scholarly journals Histone methyltransferase G9a diminishes expression of cannabinoid CB1 receptors in primary sensory neurons in neuropathic pain

2020 ◽  
Vol 295 (11) ◽  
pp. 3553-3562 ◽  
Author(s):  
Yi Luo ◽  
Jixiang Zhang ◽  
Lin Chen ◽  
Shao-Rui Chen ◽  
Hong Chen ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Nerve Injury ◽  
Sensory Neurons ◽  
Analgesic Effect ◽  
Spinal Cord Dorsal Horn ◽  
Epigenetic Mechanism ◽  
Mrna Levels ◽  
Primary Sensory Neurons ◽  
Drg Neurons ◽  
Histone 3

Type 1 cannabinoid receptors (CB1Rs) are expressed in the dorsal root ganglion (DRG) and contribute to the analgesic effect of cannabinoids. However, the epigenetic mechanism regulating the expression of CB1Rs in neuropathic pain is unknown. G9a (encoded by the Ehmt2 gene), a histone 3 at lysine 9 methyltransferase, is a key chromatin regulator responsible for gene silencing. In this study, we determined G9a's role in regulating CB1R expression in the DRG and in CB1R-mediated analgesic effects in an animal model of neuropathic pain. We show that nerve injury profoundly reduced mRNA levels of CB1Rs but increased the expression of CB2 receptors in the rat DRG. ChIP results indicated increased enrichment of histone 3 at lysine 9 dimethylation, a G9a-catalyzed repressive histone mark, at the promoter regions of the CB1R genes. G9a inhibition in nerve-injured rats not only up-regulated the CB1R expression level in the DRG but also potentiated the analgesic effect of a CB1R agonist on nerve injury-induced pain hypersensitivity. Furthermore, in mice lacking Ehmt2 in DRG neurons, nerve injury failed to reduce CB1R expression in the DRG and to decrease the analgesic effect of the CB1R agonist. Moreover, nerve injury diminished the inhibitory effect of the CB1R agonist on synaptic glutamate release from primary afferent nerves to spinal cord dorsal horn neurons in WT mice but not in mice lacking Ehmt2 in DRG neurons. Our findings reveal that nerve injury diminishes the analgesic effect of CB1R agonists through G9a-mediated CB1R down-regulation in primary sensory neurons.

scholarly journals BKCa Channel Inhibition by Peripheral Nerve Injury Is Restored by the Xanthine Derivative KMUP-1 in Dorsal Root Ganglia

Cells ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 949
Author(s):  
Kuang-I Cheng ◽  
Kan-Ting Yang ◽  
Chien-Lun Kung ◽  
Yu-Chi Cheng ◽  
Jwu-Lai Yeh ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Patch Clamp ◽  
Peripheral Nerve ◽  
Nerve Injury ◽  
Peripheral Nerve Injury ◽  
Dorsal Root ◽  
Bkca Channel ◽  
Mrna Levels ◽  
Drg Neurons ◽  
Perforated Patch Clamp

This study explored whether KMUP-1 improved chronic constriction injury (CCI)-induced BKCa current inhibition in dorsal root ganglion (DRG) neurons. Rats were randomly assigned to four groups: sham, sham + KMUP-1, CCI, and CCI + KMUP-1 (5 mg/kg/day, i.p.). DRG neuronal cells (L4–L6) were isolated on day 7 after CCI surgery. Perforated patch-clamp and inside-out recordings were used to monitor BKCa currents and channel activities, respectively, in the DRG neurons. Additionally, DRG neurons were immunostained with anti-NeuN, anti-NF200 and anti-BKCa. Real-time PCR was used to measure BKCa mRNA levels. In perforated patch-clamp recordings, CCI-mediated nerve injury inhibited BKCa currents in DRG neurons compared with the sham group, whereas KMUP-1 prevented this effect. CCI also decreased BKCa channel activity, which was recovered by KMUP-1 administration. Immunofluorescent staining further demonstrated that CCI reduced BKCa-channel proteins, and KMUP-1 reversed this. KMUP-1 also changed CCI-reduced BKCa mRNA levels. KMUP-1 prevented CCI-induced neuropathic pain and BKCa current inhibition in a peripheral nerve injury model, suggesting that KMUP-1 could be a potential agent for controlling neuropathic pain.

Antidepressants in Cancer Pain

1991 ◽  
Vol 7 (4) ◽  
pp. 42-44 ◽  
Author(s):  
Alberto E. Panerai ◽  
Mauro Bianchi ◽  
Paola Sacerdote ◽  
Carla Ripamonti ◽  
Vittorio Ventafridda ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Cancer Pain ◽  
Beneficial Effect ◽  
Nerve Injury ◽  
Analgesic Effect ◽  
Tricyclic Antidepressants ◽  
Antidepressant Drugs ◽  
Depressive Illness ◽  
Morphine Analgesia

Studies conducted in recent years have helped define the role of antidepressant drugs in the management of cancer pain. The anti-nociceptive action of these agents seems to be independent of beneficial effect on depression or mood. Among antidepressant drugs, those of the tricyclic class are preferred when an analgesic effect is sought. Their primary application is for pain due to nerve injury, so-called “neuropathic pain”. Although the co-administration of tricyclic antidepressants may increase plasma morphine concentrations, any potentiation of morphine analgesia is thought not to be due to an increased bioavailability of the opiate, but to an intrinsic analgesic effect of antidepressants. On this basis, the use of antidepressants in combination with opioids for the treatment of cancer pain is suitable when a component of deafferentation is present or when there is concomitant depressive illness.

Vasoinhibin Suppresses the Neurotrophic Effects of VEGF and NGF in Newborn Rat Primary Sensory Neurons

2017 ◽  
Vol 106 (3) ◽  
pp. 221-233 ◽  
Author(s):  
Ximena Castillo ◽  
Zesergio Melo ◽  
Alfredo Varela-Echavarría ◽  
Elisa Tamariz ◽  
Rodrigo M. Aroña ◽  
...  
Keyword(s):  
Growth Factor ◽  
Neurite Outgrowth ◽  
Sensory Neurons ◽  
Target Cells ◽  
Vascular Endothelial ◽  
Primary Sensory Neurons ◽  
Drg Neurons ◽  
Newborn Rat ◽  
Akt Phosphorylation ◽  
Endothelial Growth Factor

Background/Aims: Studies on the biological actions of vasoinhibins have focused mainly on endothelial cells. However, there is incipient knowledge about how vasoinhibins affect the nervous system, even if the target cells and mechanisms of action involved in these effects are unknown. Methods: In order to determine if neurons are direct targets of vasoinhibins, we examined cellular outcomes and the intracellular pathways involved in the neuronal actions of vasoinhibins using newborn rat dorsal root ganglion (DRG) neurons as a model system. Results: Vascular endothelial growth factor (VEGF) or nerve growth factor (NGF) treatment for 48 h resulted in neurite outgrowth stimulation in both DRG cultured explants and isolated primary sensory neurons. Interestingly, a recombinant vasoinhibin containing the first 123 amino acids of human prolactin antagonized the VEGF- and NGF-induced stimulation of neurite outgrowth. Vasoinhibin significantly reduced the density of neurites in DRG explants and obliterated neuritogenesis in isolated DRG neurons in primary culture, supporting a direct neuronal effect of vasoinhibin. In cultures of isolated DRG cells, virtually all β3-tubulin-labeled cells express TrkA, and the majority of these cells also express VEGFR2. Short-term VEGF or NGF treatment of DRG explants resulted in increased ERK1/2 and AKT phosphorylation, whereas incubation of DRG with the combination of either VEGF or NGF together with vasoinhibin resulted in blunted VEGF- or NGF-induced phosphorylation of both ERK1/2 and AKT. Conclusion: Our results show that primary sensory neurons are direct targets of vasoinhibin, and suggest that vasoinhibin inhibition of neurite outgrowth involves the disruption of ERK and AKT phosphorylation cascades.

Co-administered gabapentin and venlafaxine in nerve injured rats: Effect on mechanical hypersensitivity, motor function and pharmacokinetics

2010 ◽  
Vol 1 (2) ◽  
pp. 91-97 ◽  
Author(s):  
Anna Folkesson ◽  
Per Hartvig Honoré ◽  
Ole J. Bjerrum
Keyword(s):  
Neuropathic Pain ◽  
Adverse Effects ◽  
Nerve Injury ◽  
Analgesic Effect ◽  
Time Course ◽  
Maximum Effect ◽  
Inhibitory System ◽  
Time Curve ◽  
Mechanical Hypersensitivity ◽  
Prolonged Duration

AbstractA high proportion of patients suffering from neuropathic pain do not receive satisfactory pain relief from their current treatment, due to incomplete efficacy and dose-limiting adverse effects. Hence, one strategy to improve treatment outcome is the use of a combination of analgesic drugs. The potential benefits of such approach include improved and prolonged duration of analgesic effect and fewer or milder adverse effects with lower doses of each drug. Gabapentin is recommended as a first-line drug in the treatment of neuropathic pain, and has recently been demonstrated to act on supraspinal structures to stimulate the descending noradrenergic pain inhibitory system. Hypothetically, the analgesic effect of gabapentin may be potentiated if combined with a drug that prolongs the action of noradrenaline.In this study, gabapentin was co-administered with the serotonin and noradrenaline reuptake inhibitor venlafaxine, and subsequently evaluated for its effect on mechanical hypersensitivity in the rat spared nerve injury model of neuropathic pain. In this model, two branches of the sciatic nerve (the tibial and common peroneal nerves) are ligated and cut, leaving the third branch (the sural nerve) intact to innervate the hind paw of the animal. Treatment-induced ataxia was tested in order to exclude biased effect measurements. Finally, the pharmacokinetics of gabapentin was investigated alone and in combination with venlafaxine to elucidate any alterations which may have consequences for the pharmacological effect and safety.The overall effect on nerve injury-induced hypersensitivity of co-administered gabapentin (60 mg/kg s.c.) and venlafaxine (60 mg/kg s.c.), measured as the area under the effect-time curve during the three hour time course of testing, was similar to the highest dose of gabapentin (200 mg/kg s.c.) tested in the study. However, this dose of gabapentin was associated with ataxia and severe somnolence, while the combination was not. Furthermore, when administered alone, an effect delay of approximately one hour was observed for gabapentin (60 mg/kg s.c.) with maximum effect occurring 1.5 to 2.5 h after dosing, while venlafaxine (60 mg/kg s.c.) was characterised by a rapid onset of action (within 30 min) which declined to baseline levels before the end of the three hour time of testing. The effect of co-administered drugs (both 60 mg/kg s.c.), in the doses used here, can be interpreted as additive with prolonged duration in comparison to each drug administered alone. An isobolographic study design, enable to accurately classify the combination effect into additive, antagonistic or synergistic, was not applied. The pharmacokinetics of gabapentin was not altered by co-administered venlafaxine, implying that a pharmacokinetic interaction does not occur. The effect of gabapentin on the pharmacokinetics of venlafaxine was not studied, since any alterations are unlikely to occur on the basis of the pharmacokinetic properties of gabapentin.In conclusion, the results from this preclinical study support the rationale for improved effect and less adverse effects through combination therapy with gabapentin and venlafaxine in the management of neuropathic pain.

scholarly journals Toll-like receptor 7 contributes to neuropathic pain by activating NF-κB in primary sensory neurons

2020 ◽  
Vol 87 ◽  
pp. 840-851 ◽  
Author(s):  
Long He ◽  
Guang Han ◽  
Shaogen Wu ◽  
Shibin Du ◽  
Yang Zhang ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Sensory Neurons ◽  
Primary Sensory Neurons ◽  
Toll Like Receptor
Sign in / Sign up

Export Citation Format

Share Document