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International Journal of Molecular... Apr 2024Venom peptides have evolved to target a wide range of membrane proteins through diverse mechanisms of action and structures, providing promising therapeutic leads for...
Venom peptides have evolved to target a wide range of membrane proteins through diverse mechanisms of action and structures, providing promising therapeutic leads for diseases, including pain, epilepsy, and cancer, as well as unique probes of ion channel structure-function. In this work, a high-throughput FLIPR window current screening assay on T-type Ca3.2 guided the isolation of a novel peptide named ω-Buthitoxin-Hf1a from scorpion crude venom. At only 10 amino acid residues with one disulfide bond, it is not only the smallest venom peptide known to target T-type Cas but also the smallest structured scorpion venom peptide yet discovered. Synthetic Hf1a peptides were prepared with C-terminal amidation (Hf1a-NH) or a free C-terminus (Hf1a-OH). Electrophysiological characterization revealed Hf1a-NH to be a concentration-dependent partial inhibitor of Ca3.2 (IC = 1.18 μM) and Ca3.3 (IC = 0.49 μM) depolarized currents but was ineffective at Ca3.1. Hf1a-OH did not show activity against any of the three T-type subtypes. Additionally, neither form showed activity against N-type Ca2.2 or L-type calcium channels. The three-dimensional structure of Hf1a-NH was determined using NMR spectroscopy and used in docking studies to predict its binding site at Ca3.2 and Ca3.3. As both Ca3.2 and Ca3.3 have been implicated in peripheral pain signaling, the analgesic potential of Hf1a-NH was explored in vivo in a mouse model of incision-induced acute post-surgical pain. Consistent with this role, Hf1a-NH produced antiallodynia in both mechanical and thermal pain.
Topics: Animals; Calcium Channels, T-Type; Mice; Scorpion Venoms; Hyperalgesia; Disease Models, Animal; Pain, Postoperative; Calcium; Male; Humans; Calcium Channel Blockers
PubMed: 38731963
DOI: 10.3390/ijms25094745 -
Molecules (Basel, Switzerland) Apr 2024Various plant species from the genus have been claimed to be beneficial for pain relief. The PRISMA approach was adopted to identify studies that reported analgesic... (Review)
Review
Various plant species from the genus have been claimed to be beneficial for pain relief. The PRISMA approach was adopted to identify studies that reported analgesic properties of plants from the genus. Out of 450 records returned, 19 primary studies revealed the analgesic potential of nine species including (1) , (2) , (3) , (4) , (5) , (6) , (7) , (8) and (9) . Six of the species, 1, 3, 4, 7, 8 and 9, demonstrated peripheral antinociceptive properties as they inhibited acetic-acid-induced writhing in animal models. Species 1, 3, 4, 8 and 9 further showed effects via the central analgesic route at the spinal level by increasing the latencies of heat stimulated-nocifensive responses in the tail flick assay. The hot plate assay also revealed the efficacies of 4 and 9 at the supraspinal level. Species 6 was reported to ameliorate hyperalgesia induced via partial sciatic nerve ligation (PSNL). The antinociceptive effects of 1 and 3 were attributed to the regulatory effects of their bioactive compounds on inflammatory mediators. As for 2 and 5, their analgesic effect may be a result of their activity with the 5-hydroxytryptamine 1A receptor (5-HTR) which disrupted the pain-stimulating actions of 5-HT. Antinociceptive activities were documented for various major compounds of the plants. Overall, the findings suggested species as good sources of antinociceptive compounds that can be further developed to complement or substitute prescription drugs for pain management.
Topics: Litsea; Analgesics; Animals; Plant Extracts; Pain; Humans
PubMed: 38731572
DOI: 10.3390/molecules29092079 -
Molecules (Basel, Switzerland) Apr 2024L. (hemp) is a herbaceous plant rich in cannabinoids with a long history of use in pain treatment. The most well-characterized cannabinoids, cannabidiol (CBD) and...
L. (hemp) is a herbaceous plant rich in cannabinoids with a long history of use in pain treatment. The most well-characterized cannabinoids, cannabidiol (CBD) and Δ9-tetrahydrocannabinol (Δ9-THC), garnered much attention in chemotherapy-induced peripheral neuropathy (CIPN) treatment. However, few studies have investigated the biological benefits and mechanism of hemp extract on CIPN. In the present study, hemp extract (JG) rich in cannabinoids was extracted by supercritical fluid carbon dioxide extraction (SFCE). The antinociceptive efficacy was evaluated using a paclitaxel-induced peripheral neuropathy (PIPN) rat model based on behavioral tests. Further omics-based approaches were applied to explore the potential mechanisms. The results showed that JG decreased mechanical allodynia, thermal hyperalgesia, and inflammatory cytokines in PIPN rats significantly. Transcriptome analysis identified seven key genes significantly regulated by JG in PIPN model rats, mainly related to the neuroactive ligand-receptor interaction pathway, PPAR signaling pathway, and cAMP signaling pathway. In metabolomic analysis, a total of 39 significantly altered metabolites were identified, mainly correlated with pentose and glucuronate interconversions and the glycerophospholipid metabolism pathway. Gut microbiota analysis suggested that increased community and in PIPN rats can be reversed significantly by JG. In conclusion, hemp extract exhibited antinociceptive effects on PIPN. The analgesic mechanism was probably related to the regulation of inflammation, neuroactive ligand-receptor interaction pathway, sphingolipid metabolism, etc. This study provides novel insights into the functional interactions of L. extract on PIPN.
Topics: Animals; Cannabis; Neuralgia; Plant Extracts; Rats; Analgesics; Paclitaxel; Male; Metabolomics; Disease Models, Animal; Hyperalgesia; Cannabinoids; Multiomics
PubMed: 38731449
DOI: 10.3390/molecules29091958 -
Cells Apr 2024Strain differences have been reported for motor behaviors, and only a subset of spinal cord injury (SCI) patients develop neuropathic pain, implicating genetic or...
Strain differences have been reported for motor behaviors, and only a subset of spinal cord injury (SCI) patients develop neuropathic pain, implicating genetic or genomic contribution to this condition. Here, we evaluated neuropsychiatric behaviors in A/J, BALB/c, and C57BL/6 male mice and tested genetic or genomic alterations following SCI. A/J and BALB/c naive mice showed significantly less locomotor activity and greater anxiety-like behavior than C57BL/6 mice. Although SCI elicited locomotor dysfunction, C57BL/6 and A/J mice showed the best and the worst post-traumatic recovery, respectively. Mild (m)-SCI mice showed deficits in gait dynamics. All moderate/severe SCI mice exhibited similar degrees of anxiety/depression. mSCI in BALB/c and A/J mice resulted in depression, whereas C57BL/6 mice did not exhibit depression. mSCI mice had significantly lower mechanical thresholds than their controls, indicating high cutaneous hypersensitivity. C57BL/6, but not A/J and BLAB/c mice, showed significantly lower heat thresholds than their controls. C57BL/6 mice exhibited spontaneous pain. RNAseq showed that genes in immune responses and wound healing were upregulated, although A/J mice showed the largest increase. The cell cycle and the truncated isoform of trkB genes were robustly elevated in SCI mice. Thus, different genomics are associated with post-traumatic recovery, underscoring the likely importance of genetic factors in SCI.
Topics: Animals; Spinal Cord Injuries; Hyperalgesia; Locomotion; Mice; Depression; Male; Mice, Inbred C57BL; Disease Models, Animal; Species Specificity
PubMed: 38727295
DOI: 10.3390/cells13090759 -
BMC Musculoskeletal Disorders May 2024The development of neuropathic pain (NP) is one of the reasons why the pain is difficult to treat, and microglial activation plays an important role in NP. Recently,...
BACKGROUND
The development of neuropathic pain (NP) is one of the reasons why the pain is difficult to treat, and microglial activation plays an important role in NP. Recently, platelet-rich plasma (PRP) has emerged as a novel therapeutic method for knee osteoarthritis (KOA). However, it's unclarified whether PRP has analgesic effects on NP induced by KOA and the underlying mechanisms unknown.
PURPOSE
To observe the analgesic effects of PRP on NP induced by KOA and explore the potential mechanisms of PRP in alleviating NP.
METHODS
KOA was induced in male rats with intra-articular injections of monosodium iodoacetate (MIA) on day 0. The rats received PRP or NS (normal saline) treatment at days 15, 17, and 19 after modeling. The Von Frey and Hargreaves tests were applied to assess the pain-related behaviors at different time points. After euthanizing the rats with deep anesthesia at days 28 and 42, the corresponding tissues were taken for subsequent experiments. The expression of activating transcription factor 3 (ATF3) in dorsal root ganglia (DRG) and ionized-calcium-binding adapter molecule-1(Iba-1) in the spinal dorsal horn (SDH) was detected by immunohistochemical staining. In addition, the knee histological assessment was performed by hematoxylin-eosin (HE) staining.
RESULTS
The results indicated that injection of MIA induced mechanical allodynia and thermal hyperalgesia, which could be reversed by PRP treatment. PRP downregulated the expression of ATF3 within the DRG and Iba-1 within the SDH. Furthermore, an inhibitory effect on cartilage degeneration was observed in the MIA + PRP group only on day 28.
CONCLUSION
These results indicate that PRP intra-articular injection therapy may be a potential therapeutic agent for relieving NP induced by KOA. This effect could be attributed to downregulation of microglial activation and reduction in nerve injury.
Topics: Animals; Platelet-Rich Plasma; Male; Neuralgia; Microglia; Rats; Rats, Sprague-Dawley; Osteoarthritis, Knee; Down-Regulation; Activating Transcription Factor 3; Ganglia, Spinal; Disease Models, Animal; Injections, Intra-Articular; Calcium-Binding Proteins; Iodoacetic Acid; Microfilament Proteins
PubMed: 38725009
DOI: 10.1186/s12891-024-07437-7 -
The Journal of Headache and Pain May 2024GABA, a key inhibitory neurotransmitter, has synaptic and extrasynaptic receptors on the postsynaptic neuron. Background GABA, which spills over from the synaptic cleft,...
BACKGROUND
GABA, a key inhibitory neurotransmitter, has synaptic and extrasynaptic receptors on the postsynaptic neuron. Background GABA, which spills over from the synaptic cleft, acts on extrasynaptic delta subunit containing GABAA receptors. The role of extrasynaptic GABAergic input in migraine is unknown. We investigated the susceptibility to valid migraine-provoking substances with clinically relevant behavioral readouts in Genetic Absence Epilepsy of Rats Strasbourg (GAERS), in which the GABAergic tonus was altered. Subsequently, we screened relevant GABAergic mechanisms in Wistar rats by pharmacological means to identify the mechanisms.
METHODS
Wistar and GAERS rats were administered nitroglycerin (10 mg/kg) or levcromakalim (1 mg/kg). Mechanical allodynia and photophobia were assessed using von Frey monofilaments and a dark-light box. Effects of GAT-1 blocker tiagabine (5 mg/kg), GABAB receptor agonist baclofen (2 mg/kg), synaptic GABAA receptor agonist diazepam (1 mg/kg), extrasynaptic GABAA receptor agonists gaboxadol (4 mg/kg), and muscimol (0.75 mg/kg), T-type calcium channel blocker ethosuximide (100 mg/kg) or synaptic GABAA receptor antagonist flumazenil (15 mg/kg) on levcromakalim-induced migraine phenotype were screened.
RESULTS
Unlike Wistar rats, GAERS exhibited no reduction in mechanical pain thresholds or light aversion following nitroglycerin or levcromakalim injection. Ethosuximide did not reverse the resistant phenotype in GAERS, excluding the role of T-type calcium channel dysfunction in this phenomenon. Tiagabine prevented levcromakalim-induced mechanical allodynia in Wistar rats, suggesting a key role in enhanced GABA spillover. Baclofen did not alleviate mechanical allodynia. Diazepam failed to mitigate levcromakalim-induced migraine phenotype. Additionally, the resistant phenotype in GAERS was not affected by flumazenil. Extrasynaptic GABAA receptor agonists gaboxadol and muscimol inhibited periorbital allodynia in Wistar rats.
CONCLUSION
Our study introduced a rat strain resistant to migraine-provoking agents and signified a critical involvement of extrasynaptic δGABAergic receptors. Extrasynaptic δ GABAA receptors, by mediating constant background inhibition on the excitability of neurons, stand as a novel drug target with a therapeutic potential in migraine.
Topics: Animals; Rats, Wistar; Migraine Disorders; Rats; Receptors, GABA-A; Male; Phenotype; Disease Models, Animal; Hyperalgesia; Epilepsy, Absence; Nitroglycerin; Photophobia
PubMed: 38724972
DOI: 10.1186/s10194-024-01777-4 -
The Journal of Headache and Pain May 2024Chronic migraine (CM) is a debilitating neurofunctional disorder primarily affecting females, characterized by central sensitization. Central sensitization refers to the...
BACKGROUND
Chronic migraine (CM) is a debilitating neurofunctional disorder primarily affecting females, characterized by central sensitization. Central sensitization refers to the enhanced response to sensory stimulation, which involves changes in neuronal excitability, synaptic plasticity, and neurotransmitter release. Environmental enrichment (EE) can increase the movement, exploration, socialization and other behaviors of mice. EE has shown promising effects in various neurological disorders, but its impact on CM and the underlying mechanism remains poorly understood. Therefore, the purpose of this study was to determine whether EE has the potential to serve as a cost-effective intervention strategy for CM.
METHODS
A mouse CM model was successfully established by repeated administration of nitroglycerin (NTG). We selected adult female mice around 8 weeks old, exposed them to EE for 2 months, and then induced the CM model. Nociceptive threshold tests were measured using Von Frey filaments and a hot plate. The expression of c-Fos, calcitonin gene-related peptide (CGRP) and inflammatory response were measured using WB and immunofluorescence to evaluate central sensitization. RNA sequencing was used to find differentially expressed genes and signaling pathways. Finally, the expression of the target differential gene was investigated.
RESULTS
Repeated administration of NTG can induce hyperalgesia in female mice and increase the expression of c-Fos and CGRP in the trigeminal nucleus caudalis (TNC). Early exposure of mice to EE reduced NTG-induced hyperalgesia in CM mice. WB and immunofluorescence revealed that EE inhibited the overexpression of c-Fos and CGRP in the TNC of CM mice and alleviated the inflammatory response of microglia activation. RNA sequencing analysis identified that several central sensitization-related signaling pathways were altered by EE. VGluT1, a key gene involved in behavior, internal stimulus response, and ion channel activity, was found to be downregulated in mice exposed to EE.
CONCLUSION
EE can significantly ameliorate hyperalgesia in the NTG-induced CM model. The mechanisms may be to modulate central sensitization by reducing the expression of CGRP, attenuating the inflammatory response, and downregulating the expression of VGluT1, etc., suggesting that EE can serve as an effective preventive strategy for CM.
Topics: Animals; Nitroglycerin; Migraine Disorders; Hyperalgesia; Female; Disease Models, Animal; Central Nervous System Sensitization; Mice; Calcitonin Gene-Related Peptide; Environment; Mice, Inbred C57BL
PubMed: 38724948
DOI: 10.1186/s10194-024-01779-2 -
Frontiers in Pain Research (Lausanne,... 2024This study investigates the impact of combining psychophysical stress, induced by forced swim (FSS), with masseter inflammation on reactive oxygen species (ROS)...
This study investigates the impact of combining psychophysical stress, induced by forced swim (FSS), with masseter inflammation on reactive oxygen species (ROS) production in trigeminal ganglia (TG), TRPA1 upregulation in TG, and mechanical hyperalgesia. In a rat model, we demonstrate that FSS potentiates and prolongs CFA-induced ROS upregulation within TG. The ROS levels in CFA combined with FSS group surpass those in the CFA-only group on days 4 and 28 post-treatment. FSS also enhances TRPA1 upregulation in TG, with prolonged expression compared to CFA alone. Furthermore, CFA-induced mechanical hyperalgesia is significantly prolonged by FSS, persisting up to day 28. PCR array analyses reveal distinct alterations in oxidative stress genes under CFA and CFA combined with FSS conditions, suggesting an intricate regulation of ROS within TG. Notably, genes like , , , and exhibit significant changes, providing potential targets for managing oxidative stress and inflammatory pain. Western blot and immunohistochemistry confirm DUOX1 protein upregulation and localization in TG neurons, indicating a role in ROS generation under inflammatory and stress conditions. This study underscores the complex interplay between psychophysical stress, inflammation, and oxidative stress in the trigeminal system, offering insights into novel therapeutic targets for pain management.
PubMed: 38721062
DOI: 10.3389/fpain.2024.1372942 -
Pediatric Neurology Jul 2024The pediatric migraine phenotype may exhibit differences to adults, leading to diagnostic challenges. We aimed to perform a cross-sectional systematic study to...
BACKGROUND
The pediatric migraine phenotype may exhibit differences to adults, leading to diagnostic challenges. We aimed to perform a cross-sectional systematic study to characterize the extended phenotype of pediatric migraine.
METHODS
New migraine patients presenting to the Children's Headache Clinic were included (n = 105). Data were collected via a detailed symptom questionnaire at the first clinical encounter and were analyzed using descriptive statistics, Cohen kappa (k), Spearman correlation (ρ), and Poisson and binomial logistic regression models within SPSS.
RESULTS
Patients were 65% female and aged five to 17 years (median 14, interquartile range [IQR] 11 to 15), with a mean disease duration of 4.7 years (S.D. 2.8). Monthly headache frequency was 1 to 30 days (median 30, IQR 12 to 30). Attack duration varied between 2 and 168 hours (median 12, IQR 5 to 72). The majority (81%) experienced bilateral headache. Premonitory symptoms (PS) were reported by 93% (range 0 to 7; mood change and tiredness most commonly), cranial autonomic symptoms (CAS) by 58% (range 0 to 6; pallor and lacrimation most commonly), and premonitory CAS by 23%. Vertigo (53%) and allodynia (16%) were present. The laterality of headache and CAS showed agreement (k = 0.5, P < 0.001). For every year of disease duration, 1.07 times more PS were reported (95% confidence interval [CI] 1.03 to 1.12, P < 0.001). The number of CAS (odds ratio 2.13, 95% CI 1.2 to 3.8, P = 0.01) significantly predicted allodynia.
CONCLUSIONS
Children display a more enriched PS phenotype with disease chronicity. CAS and allodynia may be markers of central sensitization with shared neurobiological mechanisms in the absence of peripheral nociceptor activation.
Topics: Humans; Migraine Disorders; Cross-Sectional Studies; Female; Child; Male; Adolescent; Phenotype; Child, Preschool
PubMed: 38718550
DOI: 10.1016/j.pediatrneurol.2024.03.026 -
Molecular Pain 2024Recent studies have shown that peripheral nerve regeneration process is closely related to neuropathic pain. Toll-like receptor 4 (TLR4) signaling was involved in...
Recent studies have shown that peripheral nerve regeneration process is closely related to neuropathic pain. Toll-like receptor 4 (TLR4) signaling was involved in different types of pain and nerve regeneration. TLR4 induced the recruitment of myeloid differentiation factor-88 adaptor protein (MyD88) and NF-κB-depended transcriptional process in sensory neurons and glial cells, which produced multiple cytokines and promoted the induction and persistence of pain. Our study aimed to investigate procyanidins's effect on pain and nerve regeneration via TLR4-Myd88 signaling. Spinal nerve ligation (SNL) model was established to measure the analgesic effect of procyanidins. Anatomical measurement of peripheral nerve regeneration was measured by microscopy and growth associated protein 43 (GAP43) staining. Western blotting and/or immunofluorescent staining were utilized to detect TLR4, myeloid differentiation factor-88 adaptor protein (MyD88), ionized calcium-binding adapter molecule 1 (IBA1) and nuclear factor kappa-B-p65 (NF-κB-p65) expression, as well as the activation of astrocyte and microglia. The antagonist of TLR4 (LPS-RS-Ultra, LRU) were intrathecally administrated to assess the behavioral effects of blocking TLR4 signaling on pain and nerve regeneration. Procyanidins reduced mechanical allodynia, thermal hyperalgesia and significantly suppressed the number of nerve fibers regenerated and the degree of myelination in SNL model. Compared with sham group, TLR4, MyD88, IBA1 and phosphorylation of NF-κB-p65 were upregulated in SNL rats which were reversed by procyanidins administration. Additionally, procyanidins also suppressed activation of spinal astrocytes and glial cells. Suppression of TLR4-MyD88 signaling contributes to the alleviation of neuropathic pain and reduction of nerve regeneration by procyanidins.
Topics: Animals; Proanthocyanidins; Toll-Like Receptor 4; Neuralgia; Myeloid Differentiation Factor 88; Nerve Regeneration; Signal Transduction; Rats, Sprague-Dawley; Male; Grape Seed Extract; Rats; Microglia; Astrocytes; Spinal Nerves
PubMed: 38716504
DOI: 10.1177/17448069241256466