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New Advance on Molecular Targets for the Treatment of Pain
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New Advance on Molecular Targets for the Treatment of Pain

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 16439

Special Issue Editor

Dr. Bong Hyo Lee

E-Mail Website
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

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Keywords

  • pain
  • chronic pain
  • molecular targets
  • pain signaling

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Published Papers (7 papers)

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Research

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12 pages, 2753 KiB  
Article
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 1260
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 [...] Read more.
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  
Article
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
Cited by 1 | Viewed by 1581
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 [...] Read more.
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  
Article
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 3 | Viewed by 2206
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 [...] Read more.
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  
Article
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 3 | Viewed by 1942
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 [...] Read more.
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  
Article
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 11 | Viewed by 2275
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 Nav1.8 and Nav1.9 sodium channels in nociceptive sensitization following plantar incision in mice [...] Read more.
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 Nav1.8 and Nav1.9 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 Nav1.8, Nav1.9, TNF-α, and COX-2 was evaluated by Real-Time PCR in dorsal root ganglia (DRG). Knockdown mice for Nav1.8 and Nav1.9 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 Nav1.8 and Nav1.9 in DRG. Antisense oligodeoxynucleotides reduced hypernociception and downregulated Nav1.8 and Nav1.9. 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 Nav1.8 and Nav1.9. Antagonizing NF-κB and p38 mitogen-activated protein kinase (MAPK), but not ERK or JNK, reduced both hypernociception and hyperexpression of Nav1.8 and Nav1.9. This study proposes the contribution of the TNF-α/p38/NF-κB/Nav1.8 and Nav1.9 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  
Review
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 2727
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 [...] Read more.
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  
Review
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 6 | Viewed by 3441
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 Gi/o protein-coupled cannabinoid CB1 and CB2 receptors. The [...] Read more.
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 Gi/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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