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A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Pharmacology".

Deadline for manuscript submissions: 20 June 2024 | Viewed by 16727

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Prof. Dr. Sergio Marques Borghi

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Departament of Pathology, Center of Biological Sciences, Londrina State University, Londrina, Paraná 86057-970, Brazil
Interests: flavonoids; citrus fruits; oxidative stress; antioxidants; inflammation; infection; pain
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Dear Colleagues,

Neuropathic pain represents one of the most challenging conditions in medicine due to its difficult diagnosis and management and permanent sequelae. It originates from injuries in somatosensorial components of both the peripheral and central nervous systems. The prevalence of neuropathic pain may range from 7 to 10% in the general population, greatly impacting the quality of life of patients. Nociceptive transmission in neuropathic pain is dysregulated. Maladaptive responses involving neurons, immune and glial cells underpin this complex condition. Evidence demonstrates electrophysiological, morphological, and molecular plastic disturbances as drivers of the hyperexcitability state found in neuropathic pain conditions. Clinical conditions with a neuropathic component include chemotherapy-induced neuropathic pain, postherpetic neuralgia, trigeminal neuralgia, diabetic neuropathy, painful radiculopathy, postamputation pain, post-stroke pain, etc. Currently, neuropathic pain treatment encompasses tricyclic antidepressants, topical capsaicin or lidocaine, serotonin and norepinephrine reuptake inhibitors, serotonin-specific reuptake inhibitors, opioids up to interventional therapies such as epidural treatments together with a multidisciplinary team care targeting improvements in sleep, rehabilitation psychology, and exercises. However, a large proportion of patients still cannot find ways to adequately manage their pain, and the side effects of treatment are a relevant factor permeating all treatment options. In this sense, unveiling novel emerging molecules capable of shaping neuropathic pain pathology towards pain relief might be necessary to promote further research in this field.

This Special Issue aims to compile papers that address novel advances in the pharmacotherapy of neuropathic pain. We welcome the submission of many types of studies, including reviews and original preclinical and clinical articles.

Prof. Dr. Sergio Marques Borghi
Guest Editor

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Keywords

neuropathy
nerve damage
somatosensory system
pharmacology
natural products
lipid mediators
biologicals
anticonvulsants
cannabinoids

Published Papers (9 papers)

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Research

Jump to: Review

15 pages, 2888 KiB

Open AccessArticle

URB937 Prevents the Development of Mechanical Allodynia in Male Rats with Trigeminal Neuralgia

by Chiara Demartini, Rosaria Greco, Anna Maria Zanaboni, Miriam Francavilla, Sara Facchetti and Cristina Tassorelli

Pharmaceuticals 2023, 16(11), 1626; https://doi.org/10.3390/ph16111626 - 18 Nov 2023

Cited by 1 | Viewed by 1175

Abstract

Cannabinoids are proposed for alleviating neuropathic pain, but their use is limited by cannabimimetic side effects. The inhibition of the fatty acid amide hydrolase (FAAH), the degrading enzyme of the endocannabinoid anandamide, has received attention as an alternative to cannabinoids in the treatment of neuropathic pain. Here, we investigated the effect of URB937, a blood–brain barrier impermeant FAAH inhibitor, on experimentally induced mechanical allodynia in an animal model of trigeminal neuralgia. Male Sprague-Dawley rats were subjected to chronic constriction injury of the infraorbital nerve (IoN-CCI); operated animals were treated sub-chronically with URB937 (1 mg/kg, i.p.) or vehicle before or after trigeminal mechanical allodynia establishment. We also assayed mRNA expression levels of the pain neuropeptide calcitonin gene-related peptide (CGRP) and cytokines in the medulla, cervical spinal cord, and trigeminal ganglion ipsilateral to IoN-CCI using rt-PCR. URB937 treatment prevented the development of mechanical allodynia and IoN-CCI-induced changes in mRNA expression levels of CGRP and cytokines in the evaluated areas. When administered after allodynia development, URB937 prevented IoN-CCI-induced changes in CGRP and cytokine gene expression; this was not associated with a significant abrogation of the mechanical allodynia. These findings suggest that URB937 may counteract, but not reverse, the development of allodynia in trigeminal neuralgia. Further research is needed to elucidate the underlying mechanisms. Full article

(This article belongs to the Special Issue Pharmacotherapy of Neuropathic Pain)

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14 pages, 2284 KiB

Open AccessArticle

Involvement of the Spinal Serotonergic System in the Analgesic Effect of [6]-Shogaol in Oxaliplatin-Induced Neuropathic Pain in Mice

by Juan Gang, Keun-Tae Park, Suyong Kim and Woojin Kim

Pharmaceuticals 2023, 16(10), 1465; https://doi.org/10.3390/ph16101465 - 15 Oct 2023

Cited by 1 | Viewed by 962

Abstract

Oxaliplatin is a chemotherapy drug that can induce severe acute neuropathy in patients within hours of treatment. In our previous study, 10 mg/kg [6]-shogaol (i.p.) significantly alleviated cold and mechanical allodynia induced by a 6 mg/kg oxaliplatin injection (i.p.); however, the precise serotonin-modulatory effect has not been investigated. In this study, we showed that intrathecal injections of NAN-190 (5-HT_1A receptor antagonist, 1 µg) and MDL-72222 (5-HT₃ receptor antagonist, 15 µg), but not ketanserin (5-HT_2A receptor antagonist, 1 µg), significantly blocked the analgesic effect of [6]-shogaol (10 mg/kg, i.p.). Furthermore, the gene expression of the serotonin-synthesizing enzyme tryptophan hydroxylase 2 (TPH2) and serotonin levels in the spinal cord and serum were significantly downregulated (p < 0.0001 and p = 0.0002) and upregulated (p = 0.0298 and p = 0.0099) after oxaliplatin and [6]-shogaol administration, respectively. Moreover, both the gene and protein expression of the spinal serotonin receptors 5-HT_1A and 5-HT₃ significantly increased after [6]-shogaol injections (p < 0.0001). Finally, intrathecal injections of both receptor agonists (8-OH-DPAT; 5-HT_1A receptor agonist, 10 µg and m-CPBG; 5-HT₃ receptor agonist, 15 µg) mimicked the effects of [6]-shogaol in oxaliplatin-injected mice. Taken together, these results demonstrate that [6]-shogaol attenuates oxaliplatin-induced neuropathic pain by modulating the spinal serotoninergic system. Full article

(This article belongs to the Special Issue Pharmacotherapy of Neuropathic Pain)

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13 pages, 4350 KiB

Open AccessArticle

Chronic Cannabigerol as an Effective Therapeutic for Cisplatin-Induced Neuropathic Pain

by Rahul Nachnani, Diana E. Sepulveda, Jennifer L. Booth, Shouhao Zhou, Nicholas M. Graziane, Wesley M. Raup-Konsavage and Kent E. Vrana

Pharmaceuticals 2023, 16(10), 1442; https://doi.org/10.3390/ph16101442 - 11 Oct 2023

Cited by 1 | Viewed by 1717

Abstract

Cannabigerol (CBG), derived from the cannabis plant, acts as an acute analgesic in a model of cisplatin-induced peripheral neuropathy (CIPN) in mice. There are no curative, long-lasting treatments for CIPN available to humans. We investigated the ability of chronic CBG to alleviate mechanical hypersensitivity due to CIPN in mice by measuring responses to 7 and 14 days of daily CBG. We found that CBG treatment (i.p.) for 7 and 14 consecutive days significantly reduced mechanical hypersensitivity in male and female mice with CIPN and reduced pain sensitivity up to 60–70% of baseline levels (p < 0.001 for all), 24 h after the last injection. Additionally, we found that daily treatment with CBG did not evoke tolerance and did not incur significant weight change or adverse events. The efficacy of CBG was independent of the estrous cycle phase. Therefore, chronic CBG administration can provide at least 24 h of antinociceptive effect in mice. These findings support the study of CBG as a long-lasting neuropathic pain therapy, which acts without tolerance in both males and females. Full article

(This article belongs to the Special Issue Pharmacotherapy of Neuropathic Pain)

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24 pages, 3542 KiB

Open AccessArticle

Pregabalin–Tolperisone Combination to Treat Neuropathic Pain: Improved Analgesia and Reduced Side Effects in Rats

by Nariman Essmat, Anna Rita Galambos, Péter P. Lakatos, Dávid Árpád Karádi, Amir Mohammadzadeh, Sarah Kadhim Abbood, Orsolya Geda, Rudolf Laufer, Kornél Király, Pál Riba, Zoltán S. Zádori, Éva Szökő, Tamás Tábi and Mahmoud Al-Khrasani

Pharmaceuticals 2023, 16(8), 1115; https://doi.org/10.3390/ph16081115 - 07 Aug 2023

Cited by 5 | Viewed by 2399

Abstract

The current treatment of neuropathic pain (NP) is unsatisfactory; therefore, effective novel agents or combination-based analgesic therapies are needed. Herein, oral tolperisone, pregabalin, and duloxetine were tested for their antinociceptive effect against rat partial sciatic nerve ligation (pSNL)-induced tactile allodynia described by a decrease in the paw withdrawal threshold (PWT) measured by a dynamic plantar aesthesiometer. On day 7 after the operation, PWTs were assessed at 60, 120, and 180 min post-treatment. Chronic treatment was continued for 2 weeks, and again, PWTs were measured on day 14 and 21. None of the test compounds produced an acute antiallodynic effect. In contrast, after chronic treatment, tolperisone and pregabalin alleviated allodynia. In other experiments, on day 14, the acute antiallodynic effect of the tolperisone/pregabalin or duloxetine combination was measured. As a novel finding, a single dose of the tolperisone/pregabalin combination could remarkably alleviate allodynia acutely. It also restored the neuropathy-induced elevated CSF glutamate content. Furthermore, the combination is devoid of adverse effects related to motor and gastrointestinal transit functions. Tolperisone and pregabalin target voltage-gated sodium and calcium channels, respectively. The dual blockade effect of the combination might explain its advantageous acute analgesic effect in the present work. Full article

(This article belongs to the Special Issue Pharmacotherapy of Neuropathic Pain)

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18 pages, 1311 KiB

Open AccessArticle

Cannabis-Based Medicine for Neuropathic Pain and Spasticity—A Multicenter, Randomized, Double-Blinded, Placebo-Controlled Trial

by Julie Schjødtz Hansen, Stefan Gustavsen, Homayoun Roshanisefat, Matthias Kant, Fin Biering-Sørensen, Claus Andersen, Anna Olsson, Helene Højsgaard Chow, Nasrin Asgari, Julie Richter Hansen, Helle Hvilsted Nielsen, Rikke Middelhede Hansen, Thor Petersen, Annette Bang Oturai, Finn Sellebjerg, Eva Aggerholm Sædder, Helge Kasch, Peter Vestergaard Rasmussen, Nanna Brix Finnerup and Kristina Bacher Svendsen

Pharmaceuticals 2023, 16(8), 1079; https://doi.org/10.3390/ph16081079 - 28 Jul 2023

Cited by 7 | Viewed by 3039

Abstract

Patients with multiple sclerosis (MS) and spinal cord injury (SCI) commonly sustain central neuropathic pain (NP) and spasticity. Despite a lack of consistent evidence, cannabis-based medicine (CBM) has been suggested as a supplement treatment. We aimed to investigate the effect of CBM on NP and spasticity in patients with MS or SCI. We performed a randomized, double-blinded, placebo-controlled trial in Denmark. Patients aged ≥18 years with NP (intensity >3, ≤9 on a numerical rating scale (NRS0-10) and/or spasticity (>3 on NRS0-10) were randomized to treatment consisting of either delta-9-tetrahydrocannabinol (THC), cannabidiol (CBD), a combination of THC&CBD in maximum doses of 22.5 mg, 45 mg and 22.5/45 mg per day, respectively, or placebo. A baseline registration was performed before randomization. Treatment duration was six weeks followed by a one-week phaseout. Primary endpoints were the intensity of patient-reported NP and/or spasticity. Between February 2019 and December 2021, 134 patients were randomized (MS n = 119, SCI n = 15), where 32 were assigned to THC, 31 to CBD, 31 to THC&CBD, and 40 to placebo. No significant difference was found for: mean pain intensity (THC 0.42 (−0.54–1.38), CBD 0.45 (−0.47–1.38) and THC&CBD 0.16 (−0.75–1.08)), mean spasticity intensity (THC 0.24 (−0.67–1.45), CBD 0.46 (−0.74–1.65), and THC&CBD 0.10 (−1.18–1.39), secondary outcomes (patient global impression of change and quality of life), or any tertiary outcomes. We aimed to include 448 patients in the trial; however, due to COVID-19 and recruitment challenges, fewer were included. Nevertheless, in this four-arm parallel trial, no effect was found between placebo and active treatment with THC or CBD alone or in combination on NP or spasticity in patients with either MS or SCI. The trial was registered with the EU Clinical Trials Register EudraCT (2018-002315-98). Full article

(This article belongs to the Special Issue Pharmacotherapy of Neuropathic Pain)

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13 pages, 1650 KiB

Open AccessArticle

Mirogabalin Decreases Pain-like Behaviors by Inhibiting the Microglial/Macrophage Activation, p38MAPK Signaling, and Pronociceptive CCL2 and CCL5 Release in a Mouse Model of Neuropathic Pain

by Renata Zajączkowska, Katarzyna Pawlik, Katarzyna Ciapała, Anna Piotrowska, Agata Ciechanowska, Ewelina Rojewska, Magdalena Kocot-Kępska, Wioletta Makuch, Jerzy Wordliczek and Joanna Mika

Pharmaceuticals 2023, 16(7), 1023; https://doi.org/10.3390/ph16071023 - 19 Jul 2023

Cited by 2 | Viewed by 1242

Abstract

Neuropathic pain is a chronic condition that significantly reduces the quality of life of many patients as a result of ineffective pain relief therapy. For that reason, looking for new analgesics remains an important issue. Mirogabalin is a new gabapentinoid that is a specific ligand for the α2σ-1 and α2σ-2 subunits of voltage-gated calcium channels. In the present study, we compared the analgesic effect of pregabalin and mirogabalin in a neuropathic pain chronic constriction injury (CCI) of the sciatic nerve in a mouse model. The main purpose of our study was to determine the effectiveness of mirogabalin administered both once and repeatedly and to explain how the drug influences highly activated cells at the spinal cord level in neuropathy. We also sought to understand whether mirogabalin modulates the selected intracellular pathways (p38MAPK, ERK, JNK) and chemokines (CCL2, CCL5) important for nociceptive transmission, which is crucial information from a clinical perspective. First, our study provides evidence that a single mirogabalin administration diminishes tactile hypersensitivity more effectively than pregabalin. Second, research shows that several indirect mechanisms may be responsible for the beneficial analgesic effect of mirogabalin. This study reports that repeated intraperitoneally (i.p.) mirogabalin administration strongly prevents spinal microglia/macrophage activation evoked by nerve injury, slightly suppresses astroglia and neutrophil infiltration, and reduces the p38MAPK levels associated with neuropathic pain, as measured on Day 7. Moreover, mirogabalin strongly diminished the levels of the pronociceptive chemokines CCL2 and CCL5. Our results indicate that mirogabalin may represent a new strategy for the effective pharmacotherapy of neuropathic pain. Full article

(This article belongs to the Special Issue Pharmacotherapy of Neuropathic Pain)

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Review

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11 pages, 1518 KiB

Open AccessReview

Pharmacological Topical Therapy for Intra-Oral Post Traumatic Trigeminal Neuropathic Pain: A Comprehensive Review

by Yair Sharav, Shimrit Heiliczer, Rafael Benoliel and Yaron Haviv

Pharmaceuticals 2024, 17(2), 264; https://doi.org/10.3390/ph17020264 - 19 Feb 2024

Viewed by 755

Abstract

Background: The efficacy of topical treatments in alleviating neuropathic pain is well-established. However, there is a paucity of research on topical interventions designed specifically for intra-oral application, where the tissue composition differs from that of exposed skin. Methods: This comprehensive review endeavors to assess the extant evidence regarding the efficacy of topical treatments in addressing neuropathic pain within the oral cavity. Utilizing combinations of search terms, we conducted a thorough search across standard electronic bibliographic databases—MEDLINE (via PubMed), Embase, Google Scholar, and Up to Date. The variables under scrutiny encompassed topical treatment, local intervention, chronic oral and orofacial pain, and neuropathic pain. All pertinent studies published in the English language between 1992 and 2022 were included in our analysis. Results: Fourteen relevant manuscripts were identified, primarily consisting of expert opinions and case reports. The comprehensive review suggests that topical treatments, especially when applied under a stent, could be effective in mitigating neuropathic pain in the oral area. However, it is crucial to conduct further studies to confirm these preliminary results. The limitations of the reviewed studies, mainly the reliance on expert opinions, small sample sizes, inconsistent study designs, and a lack of long-term follow-up data, highlight the need for more rigorous research. Conclusions: Although initial findings indicate topical treatments may be effective for oral neuropathic pain, the limitations of current studies call for more thorough research. Further comprehensive studies are essential to validate the efficacy of these treatments, standardize procedures, and determine long-term results. This will provide clearer guidance for treating chronic neuropathic pain in the oral cavity. Full article

(This article belongs to the Special Issue Pharmacotherapy of Neuropathic Pain)

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23 pages, 937 KiB

Open AccessReview

Exploring Cholinergic Compounds for Peripheral Neuropathic Pain Management: A Comprehensive Scoping Review of Rodent Model Studies

by Edouard Montigné and David Balayssac

Pharmaceuticals 2023, 16(10), 1363; https://doi.org/10.3390/ph16101363 - 27 Sep 2023

Viewed by 1081

Abstract

Neuropathic pain affects about 7–8% of the population, and its management still poses challenges with unmet needs. Over the past decades, researchers have explored the cholinergic system (muscarinic and nicotinic acetylcholine receptors: mAChR and nAChR) and compounds targeting these receptors as potential analgesics for neuropathic pain management. This scoping review aims to provide an overview of studies on peripheral neuropathic pain (PNP) in rodent models, exploring compounds targeting cholinergic neurotransmission. The inclusion criteria were original articles on PNP in rodent models that explored the use of compounds directly targeting cholinergic neurotransmission and reported results of nociceptive behavioral assays. The literature search was performed in the PubMed and Web of Science databases (1 January 2000–22 April 2023). The selection process yielded 82 publications, encompassing 62 compounds. The most studied compounds were agonists of α4β2 nAChR and α7 nAChR, and antagonists of α9/α10 nAChR, along with those increasing acetylcholine and targeting mAChRs. Studies mainly reported antinociceptive effects in traumatic PNP models, and to a lesser extent, chemotherapy-induced neuropathy or diabetic models. These preclinical studies underscore the considerable potential of cholinergic compounds in the management of PNP, warranting the initiation of clinical trials. Full article

(This article belongs to the Special Issue Pharmacotherapy of Neuropathic Pain)

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16 pages, 789 KiB

Open AccessReview

Stroke-Induced Central Pain: Overview of the Mechanisms, Management, and Emerging Targets of Central Post-Stroke Pain

by Anugeetha Thacheril Mohanan, Sermugapandian Nithya, Yousra Nomier, Dalin A. Hassan, Abdulmajeed M. Jali, Marwa Qadri and Shamna Machanchery

Pharmaceuticals 2023, 16(8), 1103; https://doi.org/10.3390/ph16081103 - 04 Aug 2023

Cited by 1 | Viewed by 3461

Abstract

The incidence of stroke plays the foremost role in the genesis of central neuropathic pain. Central post-stroke pain (CPSP) is a central pain arising from a vascular lesion in the central nervous system that elicits somatosensory deficits, often contralateral to stroke lesions. It is expressed as continuous or intermittent pain accompanied by sensory abnormalities like dysesthesia and allodynia. CPSP remains de-emphasized due to the variation in onset and diversity in symptoms, besides the difficulty of distinguishing it from other post-stroke pains, often referred to as a diagnosis of exclusion. Spinothalamic dysfunction, disinhibition of the medial thalamus, and neuronal hyperexcitability combined with deafferentation in thalamocortical regions are the mechanisms underlying central pain, which play a significant role in the pathogenesis of CPSP. The treatment regimen for CPSP seems to be perplexed in nature; however, based on available studies, amitriptyline and lamotrigine are denoted as first-line medications and non-pharmacological choices may be accounted for cases intractable to pharmacotherapy. This review attempts to provide an overview of the mechanisms, existing management approaches, and emerging targets of CPSP. A profound understanding of CPSP aids in optimizing the quality of life among stroke sufferers and facilitates further research to develop newer therapeutic agents for managing CPSP. Full article

(This article belongs to the Special Issue Pharmacotherapy of Neuropathic Pain)

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