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New Advance on Molecular Targets for the Treatment of Pain

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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 (30 March 2024) | Viewed by 12334

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Special Issue Editor

Dr. Bong Hyo Lee

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Guest Editor

Department of Acupuncture, Moxibustion and Acupoint, College of Korean Medicine, Daegu Haany University, Daegu 42158, Republic of Korea
Interests: acupuncture; complementary and alternative medicine; drug addiction; opioid
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Although the incidence rate of chronic pain is very high, because various chronic pain conditions have different causes, and its pathophysiological mechanism is not completely clear, its treatment effect is limited and will produce different degrees of side effects. Therefore, there is an urgent need for new and effective therapies to control and prevent different types of chronic pain. In this special collection, we will explore novel molecular targets for the treatment of pain that improve analgesic efficacy. Potential areas of interest include but are not limited to research on signal transduction and real modulators of pain signaling. In this regard，provide recent advances and future directions in the pathophysiology and treatment of chronic pain. However, manuscripts describing new methods for the study of pain or opinion articles exposing a particular point of view about any aspect of chronic pain are also welcome.

Dr. Bong Hyo Lee
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

pain
chronic pain
molecular targets
pain signaling

Published Papers (7 papers)

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Research

Jump to: Review

12 pages, 2753 KiB

Open AccessArticle

A Single Injection of rAAV-shmTOR in Peripheral Nerve Persistently Attenuates Nerve Injury-Induced Mechanical Allodynia

by Minkyung Park, Ha-Na Woo, Chin Su Koh, Heesue Chang, Ji Hyun Kim, Keerang Park, Jin Woo Chang, Heuiran Lee and Hyun Ho Jung

Int. J. Mol. Sci. 2023, 24(21), 15918; https://doi.org/10.3390/ijms242115918 - 2 Nov 2023

Viewed by 843

Abstract

Activation of mammalian target of rapamycin (mTOR) has been known as one of the contributing factors in nociceptive sensitization after peripheral injury. Its activation followed by the phosphorylation of downstream effectors causes hyperexcitability of primary sensory neurons in the dorsal root ganglion. We investigated whether a single injection of rAAV-shmTOR would effectively downregulate both complexes of mTOR in the long-term and glial activation as well. Male SD rats were categorized into shmTOR (n = 29), shCON (n = 23), SNI (n = 13), and Normal (n = 8) groups. Treatment groups were injected with rAAV-shmTOR or rAAV-shCON, respectively. DRG tissues and sciatic nerve were harvested for Western blot and immunohistochemical analyses. Peripheral sensitization was gradually attenuated in the shmTOR group, and it reached a peak on PID 21. Western blot analysis showed that both p-mTORC1 and p-mTORC2 were downregulated in the DRG compared to shCON and SNI groups. We also found decreased expression of phosphorylated p38 and microglial activation in the DRG. We first attempted a therapeutic strategy for neuropathic pain with a low dose of AAV injection by interfering with the mTOR signaling pathway, suggesting its potential application in pain treatment. Full article

(This article belongs to the Special Issue New Advance on Molecular Targets for the Treatment of Pain)

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22 pages, 3832 KiB

Open AccessArticle

PNA6, a Lactosyl Analogue of Angiotensin-(1-7), Reverses Pain Induced in Murine Models of Inflammation, Chemotherapy-Induced Peripheral Neuropathy, and Metastatic Bone Disease

by Maha I. Sulaiman, Wafaa Alabsi, Lajos Szabo, Meredith Hay, Robin Polt, Tally M. Largent-Milnes and Todd W. Vanderah

Int. J. Mol. Sci. 2023, 24(19), 15007; https://doi.org/10.3390/ijms241915007 - 9 Oct 2023

Viewed by 1095

Abstract

Pain is the most significant impairment and debilitating challenge for patients with bone metastasis. Therefore, the primary objective of current therapy is to mitigate and prevent the persistence of pain. Thus, cancer-induced bone pain is described as a multifaceted form of discomfort encompassing both inflammatory and neuropathic elements. We have developed a novel non-addictive pain therapeutic, PNA6, that is a derivative of the peptide Angiotensin-(1-7) and binds the Mas receptor to decrease inflammation-related cancer pain. In the present study, we provide evidence that PNA6 attenuates inflammatory, chemotherapy-induced peripheral neuropathy (CIPN) and cancer pain confined to the long bones, exhibiting longer-lasting efficacious therapeutic effects. PNA6, Asp-Arg-Val-Tyr-Ile-His-Ser-(O-β-Lact)-amide, was successfully synthesized using solid phase peptide synthesis (SPPS). PNA6 significantly reversed inflammatory pain induced by 2% carrageenan in mice. A second murine model of platinum drug-induced painful peripheral neuropathy was established using oxaliplatin. Mice in the oxaliplatin-vehicle treatment groups demonstrated significant mechanical allodynia compared to the oxaliplatin-PNA6 treatment group mice. In a third study modeling a complex pain state, E0771 breast adenocarcinoma cells were implanted into the femur of female C57BL/6J wild-type mice to induce cancer-induced bone pain (CIBP). Both acute and chronic dosing of PNA6 significantly reduced the spontaneous pain behaviors associated with CIBP. These data suggest that PNA6 is a viable lead candidate for treating chronic inflammatory and complex neuropathic pain. Full article

(This article belongs to the Special Issue New Advance on Molecular Targets for the Treatment of Pain)

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16 pages, 1363 KiB

Open AccessArticle

Evidence for Endogenous Opioid Dependence Related to Latent Sensitization in a Rat Model of Chronic Inflammatory Pain

by Julio César Morales-Medina, Nicola Pugliese, Alessandro Di Cerbo, Claudia Zizzadoro and Tommaso Iannitti

Int. J. Mol. Sci. 2023, 24(3), 2812; https://doi.org/10.3390/ijms24032812 - 1 Feb 2023

Cited by 1 | Viewed by 1772

Abstract

Studies performed in a mouse model of chronic inflammatory pain induced by intraplantar injection of complete Freund’s adjuvant (CFA) have shown that constitutive activation of the endogenous opioid signaling, besides serving as a mechanism of endogenous analgesia that tonically represses pain sensitization, also generates a state of endogenous opioid dependence. Since species-related differences concerning pain biology and addictive behaviors occur between mice and rats, the present study explored whether the coexistence of endogenous opioid analgesia and endogenous opioid dependence also characterizes a homologous rat model. To this aim, CFA-injured Wistar rats were treated with either 3 mg/kg or 10 mg/kg of the opioid receptor inverse agonist naltrexone (NTX) during the pain remission phase and monitored for 60 min for possible withdrawal behaviors. At 3 mg/kg, NTX, besides inducing the reinstatement of mechanical allodynia, also caused a distinct appearance of ptosis, with slight but nonsignificant changes to the occurrence of teeth chatters and rearing. On the other hand, 10 mg/kg of NTX failed to unmask pain sensitization and induced significantly lower levels of ptosis than 3 mg/kg. Such an NTX-related response pattern observed in the rat CFA model seems to differ substantially from the pattern previously described in the mouse CFA model. This supports the knowledge that mice and rats are not identical in terms of pharmacological response and stresses the importance of choosing the appropriate species for preclinical pain research purposes depending on the scientific question being asked. Full article

(This article belongs to the Special Issue New Advance on Molecular Targets for the Treatment of Pain)

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20 pages, 3633 KiB

Open AccessArticle

Ca²⁺-Permeable AMPA Receptors Contribute to Changed Dorsal Horn Neuronal Firing and Inflammatory Pain

by Olga Kopach, Yulia Dobropolska, Pavel Belan and Nana Voitenko

Int. J. Mol. Sci. 2023, 24(3), 2341; https://doi.org/10.3390/ijms24032341 - 25 Jan 2023

Cited by 2 | Viewed by 1436

Abstract

The dorsal horn (DH) neurons of the spinal cord play a critical role in nociceptive input integration and processing in the central nervous system. Engaged neuronal classes and cell-specific excitability shape nociceptive computation within the DH. The DH hyperexcitability (central sensitisation) has been considered a fundamental mechanism in mediating nociceptive hypersensitivity, with the proven role of Ca²⁺-permeable AMPA receptors (AMPARs). However, whether and how the DH hyperexcitability relates to changes in action potential (AP) parameters in DH neurons and if Ca²⁺-permeable AMPARs contribute to these changes remain unknown. We examined the cell-class heterogeneity of APs generated by DH neurons in inflammatory pain conditions to address these. Inflammatory-induced peripheral hypersensitivity increased DH neuronal excitability. We found changes in the AP threshold and amplitude but not kinetics (spike waveform) in DH neurons generating sustained or initial bursts of firing patterns. In contrast, there were no changes in AP parameters in the DH neurons displaying a single spike firing pattern. Genetic knockdown of the molecular mechanism responsible for the upregulation of Ca²⁺-permeable AMPARs allowed the recovery of cell-specific AP changes in peripheral inflammation. Selective inhibition of Ca²⁺-permeable AMPARs in the spinal cord alleviated nociceptive hypersensitivity, both thermal and mechanical modalities, in animals with peripheral inflammation. Thus, Ca²⁺-permeable AMPARs contribute to shaping APs in DH neurons and nociceptive hypersensitivity. This may represent a neuropathological mechanism in the DH circuits, leading to aberrant signal transfer to other nociceptive pathways. Full article

(This article belongs to the Special Issue New Advance on Molecular Targets for the Treatment of Pain)

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17 pages, 2157 KiB

Open AccessArticle

Unveiling Targets for Treating Postoperative Pain: The Role of the TNF-α/p38 MAPK/NF-κB/Nav1.8 and Nav1.9 Pathways in the Mouse Model of Incisional Pain

by Flávia Oliveira de Lima, Pedro Santana Sales Lauria, Renan Fernandes do Espírito-Santo, Afrânio Ferreira Evangelista, Tâmara Magalhães Oliveira Nogueira, Dionéia Araldi, Milena Botelho Pereira Soares and Cristiane Flora Villarreal

Int. J. Mol. Sci. 2022, 23(19), 11630; https://doi.org/10.3390/ijms231911630 - 1 Oct 2022

Cited by 6 | Viewed by 1760

Abstract

Although the mouse model of incisional pain is broadly used, the mechanisms underlying plantar incision-induced nociception are not fully understood. This work investigates the role of Na_v1.8 and Na_v1.9 sodium channels in nociceptive sensitization following plantar incision in mice and the signaling pathway modulating these channels. A surgical incision was made in the plantar hind paw of male Swiss mice. Nociceptive thresholds were assessed by von Frey filaments. Gene expression of Na_v1.8, Na_v1.9, TNF-α, and COX-2 was evaluated by Real-Time PCR in dorsal root ganglia (DRG). Knockdown mice for Na_v1.8 and Na_v1.9 were produced by antisense oligodeoxynucleotides intrathecal treatments. Local levels of TNF-α and PGE₂ were immunoenzymatically determined. Incised mice exhibited hypernociception and upregulated expression of Na_v1.8 and Na_v1.9 in DRG. Antisense oligodeoxynucleotides reduced hypernociception and downregulated Na_v1.8 and Na_v1.9. TNF-α and COX-2/PGE₂ were upregulated in DRG and plantar skin. Inhibition of TNF-α and COX-2 reduced hypernociception, but only TNF-α inhibition downregulated Na_v1.8 and Na_v1.9. Antagonizing NF-κB and p38 mitogen-activated protein kinase (MAPK), but not ERK or JNK, reduced both hypernociception and hyperexpression of Na_v1.8 and Na_v1.9. This study proposes the contribution of the TNF-α/p38/NF-κB/Na_v1.8 and Na_v1.9 pathways to the pathophysiology of the mouse model of incisional pain. Full article

(This article belongs to the Special Issue New Advance on Molecular Targets for the Treatment of Pain)

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Review

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16 pages, 1405 KiB

Open AccessReview

Optogenetic and Chemogenic Control of Pain Signaling: Molecular Markers

by Josue Vidal Espinosa-Juárez, Erwin Chiquete, Bruno Estañol and José de Jesús Aceves

Int. J. Mol. Sci. 2023, 24(12), 10220; https://doi.org/10.3390/ijms241210220 - 16 Jun 2023

Cited by 2 | Viewed by 2003

Abstract

Pain is a complex experience that involves physical, emotional, and cognitive aspects. This review focuses specifically on the physiological processes underlying pain perception, with a particular emphasis on the various types of sensory neurons involved in transmitting pain signals to the central nervous system. Recent advances in techniques like optogenetics and chemogenetics have allowed researchers to selectively activate or inactivate specific neuronal circuits, offering a promising avenue for developing more effective pain management strategies. The article delves into the molecular targets of different types of sensory fibers such as channels, for example, TRPV1 in C-peptidergic fiber, TRPA1 in C-non-peptidergic receptors expressed differentially as MOR and DOR, and transcription factors, and their colocalization with the vesicular transporter of glutamate, which enable researchers to identify specific subtypes of neurons within the pain pathway and allows for selective transfection and expression of opsins to modulate their activity. Full article

(This article belongs to the Special Issue New Advance on Molecular Targets for the Treatment of Pain)

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22 pages, 2478 KiB

Open AccessReview

Microglial Cannabinoid CB₂ Receptors in Pain Modulation

by Kangtai Xu, Yifei Wu, Zhuangzhuang Tian, Yuanfan Xu, Chaoran Wu and Zilong Wang

Int. J. Mol. Sci. 2023, 24(3), 2348; https://doi.org/10.3390/ijms24032348 - 25 Jan 2023

Cited by 1 | Viewed by 2544

Abstract

Pain, especially chronic pain, can strongly affect patients’ quality of life. Cannabinoids ponhave been reported to produce potent analgesic effects in different preclinical pain models, where they primarily function as agonists of G_i/o protein-coupled cannabinoid CB₁ and CB₂ receptors. The CB₁ receptors are abundantly expressed in both the peripheral and central nervous systems. The central activation of CB₁ receptors is strongly associated with psychotropic adverse effects, thus largely limiting its therapeutic potential. However, the CB₂ receptors are promising targets for pain treatment without psychotropic adverse effects, as they are primarily expressed in immune cells. Additionally, as the resident immune cells in the central nervous system, microglia are increasingly recognized as critical players in chronic pain. Accumulating evidence has demonstrated that the expression of CB₂ receptors is significantly increased in activated microglia in the spinal cord, which exerts protective consequences within the surrounding neural circuitry by regulating the activity and function of microglia. In this review, we focused on recent advances in understanding the role of microglial CB₂ receptors in spinal nociceptive circuitry, highlighting the mechanism of CB₂ receptors in modulating microglia function and its implications for CB₂ receptor- selective agonist-mediated analgesia. Full article

(This article belongs to the Special Issue New Advance on Molecular Targets for the Treatment of Pain)

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