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Novel Mechanisms and Drug Molecules Modulating Chronic Pain
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Novel Mechanisms and Drug Molecules Modulating Chronic Pain

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: closed (31 December 2021) | Viewed by 18552

Special Issue Editors

Prof. Dr. Antonio R. Artalejo

E-Mail Website
Guest Editor
Department of Pharmacology and Toxicology, Universidad Complutense de Madrid, 28040 Madrid, Spain
Interests: sensory neurobiology; pathophysiology of pain; P2X channels; nAChRs channels; drug discovery
Prof. Dr. Antonio Ferrer-Montiel

E-Mail Website
Guest Editor
IDiBE, Universitas Miguel Hernández, Edificio Torregaitán, 03202 Elche, Spain
Interests: sensory neurobiology; pathophysiology of pain; TRP channels; pain pharmacology; drug discovery
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Chronic pain is pain that persists past normal healing time, usually lasting or recurring for more than 3 months. It is a frequent condition, affecting an estimated 20% of people worldwide, and accounts for 15% to 20% of medical consultations. Accordingly, chronic pain is recognized as a global health priority.

Chronic pain is largely heterogenous in its clinical manifestations and has been divided into seven categories: (1) chronic primary pain, (2) chronic cancer pain, (3) chronic posttraumatic and postsurgical pain, (4) chronic neuropathic pain, (5) chronic headache and orofacial pain, (6) chronic visceral pain, and (7) chronic musculoskeletal pain.

Such a diversity of disorders reflects a varied etiology as well as complex underlying pathophysiological mechanisms, ultimately involving the somatosensory system at the peripheral and/or central levels. Multiple extracellular messengers, physical and chemical stimuli-sensing receptors, intracellular signal pathways, and cell types (neural and non-neural) are known to intervene and interact to perpetuate and amplify pain perception. Importantly, many of these molecular and cellular players can be potentially targeted in an attempt to relieve chronic pain.

This Special Issue will focus on basic science and translational research aiming to investigate novel molecular targets and cellular mechanisms involved in chronic pain generation, and on novel chemical entities developed for pain alleviation.

Prof. Dr. Antonio R. Artalejo
Prof. Dr. Antonio Ferrer-Montiel
Guest Editors

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Keywords

  • chronic pain
  • cancer pain
  • orofacial pain
  • migraine
  • peripheral neuropathic pain
  • central neuropathic pain
  • postsurgical pain
  • posttraumatic pain
  • visceral pain
  • musculoskeletal pain
  • fibromyalgia
  • neuroinflammation
  • drug discovery

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Published Papers (5 papers)

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Research

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12 pages, 1624 KiB  
Article
Peripheral Beta-2 Adrenergic Receptors Mediate the Sympathetic Efferent Activation from Central Nervous System to Splenocytes in a Mouse Model of Fibromyalgia
by Shiori Yamashita, Naoki Dozono, Shota Tobori, Kazuki Nagayasu, Shuji Kaneko, Hisashi Shirakawa and Hiroshi Ueda
Int. J. Mol. Sci. 2023, 24(4), 3465; https://doi.org/10.3390/ijms24043465 - 9 Feb 2023
Cited by 1 | Viewed by 2389
Abstract
Abnormalities in the peripheral immune system are involved in the pathophysiology of fibromyalgia, although their contribution to the painful symptoms remains unknown. Our previous study reported the ability of splenocytes to develop pain-like behavior and an association between the central nervous system (CNS) [...] Read more.
Abnormalities in the peripheral immune system are involved in the pathophysiology of fibromyalgia, although their contribution to the painful symptoms remains unknown. Our previous study reported the ability of splenocytes to develop pain-like behavior and an association between the central nervous system (CNS) and splenocytes. Since the spleen is directly innervated by sympathetic nerves, this study aimed to examine whether adrenergic receptors are necessary for pain development or maintenance using an acid saline-induced generalized pain (AcGP) model (an experimental model of fibromyalgia) and whether the activation of these receptors is also essential for pain reproduction by the adoptive transfer of AcGP splenocytes. The administration of selective β2-blockers, including one with only peripheral action, prevented the development but did not reverse the maintenance of pain-like behavior in acid saline-treated C57BL/6J mice. Neither a selective α1-blocker nor an anticholinergic drug affects the development of pain-like behavior. Furthermore, β2-blockade in donor AcGP mice eliminated pain reproduction in recipient mice injected with AcGP splenocytes. These results suggest that peripheral β2-adrenergic receptors play an important role in the efferent pathway from the CNS to splenocytes in pain development. Full article
(This article belongs to the Special Issue Novel Mechanisms and Drug Molecules Modulating Chronic Pain)
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24 pages, 5389 KiB  
Article
β–Lactam TRPM8 Antagonist RGM8-51 Displays Antinociceptive Activity in Different Animal Models
by Cristina Martín-Escura, Alicia Medina-Peris, Luke A. Spear, Roberto de la Torre Martínez, Luis A. Olivos-Oré, María Victoria Barahona, Sara González-Rodríguez, Gregorio Fernández-Ballester, Asia Fernández-Carvajal, Antonio R. Artalejo, Antonio Ferrer-Montiel and Rosario González-Muñiz
Int. J. Mol. Sci. 2022, 23(5), 2692; https://doi.org/10.3390/ijms23052692 - 28 Feb 2022
Cited by 10 | Viewed by 3091
Abstract
Transient receptor potential melastatin subtype 8 (TRPM8) is a cation channel extensively expressed in sensory neurons and implicated in different painful states. However, the effectiveness of TRPM8 modulators for pain relief is still a matter of discussion, since structurally diverse modulators lead to [...] Read more.
Transient receptor potential melastatin subtype 8 (TRPM8) is a cation channel extensively expressed in sensory neurons and implicated in different painful states. However, the effectiveness of TRPM8 modulators for pain relief is still a matter of discussion, since structurally diverse modulators lead to different results, depending on the animal pain model. In this work, we described the antinociceptive activity of a β–lactam derivative, RGM8-51, showing good TRPM8 antagonist activity, and selectivity against related thermoTRP channels and other pain-mediating receptors. In primary cultures of rat dorsal root ganglion (DRG) neurons, RGM8-51 potently reduced menthol-evoked neuronal firing without affecting the major ion conductances responsible for action potential generation. This compound has in vivo antinociceptive activity in response to cold, in a mouse model of oxaliplatin-induced peripheral neuropathy. In addition, it reduces cold, mechanical and heat hypersensitivity in a rat model of neuropathic pain arising after chronic constriction of the sciatic nerve. Furthermore, RGM8-51 exhibits mechanical hypersensitivity-relieving activity, in a mouse model of NTG-induced hyperesthesia. Taken together, these preclinical results substantiate that this TRPM8 antagonist is a promising pharmacological tool to study TRPM8-related diseases. Full article
(This article belongs to the Special Issue Novel Mechanisms and Drug Molecules Modulating Chronic Pain)
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17 pages, 2883 KiB  
Article
IQM-PC332, a Novel DREAM Ligand with Antinociceptive Effect on Peripheral Nerve Injury-Induced Pain
by Paula G. Socuéllamos, Luis A. Olivos-Oré, María Victoria Barahona, Pilar Cercós, Marta Pérez Pascual, Marina Arribas-Blázquez, José Ramón Naranjo, Carmen Valenzuela, Marta Gutiérrez-Rodríguez and Antonio R. Artalejo
Int. J. Mol. Sci. 2022, 23(4), 2142; https://doi.org/10.3390/ijms23042142 - 15 Feb 2022
Cited by 4 | Viewed by 2675
Abstract
Neuropathic pain is a form of chronic pain arising from damage of the neural cells that sense, transmit or process sensory information. Given its growing prevalence and common refractoriness to conventional analgesics, the development of new drugs with pain relief effects constitutes a [...] Read more.
Neuropathic pain is a form of chronic pain arising from damage of the neural cells that sense, transmit or process sensory information. Given its growing prevalence and common refractoriness to conventional analgesics, the development of new drugs with pain relief effects constitutes a prominent clinical need. In this respect, drugs that reduce activity of sensory neurons by modulating ion channels hold the promise to become effective analgesics. Here, we evaluated the mechanical antinociceptive effect of IQM-PC332, a novel ligand of the multifunctional protein downstream regulatory element antagonist modulator (DREAM) in rats subjected to chronic constriction injury of the sciatic nerve as a model of neuropathic pain. IQM-PC332 administered by intraplantar (0.01–10 µg) or intraperitoneal (0.02–1 µg/kg) injection reduced mechanical sensitivity by ≈100% of the maximum possible effect, with ED50 of 0.27 ± 0.05 µg and 0.09 ± 0.01 µg/kg, respectively. Perforated-patch whole-cell recordings in isolated dorsal root ganglion (DRG) neurons showed that IQM-PC332 (1 and 10 µM) reduced ionic currents through voltage-gated K+ channels responsible for A-type potassium currents, low, T-type, and high voltage-activated Ca2+ channels, and transient receptor potential vanilloid-1 (TRPV1) channels. Furthermore, IQM-PC332 (1 µM) reduced electrically evoked action potentials in DRG neurons from neuropathic animals. It is suggested that by modulating multiple DREAM–ion channel signaling complexes, IQM-PC332 may serve a lead compound of novel multimodal analgesics. Full article
(This article belongs to the Special Issue Novel Mechanisms and Drug Molecules Modulating Chronic Pain)
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16 pages, 3294 KiB  
Article
Netrin-1 as a Multitarget Barrier Stabilizer in the Peripheral Nerve after Injury
by Jeremy Tsung-Chieh Chen, Lea Schmidt, Christina Schürger, Mohammed K. Hankir, Susanne M. Krug and Heike L. Rittner
Int. J. Mol. Sci. 2021, 22(18), 10090; https://doi.org/10.3390/ijms221810090 - 18 Sep 2021
Cited by 10 | Viewed by 3271
Abstract
The blood–nerve barrier and myelin barrier normally shield peripheral nerves from potentially harmful insults. They are broken down during nerve injury, which contributes to neuronal damage. Netrin-1 is a neuronal guidance protein with various established functions in the peripheral and central nervous systems; [...] Read more.
The blood–nerve barrier and myelin barrier normally shield peripheral nerves from potentially harmful insults. They are broken down during nerve injury, which contributes to neuronal damage. Netrin-1 is a neuronal guidance protein with various established functions in the peripheral and central nervous systems; however, its role in regulating barrier integrity and pain processing after nerve injury is poorly understood. Here, we show that chronic constriction injury (CCI) in Wistar rats reduced netrin-1 protein and the netrin-1 receptor neogenin-1 (Neo1) in the sciatic nerve. Replacement of netrin-1 via systemic or local administration of the recombinant protein rescued injury-induced nociceptive hypersensitivity. This was prevented by siRNA-mediated knockdown of Neo1 in the sciatic nerve. Mechanistically, netrin-1 restored endothelial and myelin, but not perineural, barrier function as measured by fluorescent dye or fibrinogen penetration. Netrin-1 also reversed the decline in the tight junction proteins claudin-5 and claudin-19 in the sciatic nerve caused by CCI. Our findings emphasize the role of the endothelial and myelin barriers in pain processing after nerve damage and reveal that exogenous netrin-1 restores their function to mitigate CCI-induced hypersensitivity via Neo1. The netrin-1-neogenin-1 signaling pathway may thus represent a multi-target barrier protector for the treatment of neuropathic pain. Full article
(This article belongs to the Special Issue Novel Mechanisms and Drug Molecules Modulating Chronic Pain)
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Review

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26 pages, 1255 KiB  
Review
Monoclonal Antibodies for Chronic Pain Treatment: Present and Future
by Eva M. Sánchez-Robles, Rocío Girón, Nancy Paniagua, Carmen Rodríguez-Rivera, David Pascual and Carlos Goicoechea
Int. J. Mol. Sci. 2021, 22(19), 10325; https://doi.org/10.3390/ijms221910325 - 25 Sep 2021
Cited by 19 | Viewed by 6078
Abstract
Chronic pain remains a major problem worldwide, despite the availability of various non-pharmacological and pharmacological treatment options. Therefore, new analgesics with novel mechanisms of action are needed. Monoclonal antibodies (mAbs) are directed against specific, targeted molecules involved in pain signaling and processing pathways [...] Read more.
Chronic pain remains a major problem worldwide, despite the availability of various non-pharmacological and pharmacological treatment options. Therefore, new analgesics with novel mechanisms of action are needed. Monoclonal antibodies (mAbs) are directed against specific, targeted molecules involved in pain signaling and processing pathways that look to be very effective and promising as a novel therapy in pain management. Thus, there are mAbs against tumor necrosis factor (TNF), nerve growth factor (NGF), calcitonin gene-related peptide (CGRP), or interleukin-6 (IL-6), among others, which are already recommended in the treatment of chronic pain conditions such as osteoarthritis, chronic lower back pain, migraine, or rheumatoid arthritis that are under preclinical research. This narrative review summarizes the preclinical and clinical evidence supporting the use of these agents in the treatment of chronic pain. Full article
(This article belongs to the Special Issue Novel Mechanisms and Drug Molecules Modulating Chronic Pain)
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