. Dr. Bae Hwan Lee
Assoc. Prof. Dr. Hee Young Kim
Assoc. Prof. Dr. Hee Kee Kim
Guest Editors

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Keywords

Pain
Addiction
Drug of abuse
Neuro-plastic mechanism
Modulation
Central nervous system
Peripheral nervous system

Published Papers (11 papers)

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Editorial

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4 pages, 188 KiB

Open AccessEditorial

Neuro-Plastic Mechanisms of Pain and Addiction

by Bae Hwan Lee, Hee Young Kim and Hee Kee Kim

Int. J. Mol. Sci. 2022, 23(18), 10793; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms231810793 - 16 Sep 2022

Viewed by 1294

Abstract

Pain plays an important role in human survival [...] Full article

(This article belongs to the Special Issue Neuro-Plastic Mechanisms of Pain and Addiction)

Research

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15 pages, 3466 KiB

Open AccessArticle

β2-Adrenoceptors in the Medial Prefrontal Cortex Excitatory Neurons Regulate Anxiety-like Behavior in Mice

by Zhuogui Lei, Yukyan Lam, Cheukhin Li, Zhongqi Fu, Aruna S. Ramkrishnan, Shu Liu and Ying Li

Int. J. Mol. Sci. 2022, 23(10), 5578; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23105578 - 17 May 2022

Cited by 6 | Viewed by 2743

Abstract

The medial prefrontal cortex (mPFC) and β-adrenoceptors (βARs) have been implicated in modulating anxiety-like behavior. However, the specific contributions of the β2-AR subtype in mPFC in anxiety are still unclear. To address this issue, we used optogenetic and microRNA-based (miRNA) silencing to dissect the role of β2-AR in mPFC in anxiety-like behavior. On the one hand, we use a chimeric rhodopsin/β2-AR (Opto-β2-AR) with in vivo optogenetic techniques to selectively activate β2-adrenergic signaling in excitatory neurons of the mPFC. We found that opto-activation of β2-AR is sufficient to induce anxiety-like behavior and reduce social interaction. On the other hand, we utilize the miRNA silencing technique to specifically knock down the β2-AR in mPFC excitatory neurons. We found that the β2-AR knock down induces anxiolytic-like behavior and promotes social interaction compared to the control group. These data suggest that β2-AR signaling in the mPFC has a critical role in anxiety-like states. These findings suggest that inhibiting of β2-AR signaling in the mPFC may be an effective treatment of anxiety disorders. Full article

(This article belongs to the Special Issue Neuro-Plastic Mechanisms of Pain and Addiction)

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18 pages, 11076 KiB

Open AccessArticle

Molecular Effects of Low-Intensity Shock Wave Therapy on L6 Dorsal Root Ganglion/Spinal Cord and Blood Oxygenation Level-Dependent (BOLD) Functional Magnetic Resonance Imaging (fMRI) Changes in Capsaicin-Induced Prostatitis Rat Models

by Hung-Jen Wang, Chia-Hao Su, Yu-Ming Chen, Chun-Chieh Yu and Yao-Chi Chuang

Int. J. Mol. Sci. 2022, 23(9), 4716; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23094716 - 25 Apr 2022

Cited by 6 | Viewed by 2305

Abstract

Neurogenic inflammation and central sensitization play a role in chronic prostatitis/chronic pelvic pain syndrome. We explore the molecular effects of low-intensity shock wave therapy (Li-ESWT) on central sensitization in a capsaicin-induced prostatitis rat model. Male Sprague–Dawley rats underwent intraprostatic capsaicin (10 mM, 0.1 cm³) injections. After injection, the prostate received Li-ESWT twice, one day apart. The L6 dorsal root ganglion (DRG)/spinal cord was harvested for histology and Western blotting on days 3 and 7. The brain blood oxygenation level-dependent (BOLD) functional images were evaluated using 9.4 T fMRI before the Li-ESWT and one day after. Intraprostatic capsaicin injection induced increased NGF-, BDNF-, and COX-2-positive neurons in the L6 DRG and increased COX-2, NGF, BDNF, receptor Trk-A, and TRPV1 protein expression in the L6 DRG and the dorsal horn of the L6 spinal cord, whose effects were significantly downregulated after Li-ESWT on the prostate. Intraprostatic capsaicin injection increased activity of BOLD fMRI responses in brain regions associated with pain-related responses, such as the caudate putamen, periaqueductal gray, and thalamus, whose BOLD signals were reduced after Li-ESWT. These findings suggest a potential mechanism of Li-ESWT on modulation of peripheral and central sensitization for treating CP/CPPS. Full article

(This article belongs to the Special Issue Neuro-Plastic Mechanisms of Pain and Addiction)

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22 pages, 4868 KiB

Open AccessArticle

Synaptamide Improves Cognitive Functions and Neuronal Plasticity in Neuropathic Pain

by Anna Tyrtyshnaia, Anatoly Bondar, Sophia Konovalova and Igor Manzhulo

Int. J. Mol. Sci. 2021, 22(23), 12779; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222312779 - 26 Nov 2021

Cited by 12 | Viewed by 2746

Abstract

Neuropathic pain arises from damage or dysfunction of the peripheral or central nervous system and manifests itself in a wide variety of sensory symptoms and cognitive disorders. Many studies demonstrate the role of neuropathic pain-induced neuroinflammation in behavioral disorders. For effective neuropathic pain treatment, an integrative approach is required, which simultaneously affects several links of pathogenesis. One promising candidate for this role is synaptamide (N-docosahexaenoylethanolamine), which is an endogenous metabolite of docosahexaenoic acid. In this study, we investigated the activity of synaptamide on mice behavior and hippocampal plasticity in neuropathic pain induced by spared nerve injury (SNI). We found a beneficial effect of synaptamide on the thermal allodynia and mechanical hyperalgesia dynamics. Synaptamide prevented working and long-term memory impairment. These results are probably based on the supportive effect of synaptamide on SNI-impaired hippocampal plasticity. Nerve ligation caused microglia activation predominantly in the contralateral hippocampus, while synaptamide inhibited this effect. The treatment reversed dendritic tree degeneration, dendritic spines density reduction on CA1-pyramidal neurons, neurogenesis deterioration, and hippocampal long-term potentiation (LTP) impairment. In addition, synaptamide inhibits changes in the glutamatergic receptor expression. Thus, synaptamide has a beneficial effect on hippocampal functioning, including synaptic plasticity and hippocampus-dependent cognitive processes in neuropathic pain. Full article

(This article belongs to the Special Issue Neuro-Plastic Mechanisms of Pain and Addiction)

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13 pages, 3757 KiB

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The Peripheral Role of CCL2 in the Anti-Nociceptive Effect of Sigma-1 Receptor Antagonist BD1047 on Inflammatory Hyperalgesia in Rats

by Sungkun Chun, Jun-Ho Lee, Seo-Yeon Yoon and Young-Bae Kwon

Int. J. Mol. Sci. 2021, 22(21), 11730; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222111730 - 29 Oct 2021

Cited by 2 | Viewed by 1992

Abstract

Our recent study demonstrated that the CC-chemokine ligand 2 (CCL2) present in primary afferent fibers (PAFs) plays an important role in the microglia-dependent neuronal activation associated with zymosan-induced inflammatory pain. The present study was aimed to evaluate whether BD1047 (a prototypical sigma-1 receptor (Sig-1R) antagonist) is capable of modifying elevated levels of inflammation-evoked CCL2 as a peripheral antinociceptive mechanism. In DRG primary culture, zymosan dose-dependently increased CCL2 release from isolectin B4 (IB4)-positive DRG neurons, a process that was inhibited by co-culture with BD1047. Single treatment of BD1047 before intraplantar injection of zymosan in rats significantly reduced thermal hyperalgesia and mechanical hyperalgesia, as well as CCL2 expression in DRG neurons and microglia activation in the spinal dorsal horn. In the Complete Freund’s adjuvant (CFA)-induced inflammation model, repeated administration of BD1047 dramatically attenuated thermal hyperalgesia and mechanical hyperalgesia, and significantly diminished CCL2 immunoreactivity and microglia activation. Notably, CFA-induced inflammation significantly increased Sig-1R immunoreactivity in DRG neurons, which was co-localized with CCL2 and IB4, respectively. Taken together, our results suggest that BD1047′s anti-nociceptive property was substantially mediated by the inhibition of CCL2 release in unmyelinated PAFs and that this may, in turn, have attenuated the spinal microglia activation that is associated with inflammatory pain. Full article

(This article belongs to the Special Issue Neuro-Plastic Mechanisms of Pain and Addiction)

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13 pages, 1719 KiB

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Inhibition of Spinal TRPV1 Reduces NMDA Receptor 2B Phosphorylation and Produces Anti-Nociceptive Effects in Mice with Inflammatory Pain

by Suk-Yun Kang, Su Yeon Seo, Se Kyun Bang, Seong Jin Cho, Kwang-Ho Choi and Yeonhee Ryu

Int. J. Mol. Sci. 2021, 22(20), 11177; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222011177 - 16 Oct 2021

Cited by 11 | Viewed by 2177

Abstract

Transient receptor potential vanilloid 1 (TRPV1) has been implicated in peripheral inflammation and is a mediator of the inflammatory response to various noxious stimuli. However, the interaction between TRPV1 and N-methyl-D-aspartate (NMDA) receptors in the regulation of inflammatory pain remains poorly understood. This study aimed to investigate the analgesic effects of intrathecal administration of capsazepine, a TRPV1 antagonist, on carrageenan-induced inflammatory pain in mice and to identify its interactions with NMDA receptors. Inflammatory pain was induced by intraplantar injection of 2% carrageenan in male ICR mice. To investigate the analgesic effects of capsazepine, pain-related behaviors were evaluated using von Frey filaments and a thermal stimulator placed on the hind paw. TRPV1 expression and NMDA receptor phosphorylation in the spinal cord and glutamate concentration in the spinal cord and serum were measured. Intrathecal treatment with capsazepine significantly attenuated carrageenan-induced mechanical allodynia and thermal hyperalgesia. Moreover, carrageenan-enhanced glutamate and phosphorylation of NMDA receptor subunit 2B in the spinal cord were suppressed by capsazepine administration. These results indicate that TRPV1 and NMDA receptors in the spinal cord are associated with inflammatory pain transmission, and inhibition of TRPV1 may reduce inflammatory pain via NMDA receptors. Full article

(This article belongs to the Special Issue Neuro-Plastic Mechanisms of Pain and Addiction)

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20 pages, 5516 KiB

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Suppression of Pain in the Late Phase of Chronic Trigeminal Neuropathic Pain Failed to Rescue the Decision-Making Deficits in Rats

by Suresh Kanna Murugappan, Li Xie, Heung Yan Wong, Zafar Iqbal, Zhuogui Lei, Aruna Surendran Ramkrishnan and Ying Li

Int. J. Mol. Sci. 2021, 22(15), 7846; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22157846 - 22 Jul 2021

Cited by 5 | Viewed by 2439

Abstract

Trigeminal neuropathic pain (TNP) led to vital cognitive functional deficits such as impaired decision-making abilities in a rat gambling task. Chronic TNP caused hypomyelination in the anterior cingulate cortex (ACC) associated with decreased synchronization between ACC spikes and basal lateral amygdala (BLA) theta oscillations. The aim of this study was to investigate the effect of pain suppression on cognitive impairment in the early or late phases of TNP. Blocking afferent signals with a tetrodotoxin (TTX)-ELVAX implanted immediately following nerve lesion suppressed the allodynia and rescued decision-making deficits. In contrast, the TTX used at a later phase could not suppress the allodynia nor rescue decision-making deficits. Intra-ACC administration of riluzole reduced the ACC neural sensitization but failed to restore ACC-BLA spike-field phase synchrony during the late stages of chronic neuropathic pain. Riluzole suppressed allodynia but failed to rescue the decision-making deficits during the late phase of TNP, suggesting that early pain relief is important for recovering from pain-related cognitive impairments. The functional disturbances in ACC neural circuitry may be relevant causes for the deficits in decision making in the chronic TNP state. Full article

(This article belongs to the Special Issue Neuro-Plastic Mechanisms of Pain and Addiction)

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10 pages, 1531 KiB

Open AccessArticle

Acupuncture Modulates Intracranial Self-Stimulation of the Medial Forebrain Bundle in Rats

by Seong Shoon Yoon, Jaesuk Yun, Bong Hyo Lee, Hee Young Kim and Chae Ha Yang

Int. J. Mol. Sci. 2021, 22(14), 7519; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22147519 - 14 Jul 2021

Cited by 2 | Viewed by 2145

Abstract

Acupuncture affects the central nervous system via the regulation of neurotransmitter transmission. We previously showed that Shemen (HT7) acupoint stimulation decreased cocaine-induced dopamine release in the nucleus accumbens. Here, we used the intracranial self-stimulation (ICSS) paradigm to evaluate whether HT stimulation regulates the brain reward function of rats. We found that HT stimulation triggered a rightward shift of the frequency–rate curve and elevated the ICSS thresholds. However, HT7 stimulation did not affect the threshold-lowering effects produced by cocaine. These results indicate that HT7 points only effectively regulates the ICSS thresholds of the medial forebrain bundle in drug-naïve rats. Full article

(This article belongs to the Special Issue Neuro-Plastic Mechanisms of Pain and Addiction)

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12 pages, 1858 KiB

Open AccessArticle

Role of Lateral Hypothalamus in Acupuncture Inhibition of Cocaine Psychomotor Activity

by DanBi Ahn, Han Byeol Jang, Suchan Chang, Hyung Kyu Kim, Yeonhee Ryu, Bong Hyo Lee, Sang Chan Kim, Kyle B. Bills, Scott C. Steffensen, Yu Fan and Hee Young Kim

Int. J. Mol. Sci. 2021, 22(11), 5994; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22115994 - 01 Jun 2021

Cited by 6 | Viewed by 3451

Abstract

Acupuncture modulates the mesolimbic dopamine (DA) system; an area implicated in drug abuse. However, the mechanism by which peripheral sensory afferents, during acupuncture stimulation, modulate this system needs further investigation. The lateral hypothalamus (LH) has been implicated in reward processing and addictive behaviors. To investigate the role of the LH in mediating acupuncture effects, we evaluated the role of LH and spinohypothalamic neurons on cocaine-induced psychomotor activity and NAc DA release. Systemic injection of cocaine increased locomotor activity and 50 kHz ultrasonic vocalizations (USVs), which were attenuated by mechanical stimulation of needles inserted into HT7 but neither ST36 nor LI5. The acupuncture effects were blocked by chemical lesions of the LH or mimicked by activation of LH neurons. Single-unit extracellular recordings showed excitation of LH and spinohypothalamic neurons following acupuncture. Our results suggest that acupuncture recruits the LH to suppress the mesolimbic DA system and psychomotor responses following cocaine injection. Full article

(This article belongs to the Special Issue Neuro-Plastic Mechanisms of Pain and Addiction)

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14 pages, 2720 KiB

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Acupuncture Alleviates Anxiety and 22-kHz Ultrasonic Vocalizations in Rats Subjected to Repeated Alcohol Administration by Modulating the Brain-Derived Neurotrophic Factor/Corticotropin-Releasing Hormone Signaling Pathway

by Su Yeon Seo, Se Kyun Bang, Suk Yun Kang, Seong Jin Cho, Kwang Ho Choi and Yeon Hee Ryu

Int. J. Mol. Sci. 2021, 22(8), 4037; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22084037 - 14 Apr 2021

Cited by 7 | Viewed by 2582

Abstract

The Shenmen point (acupuncture point heart 7: HT7), located in the heart meridian, is frequently used to treat mental disorders, including drug addiction, anxiety, and depression. This study aimed to determine how HT7 regulates anxiety and negative emotions caused by repeated alcohol administration, focusing on the amygdala and paraventricular nucleus (PVN). Repeated administration of alcohol (ETOH; 2 g/kg, i.p. injection, 16% v/v) for 14 days increased the corticosterone (CORT) levels, and HT7 stimulation reduced the plasma CORT levels. HT7 stimulation mitigated anxiety-like behaviors and reduced 22-kHz ultrasonic vocalizations in rats receiving repeated ETOH injections. HT7 stimulation increased the amygdala expression of mature brain-derived neurotropic factor (mBDNF) and phosphorylated tropomyosin receptor kinase B (pTrkB) and decreased the PVN corticotropin-releasing hormone (CRH) expression. Amygdala microinjections of the TrkB antagonist ANA-12 (0.1 pmol/1 μL) reversed the increase in PVN CRH levels. The reduced PVN CRH levels were regulated by CRH-expressing neurons in the amygdala, and the increased amygdala CRH levels were affected by the HT7-stimulation induced increases in mBDNF. HT7 stimulation alleviates increased stress hormone levels and mitigates anxiety and negative emotions caused by repeated ETOH administration. These results provide scientific support for the clinical use of acupuncture to treat various alcoholism-induced diseases. Full article

(This article belongs to the Special Issue Neuro-Plastic Mechanisms of Pain and Addiction)

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12 pages, 2335 KiB

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The Roles of Superoxide on At-Level Spinal Cord Injury Pain in Rats

by Bong Hyo Lee, Jonghoon Kang, Hee Young Kim and Young S. Gwak

Int. J. Mol. Sci. 2021, 22(5), 2672; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22052672 - 06 Mar 2021

Cited by 4 | Viewed by 2764

Abstract

Background: In the present study, we examined superoxide-mediated excitatory nociceptive transmission on at-level neuropathic pain following spinal thoracic 10 contusion injury (SCI) in male Sprague Dawley rats. Methods: Mechanical sensitivity at body trunk, neuronal firing activity, and expression of superoxide marker/ionotropic glutamate receptors (iGluRs)/CamKII were measured in the T7/8 dorsal horn, respectively. Results: Topical treatment of superoxide donor t-BOOH (0.4 mg/kg) increased neuronal firing rates and pCamKII expression in the naïve group, whereas superoxide scavenger Tempol (1 mg/kg) and non-specific ROS scavenger PBN (3 mg/kg) decreased firing rates in the SCI group (* p < 0.05). SCI showed increases of iGluRs-mediated neuronal firing rates and pCamKII expression (* p < 0.05); however, t-BOOH treatment did not show significant changes in the naïve group. The mechanical sensitivity at the body trunk in the SCI group (6.2 ± 0.5) was attenuated by CamKII inhibitor KN-93 (50 μg, 3.9 ± 0.4) or Tempol (1 mg, 4 ± 0.4) treatment (* p < 0.05). In addition, the level of superoxide marker Dhet showed significant increase in SCI rats compared to the sham group (11.7 ± 1.7 vs. 6.6 ± 1.5, * p < 0.05). Conclusions: Superoxide and the pCamKII pathway contribute to chronic at-level neuropathic pain without involvement of iGluRs following SCI. Full article

(This article belongs to the Special Issue Neuro-Plastic Mechanisms of Pain and Addiction)

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