Sign in to use this feature.

Years

Between: -

Subjects

remove_circle_outline
remove_circle_outline
remove_circle_outline
remove_circle_outline
remove_circle_outline
remove_circle_outline

Journals

Article Types

Countries / Regions

Search Results (44)

Search Parameters:
Keywords = opioid-induced hyperalgesia

Order results
Result details
Results per page
Select all
Export citation of selected articles as:
25 pages, 2976 KiB  
Article
Dual Opioid–Neuropeptide FF Small Molecule Ligands Demonstrate Analgesia with Reduced Tolerance Liabilities
by Marco Mottinelli, V. Blair Journigan, Samuel Obeng, Victoria L. C. Pallares, Christophe Mѐsangeau, Coco N. Kapanda, Stephen J. Cutler, Janet A. Lambert, Shainnel O. Eans, Michelle L. Ganno, Wanhui Sheng, Tamara King, Abhisheak Sharma, Catherine Mollereau, Bonnie A. Avery, Jay P. McLaughlin and Christopher R. McCurdy
Molecules 2025, 30(13), 2851; https://doi.org/10.3390/molecules30132851 - 3 Jul 2025
Viewed by 381
Abstract
Neuropeptide FF (NPFF) receptor antagonists prevent morphine-mediated antinociceptive tolerance, and compounds with dual mu opioid receptor (MOR) agonist and NPFF antagonist activity produce antinociception without tolerance. Compounds synthesized showed affinities in radioligand competition binding assays in the nM and µM range at the [...] Read more.
Neuropeptide FF (NPFF) receptor antagonists prevent morphine-mediated antinociceptive tolerance, and compounds with dual mu opioid receptor (MOR) agonist and NPFF antagonist activity produce antinociception without tolerance. Compounds synthesized showed affinities in radioligand competition binding assays in the nM and µM range at the opioid and NPFF receptors, respectively, and displayed substitution-dependent functional profiles in the [35S]GTPγS functional assay. From six compounds screened in vivo for antinociception and ability to prevent NPFF-induced hyperalgesia in mouse warm water tail withdrawal tests, compound 22b produced dose-dependent MOR-mediated antinociception with an ED50 value (and 95% confidence interval) of 6.88 (4.71–9.47) nmol, i.c.v., and also prevented NPFF-induced hyperalgesia. Meanwhile, 22b did not demonstrate the respiratory depression, hyperlocomotion, or impaired intestinal transit of morphine. Moreover, repeated treatment with 22b produced a 1.6-fold rightward shift in antinociceptive dose response, significantly less acute antinociceptive tolerance than morphine. Evaluated for microsomal stability in vitro and in vivo pharmacokinetic profile, 22b showed suitable microsomal stability paired in vivo with a large apparent volume of distribution and a clearance smaller than the hepatic flow in rats, suggesting no extra-hepatic metabolism. In conclusion, the present study confirms that dual-action opioid–NPFF ligands may offer therapeutic promise as analgesics with fewer liabilities of use. Full article
(This article belongs to the Special Issue New Strategies for Drug Development)
Show Figures

Graphical abstract

28 pages, 6389 KiB  
Systematic Review
Pharmacological Efficacy of Intravenous Magnesium in Attenuating Remifentanil-Induced Postoperative Hyperalgesia: A Systematic Review and Meta-Analysis of Randomized Controlled Trials
by En-Bo Wu, Kuen-Lin Wu, Wei-Ti Hsu, Wei-Chin Yuan and Kuen-Bao Chen
Pharmaceuticals 2025, 18(4), 518; https://doi.org/10.3390/ph18040518 - 1 Apr 2025
Viewed by 1182
Abstract
Background/Objectives: Remifentanil-based anesthesia is linked to opioid-induced hyperalgesia (OIH), increasing postoperative pain and analgesic requirements. Magnesium, an N-methyl-D-aspartate (NMDA) receptor antagonist, might alleviate OIH. We aimed to assess whether intravenous magnesium reduces postoperative pain, analgesic requirements, and hyperalgesia in adults receiving remifentanil-based [...] Read more.
Background/Objectives: Remifentanil-based anesthesia is linked to opioid-induced hyperalgesia (OIH), increasing postoperative pain and analgesic requirements. Magnesium, an N-methyl-D-aspartate (NMDA) receptor antagonist, might alleviate OIH. We aimed to assess whether intravenous magnesium reduces postoperative pain, analgesic requirements, and hyperalgesia in adults receiving remifentanil-based anesthesia. Methods: We searched PubMed, Embase, the Cochrane Library, and Web of Science (1 December 2024) for randomized controlled trials (RCTs) comparing intravenous magnesium vs. placebo. Risk of bias was evaluated with the Cochrane RoB 2 tool, and random-effects meta-analyses were conducted. GRADE was used to assess evidence quality. Primary outcomes were postoperative analgesic requirements and pain scores; secondary outcomes included intraoperative remifentanil consumption, shivering, postoperative nausea/vomiting (PONV), extubation time, hypotension, and bradycardia. PROSPERO registration: CRD42024609911. Results: Twenty-two RCTs (n = 1362) met eligibility. Magnesium significantly decreased 24 h analgesic requirements (standardized mean difference [SMD] −1.51; 95% confidence interval [CI] −2.15 to −0.87; p < 0.0001) and pain scores (SMD −0.61; 95% CI −0.90 to −0.32; p < 0.0001), with benefits persisting up to 48 h. It also reduced intraoperative remifentanil use (SMD −0.52), shivering (odds ratio [OR] 0.25), and PONV (OR 0.66), without prolonging extubation or increasing hypotension/bradycardia risk. High heterogeneity, potential publication bias, and moderate-to-very-low evidence certainty warrant caution. Conclusions: Intravenous magnesium appears beneficial in remifentanil-based anesthesia, but further large-scale, methodologically robust trials are needed to confirm optimal and clarify safety profiles across diverse surgical populations. Full article
(This article belongs to the Section Pharmacology)
Show Figures

Figure 1

16 pages, 2931 KiB  
Article
Evaluation of the Antinociceptive Effect of Sesamin: Role of 5HT1A Serotonergic Receptors
by Roberto Camacho-Cruz, David Francisco Alcalá-Hernández, Juan Carlos Huerta-Cruz, Jesús Arrieta-Valencia, María Elena Sánchez-Mendoza, Francisco Javier Flores-Murrieta, Andrés Navarrete, Juan Gerardo Reyes-García and Héctor Isaac Rocha-González
Pharmaceutics 2025, 17(3), 330; https://doi.org/10.3390/pharmaceutics17030330 - 3 Mar 2025
Cited by 1 | Viewed by 978
Abstract
Background/Objectives: Sesame (Sesamum indicum L.) is used in folk medicine to treat painful disorders. Sesamin is the main lignan found in this plant; however, its antinociceptive potential has scarcely been studied. The aim was to investigate the antinociceptive effect of sesamin on [...] Read more.
Background/Objectives: Sesame (Sesamum indicum L.) is used in folk medicine to treat painful disorders. Sesamin is the main lignan found in this plant; however, its antinociceptive potential has scarcely been studied. The aim was to investigate the antinociceptive effect of sesamin on inflammatory and neuropathic pain models, as well as the possible mechanism of action through which sesamin mediates its own antinociceptive effect. Methods: Formalin and carrageenan animal models were used to assess inflammatory pain, whereas an L5/L6-spinal-nerve-ligated rat model was employed to evaluate neuropathic pain. Results: Oral sesamin significantly reduced carrageenan-induced hyperalgesia and inflammation, formalin-induced nociception, and L5/L6-spinal-nerve-ligation-induced allodynia. Sesamin was more effective than diclofenac in the inflammatory pain models, but it was less effective than pregabalin in the neuropathic pain model. The antinociceptive effect of sesamin, in the formalin test, was prevented by the intraperitoneal administration of methiothepin (5-HT1/5 antagonist), but not by naltrexone (an opioid antagonist) or L-NAME (an NOS inhibitor). In addition, WAY-100635 (5-HT1A antagonist), but not SB-224289 (5-HT1B antagonist), BRL-15542 (5-HT1D antagonist), and SB-699551 (5-HT5A antagonist), impeded sesamin-induced antinociception. Conclusions: This study’s results support the use of sesamin to treat inflammatory pain disorders and suggest that 5-HT1A receptors influence the antinociceptive effect of this drug. Full article
(This article belongs to the Special Issue Emerging Drugs and Formulations for Pain Treatment)
Show Figures

Figure 1

25 pages, 1720 KiB  
Review
NMDA Receptors: Distribution, Role, and Insights into Neuropsychiatric Disorders
by Marie Beaurain, Anne-Sophie Salabert, Pierre Payoux, Emmanuel Gras and Franck Talmont
Pharmaceuticals 2024, 17(10), 1265; https://doi.org/10.3390/ph17101265 - 25 Sep 2024
Cited by 8 | Viewed by 9317
Abstract
Background: N-methyl-D-aspartate receptors (NMDARs) are members of the ionotropic glutamate receptor family. These ligand-gated channels are entwined with numerous fundamental neurological functions within the central nervous system (CNS), and numerous neuropsychiatric disorders may arise from their malfunction. Methods: The purpose of the present [...] Read more.
Background: N-methyl-D-aspartate receptors (NMDARs) are members of the ionotropic glutamate receptor family. These ligand-gated channels are entwined with numerous fundamental neurological functions within the central nervous system (CNS), and numerous neuropsychiatric disorders may arise from their malfunction. Methods: The purpose of the present review is to provide a detailed description of NMDARs by addressing their molecular structures, activation mechanisms, and physiological roles in the mammalian brain. In the second part, their role in various neuropsychiatric disorders including stroke, epilepsy, anti-NMDA encephalitis, Alzheimer’s and Huntington’s diseases, schizophrenia, depression, neuropathic pain, opioid-induced tolerance, and hyperalgesia will be covered. Results: Finally, through a careful exploration of the main non-competitive NMDARs antagonists (channel-blockers). Conclusion: We discuss the strengths and limitations of the various molecular structures developed for diagnostic or therapeutic purposes. Full article
(This article belongs to the Special Issue Pharmacological Insight into NMDA Receptor Antagonists)
Show Figures

Figure 1

15 pages, 3246 KiB  
Article
Stimulator of Interferon Genes Pathway Activation through the Controlled Release of STINGel Mediates Analgesia and Anti-Cancer Effects in Oral Squamous Cell Carcinoma
by Minh Phuong Dong, Neeraja Dharmaraj, Estela Kaminagakura, Jianfei Xue, David G. Leach, Jeffrey D. Hartgerink, Michael Zhang, Hana-Joy Hanks, Yi Ye, Bradley E. Aouizerat, Kyle Vining, Carissa M. Thomas, Sinisa Dovat, Simon Young and Chi T. Viet
Biomedicines 2024, 12(4), 920; https://doi.org/10.3390/biomedicines12040920 - 21 Apr 2024
Cited by 1 | Viewed by 2669
Abstract
Oral squamous cell carcinoma (OSCC) presents significant treatment challenges due to its poor survival and intense pain at the primary cancer site. Cancer pain is debilitating, contributes to diminished quality of life, and causes opioid tolerance. The stimulator of interferon genes (STING) agonism [...] Read more.
Oral squamous cell carcinoma (OSCC) presents significant treatment challenges due to its poor survival and intense pain at the primary cancer site. Cancer pain is debilitating, contributes to diminished quality of life, and causes opioid tolerance. The stimulator of interferon genes (STING) agonism has been investigated as an anti-cancer strategy. We have developed STINGel, an extended-release formulation that prolongs the availability of STING agonists, which has demonstrated an enhanced anti-tumor effect in OSCC compared to STING agonist injection. This study investigates the impact of intra-tumoral STINGel on OSCC-induced pain using two separate OSCC models and nociceptive behavioral assays. Intra-tumoral STINGel significantly reduced mechanical allodynia in the orofacial cancer model and alleviated thermal and mechanical hyperalgesia in the hind paw model. To determine the cellular signaling cascade contributing to the antinociceptive effect, we performed an in-depth analysis of immune cell populations via single-cell RNA-seq. We demonstrated an increase in M1-like macrophages and N1-like neutrophils after STINGel treatment. The identified regulatory pathways controlled immune response activation, myeloid cell differentiation, and cytoplasmic translation. Functional pathway analysis demonstrated the suppression of translation at neuron synapses and the negative regulation of neuron projection development in M2-like macrophages after STINGel treatment. Importantly, STINGel treatment upregulated TGF-β pathway signaling between various cell populations and peripheral nervous system (PNS) macrophages and enhanced TGF-β signaling within the PNS itself. Overall, this study sheds light on the mechanisms underlying STINGel-mediated antinociception and anti-tumorigenic impact. Full article
Show Figures

Figure 1

11 pages, 526 KiB  
Article
Effect of Remimazolam on Pain Perception and Opioid-Induced Hyperalgesia in Patients Undergoing Laparoscopic Urologic Surgery—A Prospective, Randomized, Controlled Study
by Cheol Lee, Junsung Lim, Hansol Hong, Hyungjong Yu and Hayoung Lee
Medicina 2024, 60(1), 123; https://doi.org/10.3390/medicina60010123 - 9 Jan 2024
Cited by 5 | Viewed by 2324
Abstract
Background and Objectives: The effects of midazolam, a benzodiazepine, on pain perception are complex on both spinal and supraspinal levels. It is not yet known whether remimazolam clinically attenuates or worsens pain. The present study investigated the effect of intraoperative remimazolam on [...] Read more.
Background and Objectives: The effects of midazolam, a benzodiazepine, on pain perception are complex on both spinal and supraspinal levels. It is not yet known whether remimazolam clinically attenuates or worsens pain. The present study investigated the effect of intraoperative remimazolam on opioid-induced hyperalgesia (OIH) in patients undergoing general anesthesia. Materials and Methods: The patients were randomized into three groups: group RHR (6 mg/kg/h initial dose followed by 1 mg/kg/h remimazolam and 0.3 μg /kg/min remifentanil), group DHR (desflurane and 0.3 μg /kg/min remifentanil) or group DLR (desflurane and 0.05 µg/kg /min remifentanil). The primary outcome was a mechanical hyperalgesia threshold, while secondary outcomes included an area of hyperalgesia and clinically relevant pain outcomes. Results: Group RHR had a higher mechanical hyperalgesia threshold, a smaller hyperalgesia postoperative area at 24 h, a longer time to first rescue analgesia (p = 0.04), lower cumulative PCA volume containing morphine postoperatively consumed for 24 h (p < 0.01), and lower pain intensity for 12 h than group DHR (p < 0.001). However, there was no significant difference in OIH between groups RHR and DLR. Conclusions: Group RHR, which received remimazolam, attenuated OIH, including mechanically evoked pain and some clinically relevant pain outcomes caused by a high dose of remifentanil. Further research is essential to determine how clinically meaningful and important the small differences observed between the two groups are. Full article
(This article belongs to the Section Intensive Care/ Anesthesiology)
Show Figures

Figure 1

20 pages, 997 KiB  
Review
Fibromyalgia Animal Models Using Intermittent Cold and Psychological Stress
by Hiroshi Ueda and Hiroyuki Neyama
Biomedicines 2024, 12(1), 56; https://doi.org/10.3390/biomedicines12010056 - 25 Dec 2023
Cited by 5 | Viewed by 3576
Abstract
Fibromyalgia (FM) is a chronic pain condition characterized by widespread musculoskeletal pain and other frequent symptoms such as fatigue, sleep disturbance, cognitive impairment, and mood disorder. Based on the view that intermittent stress would be the most probable etiology for FM, intermittent cold- [...] Read more.
Fibromyalgia (FM) is a chronic pain condition characterized by widespread musculoskeletal pain and other frequent symptoms such as fatigue, sleep disturbance, cognitive impairment, and mood disorder. Based on the view that intermittent stress would be the most probable etiology for FM, intermittent cold- and intermittent psychological stress-induced generalized pain (ICGP and IPGP) models in mice have been developed and validated as FM-like pain models in terms of the patho-physiological and pharmacotherapeutic features that are shared with clinical versions. Both models show long-lasting and generalized pain and female-predominant sex differences after gonadectomy. Like many other neuropathic pain models, ICGP and IPGP were abolished in lysophosphatidic acid receptor 1 (LPAR1) knock-out mice or by LPAR1 antagonist treatments, although deciding the clinical importance of this mechanism depends on waiting for the development of a clinically available LPAR1 antagonist. On the other hand, the nonsteroidal anti-inflammatory drug diclofenac with morphine did not suppress hyperalgesia in these models, and this is consistent with the clinical findings. Pharmacological studies suggest that the lack of morphine analgesia is associated with opioid tolerance upon the stress-induced release of endorphins and subsequent counterbalance through anti-opioid NMDA receptor mechanisms. Regarding pharmacotherapy, hyperalgesia in both models was suppressed by pregabalin and duloxetine, which have been approved for FM treatment in clinic. Notably, repeated treatments with mirtazapine, an α2 adrenergic receptor antagonist-type antidepressant, and donepezil, a drug for treating Alzheimer’s disease, showed potent therapeutic actions in these models. However, the pharmacotherapeutic treatment should be carried out 3 months after stress, which is stated in the FM guideline, and many preclinical studies, such as those analyzing molecular and cellular mechanisms, as well as additional evidence using different animal models, are required. Thus, the ICGP and IPGP models have the potential to help discover and characterize new therapeutic medicines that might be used for the radical treatment of FM, although there are several limitations to be overcome. Full article
(This article belongs to the Special Issue Advanced Research on Fibromyalgia)
Show Figures

Figure 1

18 pages, 3479 KiB  
Article
Identification and Pharmacological Characterization of a Low-Liability Antinociceptive Bifunctional MOR/DOR Cyclic Peptide
by Yangmei Li, Shainnel O. Eans, Michelle Ganno-Sherwood, Abbe Eliasof, Richard A. Houghten and Jay P. McLaughlin
Molecules 2023, 28(22), 7548; https://doi.org/10.3390/molecules28227548 - 11 Nov 2023
Cited by 5 | Viewed by 2042
Abstract
Peptide-based opioid ligands are important candidates for the development of novel, safer, and more effective analgesics to treat pain. To develop peptide-based safer analgesics, we synthesized a mixture-based cyclic pentapeptide library containing a total of 24,624 pentapeptides and screened the mixture-based library samples [...] Read more.
Peptide-based opioid ligands are important candidates for the development of novel, safer, and more effective analgesics to treat pain. To develop peptide-based safer analgesics, we synthesized a mixture-based cyclic pentapeptide library containing a total of 24,624 pentapeptides and screened the mixture-based library samples using a 55 °C warm water tail-withdrawal assay. Using this phenotypic screening approach, we deconvoluted the mixture-based samples to identify a novel cyclic peptide Tyr-[D-Lys-Dap(Ant)-Thr-Gly] (CycloAnt), which produced dose- and time-dependent antinociception with an ED50 (and 95% confidence interval) of 0.70 (0.52–0.97) mg/kg i.p. mediated by the mu-opioid receptor (MOR). Additionally, higher doses (≥3 mg/kg, i.p.) of CycloAnt antagonized delta-opioid receptors (DOR) for at least 3 h. Pharmacological characterization of CycloAnt showed the cyclic peptide did not reduce breathing rate in mice at doses up to 15 times the analgesic ED50 value, and produced dramatically less hyperlocomotion than the MOR agonist, morphine. While chronic administration of CycloAnt resulted in antinociceptive tolerance, it was without opioid-induced hyperalgesia and with significantly reduced signs of naloxone-precipitated withdrawal, which suggested reduced physical dependence compared to morphine. Collectively, the results suggest this dual MOR/DOR multifunctional ligand is an excellent lead for the development of peptide-based safer analgesics. Full article
Show Figures

Graphical abstract

13 pages, 2424 KiB  
Article
Behavioral Effects and Analgesic Profile of Hemoglobin-Derived Valorphin and Its Synthetic Analog in Rodents
by Petar Todorov, Borislav Assenov, Dimo Angelov, Elena Dzhambazova and Daniela Pechlivanova
Biomedicines 2023, 11(10), 2783; https://doi.org/10.3390/biomedicines11102783 - 13 Oct 2023
Cited by 1 | Viewed by 1437
Abstract
Valorphin (V1) is a naturally occurring peptide derived from hemoglobin that has been found to have an affinity for opioid receptors and exhibits antinociceptive and anticonvulsant activity. Some of its synthetic analogs containing an aminophosphonate moiety show structure-dependent potent antinociceptive effects. This study [...] Read more.
Valorphin (V1) is a naturally occurring peptide derived from hemoglobin that has been found to have an affinity for opioid receptors and exhibits antinociceptive and anticonvulsant activity. Some of its synthetic analogs containing an aminophosphonate moiety show structure-dependent potent antinociceptive effects. This study aimed to reveal a detailed picture of the antinociceptive mechanisms and behavioral effects of V1 and its recently synthesized phosphopeptide analog V2p in rodents using a range of methods. The studied peptides significantly reduced acute (mean V1–9.0, V2p–5.8 vs. controls–54.1 s) and inflammatory (mean V1–57.9 and V2p–53.3 vs. controls–107.6 s) nociceptive pain in the formalin test, as well as carrageenan-induced hyperalgesia (mean V1–184.7 and V2p–107.3 vs. controls–61.8 g) in the paw pressure test. These effects are mediated by activation of opioid receptors with a predominance of kappa in V1 antinociception and by delta, kappa, and mu receptors in V2p-induced antinociception. Both peptides did not change the levels of TNF-alpha and IL-1-beta in blood serum. V1 induces depression-like behavior, and V2p shows a tendency toward anxiolysis and short-term impairment of motor coordination without affecting exploratory behavior. The results characterize valorphin and its derivative as promising analgesics that exert their effects both centrally and peripherally, without causing severe behavioral changes in experimental animals. These encouraging data are a foundation for future studies focusing on the effects of hemorphins after long-term treatment. Full article
(This article belongs to the Section Drug Discovery, Development and Delivery)
Show Figures

Graphical abstract

12 pages, 1505 KiB  
Article
The Effects of Intraoperative Remifentanil Infusion on Postoperative Opioid Consumption in Patients Who Underwent Total Knee Arthroplasty with Femoral Nerve Block
by Chanjong Chung, Jinyoung Choi, Taeyoung Lee and Sangyoong Park
J. Clin. Med. 2023, 12(15), 4975; https://doi.org/10.3390/jcm12154975 - 28 Jul 2023
Cited by 2 | Viewed by 1892
Abstract
(1) Background: Remifentanil is used for intraoperative pain control; however, it has several side effects, such as hypotension and opioid-induced hyperalgesia. We aimed to determine whether an intraoperative remifentanil infusion may increase postoperative opioid consumption in patients undergoing total knee arthroscopy (TKA) under [...] Read more.
(1) Background: Remifentanil is used for intraoperative pain control; however, it has several side effects, such as hypotension and opioid-induced hyperalgesia. We aimed to determine whether an intraoperative remifentanil infusion may increase postoperative opioid consumption in patients undergoing total knee arthroscopy (TKA) under femoral nerve block (FNB) in addition to general anesthesia. (2) Methods: We randomly assigned 66 patients who underwent total knee arthroplasty to the remifentanil (R) and control (C) groups. All patients underwent FNB and popliteal artery and posterior capsule of the knee (iPACK) block in addition to sevoflurane-based general anesthesia. Postoperative pain control was achieved using intravenous patient-controlled analgesia (IV-PCA) fentanyl. We recorded IV-PCA fentanyl consumption at various postoperative timepoints, numerical rating scale (NRS) scores, intraoperative changes in vital signs and index of nociception (qNOX), ephedrine consumption, postoperative side effects, satisfaction, and sleep quality. (3) Results: The primary outcome (the cumulative IV-PCA fentanyl usage within 48 h postoperatively) was significantly lower in the C group (541.1 ± 294.5 µg) than in the R group (717.5 ± 224.0 µg) (p < 0.001). The secondary outcome (the cumulative IV-PCA fentanyl usage within 12, 24, and 72 h) was lower in the C group than in the R group and the mean arterial pressure was lower in the R group than in the C group from immediately after tourniquet on to immediately after tourniquet off. The heart rate was lower in the R group from immediately after incision to immediately after irrigation. There was no significant between-group difference in the perioperative qNOX and NRS scores at rest and activity except for NRS scores at 72 h postoperatively. Ephedrine use was higher in the R group than in the C group (p = 0.003). There was no significant between-group difference in the incidence of postoperative nausea and vomiting, nor in the postoperative satisfaction and sleep quality. (4) Conclusions: Avoiding intraoperative remifentanil infusion may reduce total opioid consumption in patients undergoing FNB before TKA. Full article
(This article belongs to the Section Anesthesiology)
Show Figures

Figure 1

14 pages, 1097 KiB  
Article
Morphine Withdrawal-Induced Hyperalgesia in Models of Acute and Extended Withdrawal Is Attenuated by l-Tetrahydropalmatine
by Daria Oleinichenko, Soyon Ahn, Ru Song, Terrance P. Snutch and Anthony G. Phillips
Int. J. Mol. Sci. 2023, 24(10), 8872; https://doi.org/10.3390/ijms24108872 - 17 May 2023
Cited by 5 | Viewed by 2978
Abstract
Effective pain control is an underappreciated aspect of managing opioid withdrawal, and its absence presents a significant barrier to successful opioid detoxification. Accordingly, there is an urgent need for effective non-opioid treatments to facilitate opioid detoxification. l-Tetrahydropalmatine (l-THP) possesses powerful [...] Read more.
Effective pain control is an underappreciated aspect of managing opioid withdrawal, and its absence presents a significant barrier to successful opioid detoxification. Accordingly, there is an urgent need for effective non-opioid treatments to facilitate opioid detoxification. l-Tetrahydropalmatine (l-THP) possesses powerful analgesic properties and is an active ingredient in botanical formulations used in Vietnam for the treatment of opioid withdrawal syndrome. In this study, rats receiving morphine (15 mg/kg, i.p.) for 5 days per week displayed a progressive increase in pain thresholds during acute 23 h withdrawal as assessed by an automated Von Frey test. A single dose of l-THP (5 or 7.5 mg/kg, p.o.) administered during the 4th and 5th weeks of morphine treatment significantly improves pain tolerance scores. A 7-day course of l-THP treatment in animals experiencing extended withdrawal significantly attenuates hyperalgesia and reduces the number of days to recovery to baseline pain thresholds by 61% when compared to vehicle-treated controls. This indicates that the efficacy of l-THP on pain perception extends beyond its half-life. As a non-opioid treatment for reversing a significant hyperalgesic state during withdrawal, l-THP may be a valuable addition to the currently limited arsenal of opioid detoxification treatments. Full article
(This article belongs to the Special Issue Recent Progress of Opioid Research)
Show Figures

Figure 1

10 pages, 878 KiB  
Review
The Role of The Rostral Ventromedial Medulla in Stress Responses
by Marco Pagliusi and Felipe V. Gomes
Brain Sci. 2023, 13(5), 776; https://doi.org/10.3390/brainsci13050776 - 9 May 2023
Cited by 12 | Viewed by 6909
Abstract
The rostral ventromedial medulla (RVM) is a brainstem structure critical for the descending pain modulation system involved in both pain facilitation and inhibition through its projection to the spinal cord. Since the RVM is well connected with pain- and stress-engaged brain structures, such [...] Read more.
The rostral ventromedial medulla (RVM) is a brainstem structure critical for the descending pain modulation system involved in both pain facilitation and inhibition through its projection to the spinal cord. Since the RVM is well connected with pain- and stress-engaged brain structures, such as the anterior cingulate cortex, nucleus accumbens, and amygdala, its involvement in stress responses has become a matter of great interest. While chronic stress has been proposed as a trigger of pain chronification and related psychiatric comorbidities due to maladaptive stress responses, acute stress triggers analgesia and other adaptative responses. Here we reviewed and highlighted the critical role of the RVM in stress responses, mainly in acute stress-induced analgesia (SIA) and chronic stress-induced hyperalgesia (SIH), providing insights into pain chronification processes and comorbidity between chronic pain and psychiatric disorders. Full article
(This article belongs to the Section Behavioral Neuroscience)
Show Figures

Figure 1

17 pages, 3178 KiB  
Article
Antinociceptive Effects of Aaptamine, a Sponge Component, on Peripheral Neuropathy in Rats
by Chun-Sung Sung, Hao-Jung Cheng, Nan-Fu Chen, Shih-Hsuan Tang, Hsiao-Mei Kuo, Ping-Jyun Sung, Wu-Fu Chen and Zhi-Hong Wen
Mar. Drugs 2023, 21(2), 113; https://doi.org/10.3390/md21020113 - 4 Feb 2023
Cited by 14 | Viewed by 2980
Abstract
Aaptamine, a natural marine compound isolated from the sea sponge, has various biological activities, including delta-opioid agonist properties. However, the effects of aaptamine in neuropathic pain remain unclear. In the present study, we used a chronic constriction injury (CCI)-induced peripheral neuropathic rat model [...] Read more.
Aaptamine, a natural marine compound isolated from the sea sponge, has various biological activities, including delta-opioid agonist properties. However, the effects of aaptamine in neuropathic pain remain unclear. In the present study, we used a chronic constriction injury (CCI)-induced peripheral neuropathic rat model to explore the analgesic effects of intrathecal aaptamine administration. We also investigated cellular angiogenesis and lactate dehydrogenase A (LDHA) expression in the ipsilateral lumbar spinal cord after aaptamine administration in CCI rats by immunohistofluorescence. The results showed that aaptamine alleviates CCI-induced nociceptive sensitization, allodynia, and hyperalgesia. Moreover, aaptamine significantly downregulated CCI-induced vascular endothelial growth factor (VEGF), cluster of differentiation 31 (CD31), and LDHA expression in the spinal cord. Double immunofluorescent staining showed that the spinal VEGF and LDHA majorly expressed on astrocytes and neurons, respectively, in CCI rats and inhibited by aaptamine. Collectively, our results indicate aaptamine’s potential as an analgesic agent for neuropathic pain. Furthermore, inhibition of astrocyte-derived angiogenesis and neuronal LDHA expression might be beneficial in neuropathy. Full article
Show Figures

Figure 1

25 pages, 3275 KiB  
Article
Unique, Specific CART Receptor-Independent Regulatory Mechanism of CART(55-102) Peptide in Spinal Nociceptive Transmission and Its Relation to Dipeptidyl-Peptidase 4 (DDP4)
by Márk Kozsurek, Kornél Király, Klára Gyimesi, Erika Lukácsi, Csaba Fekete, Balázs Gereben, Petra Mohácsik, Zsuzsanna Helyes, Kata Bölcskei, Valéria Tékus, Károly Pap, Edina Szűcs, Sándor Benyhe, Tímea Imre, Pál Szabó, Andrea Gajtkó, Krisztina Holló and Zita Puskár
Int. J. Mol. Sci. 2023, 24(2), 918; https://doi.org/10.3390/ijms24020918 - 4 Jan 2023
Cited by 3 | Viewed by 4069
Abstract
Cocaine- and amphetamine-regulated transcript (CART) peptides are involved in several physiological and pathological processes, but their mechanism of action is unrevealed due to the lack of identified receptor(s). We provided evidence for the antihyperalgesic effect of CART(55-102) by inhibiting dipeptidyl-peptidase 4 (DPP4) in [...] Read more.
Cocaine- and amphetamine-regulated transcript (CART) peptides are involved in several physiological and pathological processes, but their mechanism of action is unrevealed due to the lack of identified receptor(s). We provided evidence for the antihyperalgesic effect of CART(55-102) by inhibiting dipeptidyl-peptidase 4 (DPP4) in astrocytes and consequently reducing neuroinflammation in the rat spinal dorsal horn in a carrageenan-evoked inflammation model. Both naturally occurring CART(55-102) and CART(62-102) peptides are present in the spinal cord. CART(55-102) is not involved in acute nociception but regulates spinal pain transmission during peripheral inflammation. While the full-length peptide with a globular motif contributes to hyperalgesia, its N-terminal inhibits this process. Although the anti-hyperalgesic effects of CART(55-102), CART(55-76), and CART(62-76) are blocked by opioid receptor antagonists in our inflammatory models, but not in neuropathic Seltzer model, none of them bind to any opioid or G-protein coupled receptors. DPP4 interacts with Toll-like receptor 4 (TLR4) signalling in spinal astrocytes and enhances the TLR4-induced expression of interleukin-6 and tumour necrosis factor alpha contributing to inflammatory pain. Depending on the state of inflammation, CART(55-102) is processed in the spinal cord, resulting in the generation of biologically active isoleucine-proline-isoleucine (IPI) tripeptide, which inhibits DPP4, leading to significantly decreased glia-derived cytokine production and hyperalgesia. Full article
(This article belongs to the Special Issue Molecular Links between Sensory Nerves, Inflammation, and Pain 2.0)
Show Figures

Figure 1

10 pages, 1215 KiB  
Article
Efficacy of Dexmedetomidine vs. Remifentanil for Postoperative Analgesia and Opioid-Related Side Effects after Gynecological Laparoscopy: A Prospective Randomized Controlled Trial
by Jung Min Koo, Youn-Jee Chung, Mihyeon Lee and Young Eun Moon
J. Clin. Med. 2023, 12(1), 350; https://doi.org/10.3390/jcm12010350 - 2 Jan 2023
Cited by 8 | Viewed by 2950
Abstract
Remifentanil is widely used for intraoperative analgesia, but often causes remifentanil-induced hyperalgesia (RIH) and related side effects. Dexmedetomidine, a non-opioid analgesic, has been used as an alternative to remifentanil to prevent RIH. We aimed to investigate the effect of dexmedetomidine on postoperative recovery [...] Read more.
Remifentanil is widely used for intraoperative analgesia, but often causes remifentanil-induced hyperalgesia (RIH) and related side effects. Dexmedetomidine, a non-opioid analgesic, has been used as an alternative to remifentanil to prevent RIH. We aimed to investigate the effect of dexmedetomidine on postoperative recovery after gynecological laparoscopy. Ninety-six adult patients undergoing elective gynecological laparoscopy were randomly assigned to the dexmedetomidine or remifentanil groups. The primary outcome was the pain score at 30 min after surgery. The secondary outcomes were intraoperative adverse events (hypotension and bradycardia) and postoperative opioid-related side effects (nausea, vomiting, requirement for rescue analgesics, and shivering). We also performed an ancillary cytokine study to evaluate oxidative stress, one of the causes of RIH. Compared with the remifentanil group, the dexmedetomidine group had lower pain scores at 30 min after surgery (4.0 ± 1.9 vs. 6.1 ± 2.0, mean ± SD, p < 0.001) and lower incidence of intraoperative hypotension and postoperative nausea, vomiting, and shivering. Furthermore, the proportion of patients requiring rescue analgesics was significantly lower in the dexmedetomidine than in the remifentanil group (25% vs. 66.7%, p < 0.001). Cytokine levels did not differ between the groups. Dexmedetomidine showed a better analgesic effect with minimal opioid-related side effects and is considered superior to remifentanil for intraoperative analgesia. Full article
(This article belongs to the Section Obstetrics & Gynecology)
Show Figures

Figure 1

Back to TopTop