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23 pages, 5379 KiB

Open AccessArticle

Fructose-1,6-Bisphosphate Reduces Chronic Constriction Injury Neuropathic Pain in Mice by Targeting Dorsal Root Ganglia Nociceptive Neuron Activation

by Amanda Martins Dionisio, Paula de Azevedo Oliveira Milanez, Ana Carla Zarpelon-Schutz, Sandra Satie Mizokami, Mariana Marques Bertozzi, Kelly Megumi Yaekashi, Doumit Camilios-Neto, Sergio Marques Borghi, Rubia Casagrande and Waldiceu A. Verri

Pharmaceuticals 2025, 18(5), 660; https://doi.org/10.3390/ph18050660 - 30 Apr 2025

Viewed by 158

Abstract

Background/Objectives: Fructose-1,6-bisphosphate (FBP) is an intermediate product of the glycolytic pathway with analgesic effect in acute inflammatory pain model via the production of adenosine. However, whether FBP is active in neuropathic pain is unknown. Therefore, we reason that it would be suitable to [...] Read more.

Background/Objectives: Fructose-1,6-bisphosphate (FBP) is an intermediate product of the glycolytic pathway with analgesic effect in acute inflammatory pain model via the production of adenosine. However, whether FBP is active in neuropathic pain is unknown. Therefore, we reason that it would be suitable to investigate the analgesic effect and mechanism of action of FBP in a model of chronic constriction injury (CCI) of sciatic nerve-induced neuropathic pain in mice. Methods: After CCI induction, mice received FBP, adenosine, A1 and/or A2A receptor antagonists, and/or inhibitors of the nitric oxide (NO)/cyclic guanosine monophosphate (cGMP)/protein kinase G (PKG)/ATP sensitive K channels (KATP) signaling pathway. Results: FBP (up to 85%) and adenosine (up to 84%) inhibited the mechanical hyperalgesia (electronic aesthesiometer) induced by CCI with similar profiles. FBP analgesia was dependent on adenosine because adenosine A1 and A2A receptors antagonists diminished FPB activity (100% and 79%, respectively). FBP analgesia was also dependent on activating the NO/cGMP/PKG/KATP signaling pathway. Furthermore, FBP treatment increased the production of NO in cultured dorsal root ganglia (DRG) neurons (100% increase), whereas neuronal nitric oxide synthase (nNOS) inhibition decreased (up to 70%) the analgesic effect of FBP. We also observed that FBP reduced the calcium levels of transient receptor potential ankyrin 1 (TRPA1)⁺ DRG neurons (85%) and paw-flinching triggered by TRPA1 activation (38%). Conclusions: FBP reduced neuropathic pain by reducing DRG neuron activation. The mechanisms involved the activation of adenosine A1 and A2A receptors to trigger the analgesic NO/cGMP/PKG/KATP signaling pathway and reducing TRPA1⁺ DRG neuron activity. Full article

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

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12 pages, 897 KiB

Open AccessArticle

Fast Analgesic Effect in Response Test with Topical Phenytoin Cream Correlates with Prolonged Pain Relief After Extended Use in Painful Diabetic Neuropathy

by David J. Kopsky, Alexander F. J. E. Vrancken, Ruben P. A. van Eijk, Ricardo Alvarez-Jimenez, Karolina M. Szadek, Remko Liebregts and Monique A. H. Steegers

Pharmaceuticals 2025, 18(2), 228; https://doi.org/10.3390/ph18020228 - 7 Feb 2025

Viewed by 720

Abstract

Background: Treatment of painful diabetic neuropathy (PDN) poses several challenges due to the limited effectiveness, high incidence of side effects, and potential drug interactions of oral neuropathic pain medication. Lacking systemic side effects, topical phenytoin cream offers a promising innovative approach to [...] Read more.

Background: Treatment of painful diabetic neuropathy (PDN) poses several challenges due to the limited effectiveness, high incidence of side effects, and potential drug interactions of oral neuropathic pain medication. Lacking systemic side effects, topical phenytoin cream offers a promising innovative approach to addressing unmet needs in neuropathic pain treatment. In this retrospective study in patients with PDN, we evaluated the analgesic effect of topical phenytoin cream in response tests and after extended use. Methods: We collected data from PDN patients who, prior to prolonged use of phenytoin 10% or 20% cream, either had an open response test (ORET), a single-blind (SIBRET), or a double-blind (DOBRET) placebo-controlled response test with phenytoin cream between November 2016 and February 2023. A positive ORET was defined as pain reduction of at least two points on the 11-point numerical scale (NRS) within 30 min after phenytoin cream application. A positive SIBRET or DOBRET required an additional pain reduction of 1 NRS point in the phenytoin treated area compared to the placebo. In patients with a positive response test, we evaluated the sustained pain reduction and the proportion of patients experiencing minimum pain relief of at least 30% (MPR30: moderate pain relief) and 50% (MPR50: considerable pain relief) after the extended use of phenytoin cream. We also assessed the correlation between the response test analgesic effect and the sustained pain relief. Results: We identified 65 patients with PDN of whom 31 (47.7%) had a positive response test. The median pain reduction in response tests was 3.0 NRS points (IQR 2.0–4.0). Extended use (median 3.3 months, IQR 1.5–12.1]) resulted in a median pain reduction of 4.0 NRS points (IQR 3.0–5.0); 26/31 (83.9%) of patients achieved MPR30, and 21/31 (67.7%) MPR50 achieved pain relief. The response test analgesic effect correlated significantly with sustained pain relief after extended use (τ = 0.72, p < 0.0001). Conclusions: In PDN patients who had a positive phenytoin cream response test, extended use of phenytoin cream provided a significant sustained pain relief. Full article

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

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19 pages, 6298 KiB

Open AccessArticle

The Melatonin Type 2 Receptor Agonist IIK7 Attenuates and Reverses Morphine Tolerance in Neuropathic Pain Rats Through the Suppression of Neuroinflammation in the Spinal Cord

by Yaswanth Kuthati and Chih-Shung Wong

Pharmaceuticals 2024, 17(12), 1638; https://doi.org/10.3390/ph17121638 - 5 Dec 2024

Cited by 1 | Viewed by 1306

Abstract

Background: Morphine analgesic tolerance (MAT) limits the clinical application of morphine in the management of chronic pain. IIK7 is a melatonin type 2 (MT2) receptor agonist known to have antioxidant properties. Oxidative stress is recognized as a critical factor in MAT. This study [...] Read more.

Background: Morphine analgesic tolerance (MAT) limits the clinical application of morphine in the management of chronic pain. IIK7 is a melatonin type 2 (MT2) receptor agonist known to have antioxidant properties. Oxidative stress is recognized as a critical factor in MAT. This study sought to assess the impact of IIK7 on the progression of MAT and its potential to reverse pre-existing MAT. Methods: Wistar rats underwent partial sciatic nerve transection (PSNT) surgery to induce neuropathic pain (NP). Seven days post nerve transection, we implanted an intrathecal (i.t.) catheter and linked it to an osmotic pump. Rats were randomly divided into the following groups: sham-operated/vehicle, PSNT/vehicle, PSNT/IIK7 50 ng/h, PSNT/MOR 15 g/h, and PSNT/MOR 15 g + IIK7 50 ng/h. We implanted two i.t. catheters for drug administration and the evaluation of the efficacy of IIK7 in reversing pre-established MAT. We linked one to an osmotic pump for MOR or saline continuous i.t. infusion. On the 7th day, the osmotic pump was disconnected, and 50 μg of IIK7 or the vehicle was administered through the second catheter. After 3 h, 15 μg of MOR or saline was administered, and the animal behavior tests were performed. We measured the levels of mRNA for Nrf2 and HO-1, pro-inflammatory cytokines (PICs), and the microglial and astrocyte activation in the spinal cord. Results: The co-administration of IIK7 with MOR delayed MAT development in PSNT rats by restoring Nrf2 and HO-1 while also inhibiting the microglial-cell and astrocyte activation, alongside the suppression of PICs. Additionally, a single injection of high-dose 50 μg IIK7 was efficient in restoring MOR’s antinociception in MOR-tolerant rats. Conclusions: Our results indicate that the co-infusion of ultra-low-dose IIK7 can delay MAT development and a high dose can reverse pre-existing MAT. Full article

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

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12 pages, 4272 KiB

Open AccessArticle

Effects of Short-Term Treatment with α-Lipoic Acid on Neuropathic Pain and Biomarkers of DNA Damage in Patients with Diabetes Mellitus

by Juozas R. Lazutka, Kristina Daniūnaitė, Veronika Dedonytė, Aistė Popandopula, Karolina Žukaitė, Žydrūnė Visockienė and Laura Šiaulienė

Pharmaceuticals 2024, 17(11), 1538; https://doi.org/10.3390/ph17111538 - 16 Nov 2024

Viewed by 2367

Abstract

Background/Objectives: Diabetes mellitus (DM) is a complex and heterogenous disease classified as a group of metabolic disorders characterized by chronic hyperglycemia resulting from defects in insulin secretion, insulin action, or both. It leads to various complications, some of which are macrovascular or microvascular [...] Read more.

Background/Objectives: Diabetes mellitus (DM) is a complex and heterogenous disease classified as a group of metabolic disorders characterized by chronic hyperglycemia resulting from defects in insulin secretion, insulin action, or both. It leads to various complications, some of which are macrovascular or microvascular complications, like diabetic polyneuropathy (DPN), having a profound impact on patients’ quality of life. Oxidative stress (OS) is one of the significant mechanisms in the development and progression of DPN. Thus, targeting OS pathways by antioxidants, such as α-lipoic acid (ALA), could represent a promising therapeutic strategy for alleviating neuropathic symptoms. The aim of our study was to evaluate whether short-term (from 4 to 9 days) intravenous administration of ALA could cause any measurable improvement in subjects with DM. Methods: Sixteen subjects with DM (six type 1 and ten type 2) and sixteen nondiabetic subjects matched by sex and age were recruited to this study. Only subjects with DM received treatment with ALA (600 mg daily). Pain intensity and biomarkers of DNA damage including plasma concentration of 8-hydroxy-2′-deoxyguanosine (8-OHdG), frequency of micronucleated lymphocytes (MN), and frequency of sister-chromatid exchanges (SCEs), were measured before and after the treatment with ALA. Results: Pain intensity and 8-OHdG levels were significantly lower in DM subjects after the ALA treatment than before the treatment. However, no changes in the frequency of SCEs and MN were observed. Conclusions: Our results show some evidence that even a short-term intravenous treatment with ALA could be beneficial for diabetic subjects, reducing pain intensity and concentration of 8-OHdG in blood plasma. Full article

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

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25 pages, 5269 KiB

Open AccessArticle

Discovery of New 3-(Benzo[b]Thiophen-2-yl)Pyrrolidine-2,5-Dione Derivatives as Potent Antiseizure and Antinociceptive Agents—In Vitro and In Vivo Evaluation

by Anna Rapacz, Marcin Jakubiec, Michał Abram, Jakub Jasiński, Karolina Chrzan, Małgorzata Góra, Anna Dziubina, Katarzyna Wójcik-Pszczoła, Paulina Koczurkiewicz-Adamczyk, Katarzyna Ciepiela, Elżbieta Pękala, Jolanta Obniska and Krzysztof Kamiński

Pharmaceuticals 2024, 17(11), 1532; https://doi.org/10.3390/ph17111532 - 15 Nov 2024

Cited by 1 | Viewed by 1061

Abstract

Background/Objectives: To address the unmet clinical needs in the treatment of epilepsy and pain, the continued development of more effective and safer anticonvulsants and analgesics is still necessary. Therefore, herein we report synthesis and antiseizure/antinociceptive evaluation of a focused series of 3-(benzo[b]thiophen-2-yl)pyrrolidine-2,5-dione [...] Read more.

Background/Objectives: To address the unmet clinical needs in the treatment of epilepsy and pain, the continued development of more effective and safer anticonvulsants and analgesics is still necessary. Therefore, herein we report synthesis and antiseizure/antinociceptive evaluation of a focused series of 3-(benzo[b]thiophen-2-yl)pyrrolidine-2,5-dione derivatives. Methods: The anticonvulsant properties were investigated in acute models of seizures, namely the maximal electroshock (MES), the 6 Hz (32 mA), and subcutaneous pentylenetetrazole (scPTZ) seizure models, whereas analgesic activity was tested in the model of a tonic pain/formalin test and oxaliplatin-induced neuropathic pain (in CD-1-mice, i.p.). In addition, a number of in vitro assays were performed, aiming at the evaluation of the drug-like properties of the compounds disclosed herein. Results: We identified 33 as a lead compound with the most promising antiseizure properties, i.e., ED₅₀ (MES) = 27.4 mg/kg and ED₅₀ (6 Hz, 32 mA) = 30.8 mg/kg. Furthermore, 33 at a dose of 100 mg/kg significantly prolonged the latency time to the first seizure episode in the scPTZ model and at high doses did not impaire coordination of mice in the rotarod test (TD₅₀ > 200 mg/kg). Apart from broad antiseizure protection, 33 demonstrated a significant analgesic effect in the formalin test (45 mg/kg, i.p.), and effectively alleviated allodynia in the oxaliplatin-induced neuropathic pain model (30 and 45 mg/kg). The binding assays suggest that the most plausible mechanism of action relies on interaction with the neuronal voltage-sensitive sodium channel (site 2). Furthermore, the drug-like potential of 33 supports favorable in vitro results, i.e., no hepatocytotoxicity and neurocytotoxicity at a high concentration of 100 μM, as well as a lack of mutagenicity at a concentration as high as 500 μM. Conclusions: Compound 33 identified in the current studies is proposed to be an interesting candidate for further preclinical development as therapy for epilepsy and neuropathic pain. Full article

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

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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 4 | Viewed by 2025

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 [...] Read more.

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 3 | Viewed by 1720

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 [...] Read more.

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 14 | Viewed by 3609

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 [...] Read more.

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 - 7 Aug 2023

Cited by 9 | Viewed by 4997

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 [...] Read more.

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 12 | Viewed by 5242

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 [...] Read more.

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 5 | Viewed by 2419

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 [...] Read more.

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

Jump to: Research

34 pages, 16779 KiB

Open AccessReview

Navigating Preclinical Models and Medications for Peripheral Neuropathy: A Review

by Abdulmajeed M. Jali, David Banji, Otilia J. F. Banji, Khalid Y. Hurubi, Faisal Y. Tawhari, Atheer A. Alameer, Atyaf S. Dohal and Raha A. Zanqoti

Pharmaceuticals 2024, 17(8), 1010; https://doi.org/10.3390/ph17081010 - 31 Jul 2024

Cited by 1 | Viewed by 2307

Abstract

Peripheral neuropathy (PN) is a multifaceted disorder characterised by peripheral nerve damage, manifesting in symptoms like pain, weakness, and autonomic dysfunction. This review assesses preclinical models in PN research, evaluating their relevance to human disease and their role in therapeutic development. The Streptozotocin [...] Read more.

Peripheral neuropathy (PN) is a multifaceted disorder characterised by peripheral nerve damage, manifesting in symptoms like pain, weakness, and autonomic dysfunction. This review assesses preclinical models in PN research, evaluating their relevance to human disease and their role in therapeutic development. The Streptozotocin (STZ)-induced diabetic rat model is widely used to simulate diabetic neuropathy but has limitations in faithfully replicating disease onset and progression. Cisplatin-induced PN models are suitable for studying chemotherapy-induced peripheral neuropathy (CIPN) and closely resemble human pathology. However, they may not fully replicate the spectrum of sensory and motor deficits. Paclitaxel-induced models also contribute to understanding CIPN mechanisms and testing neuroprotective agents. Surgical or trauma-induced models offer insights into nerve regeneration and repair strategies. Medications such as gabapentin, pregabalin, duloxetine, and fluoxetine have demonstrated promise in these models, enhancing our understanding of their therapeutic efficacy. Despite progress, developing models that accurately mirror human PN remains imperative due to its complex nature. Continuous refinement and innovative approaches are critical for effective drug discovery. This review underscores the strengths and limitations of current models and advocates for an integrated approach to address the complexities of PN better and optimise treatment outcomes. Full article

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

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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

Cited by 3 | Viewed by 2329

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 [...] Read more.

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 2535

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 [...] Read more.

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 - 4 Aug 2023

Cited by 17 | Viewed by 7331

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 [...] Read more.

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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