scholarly journals Galanin Receptor 1 Plays an Antinociceptive Effect via Inhibiting PKA Activation in the Nucleus Accumbens of Rats With Neuropathic Pain

2019 ◽  
pp. 511-518 ◽  
Author(s):  
Y. ZHANG ◽  
Y. GAO ◽  
C.-Y. LI ◽  
W. DONG ◽  
Y. DONG ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Nucleus Accumbens ◽  
Sciatic Nerve ◽  
Antinociceptive Effect ◽  
Underlying Mechanism ◽  
Galanin Receptor ◽  
Nociceptive Information ◽  
The Central Nervous System ◽  
Galanin Receptors ◽  
Galanin Receptor 1

Galanin and galanin receptors (GalRs) have been reported to be involved in the transmission and modulation of nociceptive information in the central nervous system (CNS). However, the underlying mechanism of the antinociception of GalRs in neuropathic pain remains unclear. This study investigated the antinociception induced by galanin receptor 1 (GalR1) via protein kinase A (PKA) signaling pathway in the nucleus accumbens (NAc) of rats with neuropathic pain. A mononeuropathy model was replicated by ligation of the left sciatic nerve, following which the expression of phospho-PKA (p-PKA) in the NAc were markedly up-regulated at 14th and 28th day after ligation of sciatic nerve, and p-PKA expression was down-regulated by intra-NAc injection of GalR1 agonist M617, but the GalR1 antagonist M35 did not have an effect. We also found that M35 in the NAc blocked the M617-induced increase in the hind paw withdrawal latencies (HWLs) of rats with mononeuropathy, but M35 alone had no effect on HWLs, and PKA inhibitor H-89 attenuated the M617-induced an increase in the HWLs. These results suggested that GalR1 induced an antinociception via inhibiting PKA activation, implying that GalR agonists may be potential and potent therapeutic options to treat chronic neuropathic pain.

scholarly journals The activation of galanin receptor 2 plays an antinociceptive effect in nucleus accumbens of rats with neuropathic pain

2021 ◽  
Vol 71 (1) ◽  
Author(s):  
Yan Dong ◽  
Chong-Yang Li ◽  
Xiao-Min Zhang ◽  
Ya-Nan Liu ◽  
Shuang Yang ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Nucleus Accumbens ◽  
Pain Threshold ◽  
Antinociceptive Effect ◽  
Galanin Receptor ◽  
Pain Model ◽  
Withdrawal Threshold ◽  
Neuropathic Pain Model ◽  
Galanin Receptors ◽  
Intact Rats

AbstractOur previous research has shown that galanin plays an antinociceptive effect via binding to galanin receptors (GalRs) in nucleus accumbens (NAc). This study focused on the involvement of GalR2 in galanin-induced antinociceptive effect in NAc of neuropathic pain rats. The chronic constriction injury of sciatic nerve (CCI) was used to mimic neuropathic pain model. The hind paw withdrawal latency (HWL) to thermal stimulation and hind paw withdrawal threshold (HWT) to mechanical stimulation were measured as the indicators of pain threshold. The results showed that 14 and 28 days after CCI, the expression of GalR2 was up-regulated in bilateral NAc of rats, and intra-NAc injection of GalR2 antagonist M871 reversed galanin-induced increases in HWL and HWT of CCI rats. Furthermore, intra-NAc injection of GalR2 agonist M1145 induced increases in HWL and HWT at day 14 and day 28 after CCI, which could also be reversed by M871. Finally, we found that M1145-induced antinociceptive effect in NAc of CCI rats was stronger than that in intact rats. These results imply that the GalR2 is activated in the NAc from day 14 to day 28 after CCI and GalR2 is involved in the galanin-induced antinociceptive effect in NAc of CCI rats.

Antinociceptive roles of galanin receptor 1 in nucleus accumbens of rats in a model of neuropathic pain

2015 ◽  
Vol 93 (10) ◽  
pp. 1542-1551 ◽  
Author(s):  
Hao Duan ◽  
Ying Zhang ◽  
Xiao-Min Zhang ◽  
Huan-Huan Xu ◽  
Jun Shu ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Nucleus Accumbens ◽  
Galanin Receptor ◽  
Galanin Receptor 1

scholarly journals The Effects of Dexmedetomidine Alone and in Combination with Tramadol or Amitriptyline in a Neuropathic Pain Model

2014 ◽  
Vol 2;17 (2;3) ◽  
pp. 187-195 ◽  
Author(s):  
Hanan S. M. Farghaly
Keyword(s):  
Neuropathic Pain ◽  
Side Effects ◽  
Sciatic Nerve ◽  
Mechanical Allodynia ◽  
Chronic Constriction Injury ◽  
Antinociceptive Effect ◽  
Underlying Mechanism ◽  
Mechanical Tests ◽  
Α2 Adrenoceptor ◽  
Cci Model

Background: Interactions between the sympathetic and somatic nervous system play an essential role in the pathophysiologic mechanisms of neuropathic pain. The α2-adrenoceptor agonists produce effective antinociception, but sedation is an important adverse effect. Multidrug therapy is potentially valuable to decrease side effects. Objective: The aim of the present study was to investigate the possible antinociceptive effect of dexmedetomidine, an α2-adrenoceptor agonist, and its combination with front-line treatment of neuropathic pain, i.e., amitriptyline or tramadol, in a chronic constriction injury (CCI) model of the sciatic nerve in rats. Study Design: Controlled animal study. Methods: Following unilateral ligation of the left sciatic nerve, the effect of intraperitoneal (i.p.) dexmedetomidine (5μg/kg), tramadol (5 mg/kg), and amitriptyline (30 mg/kg) on mechanical allodynia (measured by electrical von Frey apparatus) and hyperalgesia (measured by Randall and Selitto test) was studied. Results: The sham-operated rats and un-operated hind paw (right paw) press normally on the floor reproduced by a weighted pain score of 0. Behavioral and mechanical tests confirmed the development of neuropathic pain after CCI. All individual drugs and dexmedetomidine combination with either tramadol or amitriptyline were effective in reducing mechanical allodynia and hyperalgesia. Dexmedetomidine, amitriptyline, tramadol, amitriptyline+dexmedetomidine, and tramadol+dexmedetomidine combination did not produce any sedation/motor impairment (P > 0.05). Limitations: Although the combination of these drugs improved the CCI model of neuropathic pain in this study, an additional interpretation of the underlying mechanism(s) will be needed to confirm these findings. Conclusion: The combination of these drugs appears to be more effective in increasing the pain threshold after peripheral nerve injury, when compared with the administration of either of amitriptyline or tramadol alone and should be considered as a possible alternative to decrease side effects of individual drug therapy. Key words: Allodynia, amitriptyline, chronic constriction injury, dexmedetomidine, hyperalgesia, neuropathic pain, rat, tramadol

scholarly journals Relief of neuropathic pain by cell-specific manipulation of nucleus accumbens dopamine D1- and D2-receptor-expressing neurons

2022 ◽  
Vol 15 (1) ◽  
Author(s):  
Daisuke Sato ◽  
Michiko Narita ◽  
Yusuke Hamada ◽  
Tomohisa Mori ◽  
Kenichi Tanaka ◽  
...  
Keyword(s):  
Chronic Pain ◽  
Neuropathic Pain ◽  
Nucleus Accumbens ◽  
Sciatic Nerve ◽  
Nerve Injury ◽  
D2 Receptor ◽  
D1 Receptor ◽  
Cholinergic Interneurons ◽  
Chronic Pain Conditions ◽  
Stimulation Of

AbstractEmerging evidence suggests that the mesolimbic dopaminergic network plays a role in the modulation of pain. As chronic pain conditions are associated with hypodopaminergic tone in the nucleus accumbens (NAc), we evaluated the effects of increasing signaling at dopamine D1/D2-expressing neurons in the NAc neurons in a model of neuropathic pain induced by partial ligation of sciatic nerve. Bilateral microinjection of either the selective D1-receptor (Gs-coupled) agonist Chloro-APB or the selective D2-receptor (Gi-coupled) agonist quinpirole into the NAc partially reversed nerve injury-induced thermal allodynia. Either optical stimulation of D1-receptor-expressing neurons or optical suppression of D2-receptor-expressing neurons in both the inner and outer substructures of the NAc also transiently, but significantly, restored nerve injury-induced allodynia. Under neuropathic pain-like condition, specific facilitation of terminals of D1-receptor-expressing NAc neurons projecting to the VTA revealed a feedforward-like antinociceptive circuit. Additionally, functional suppression of cholinergic interneurons that negatively and positively control the activity of D1- and D2-receptor-expressing neurons, respectively, also transiently elicited anti-allodynic effects in nerve injured animals. These findings suggest that comprehensive activation of D1-receptor-expressing neurons and integrated suppression of D2-receptor-expressing neurons in the NAc may lead to a significant relief of neuropathic pain.

scholarly journals 1,3,4-Oxadiazole Derivative Attenuates Chronic Constriction Injury Induced Neuropathic Pain: A Computational, Behavioral, and Molecular Approach

2020 ◽  
Vol 10 (10) ◽  
pp. 731
Author(s):  
Muhammad Faheem ◽  
Syed Hussain Ali ◽  
Abdul Waheed Khan ◽  
Mahboob Alam ◽  
Umair Ilyas ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Neuropathic Pain ◽  
Sciatic Nerve ◽  
Pain Perception ◽  
Chronic Constriction Injury ◽  
Neuroprotective Effect ◽  
Underlying Mechanism ◽  
Contributing Factors ◽  
Neuroprotective Effects ◽  
In Silico Studies

The production and up-regulation of inflammatory mediators are contributing factors for the development and maintenance of neuropathic pain. In the present study, the post-treatment of synthetic 1,3,4 oxadiazole derivative (B3) for its neuroprotective potential in chronic constriction injury-induced neuropathic pain was applied. In-silico studies were carried out through Auto Dock, PyRx, and DSV to obtain the possible binding and interactions of the ligands (B3) with COX-2, IL-6, and iNOS. The sciatic nerve of the anesthetized rat was constricted with sutures 3/0. Treatment with 1,3,4-oxadiazole derivative was started a day after surgery and continued until the 14th day. All behavioral studies were executed on day 0, 3rd, 7th, 10th, and 14th. The sciatic nerve and spinal cord were collected for further molecular analysis. The interactions in the form of hydrogen bonding stabilizes the ligand target complex. B3 showed three hydrogen bonds with IL-6. B3, in addition to correcting paw posture/deformation induced by CCI, attenuates hyperalgesia (p < 0.001) and allodynia (p < 0.001). B3 significantly raised the level of GST and GSH in both the sciatic nerve and spinal cord and reduced the LPO and iNOS (p < 0.001). B3 attenuates the pathological changes induced by nerve injury, which was confirmed by H&E staining and IHC examination. B3 down-regulates the over-expression of the inflammatory mediator IL-6 and hence provides neuroprotective effects in CCI-induced pain. The results demonstrate that B3 possess anti-nociceptive and anti-hyperalgesic effects and thus minimizes pain perception and inflammation. The possible underlying mechanism for the neuroprotective effect of B3 probably may be mediated through IL-6.

Galanin plays a role in antinociception via binding to galanin receptors in the nucleus accumbens of rats with neuropathic pain

2019 ◽  
Vol 706 ◽  
pp. 93-98 ◽  
Author(s):  
Ying Zhang ◽  
Yi Gao ◽  
Chong-Yang Li ◽  
Wei Dong ◽  
Meng-Nan Li ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Nucleus Accumbens ◽  
Galanin Receptors

scholarly journals Conditioned medium from the stem cells of human exfoliated deciduous teeth ameliorates neuropathic pain in a partial sciatic nerve ligation model

2021 ◽  
Author(s):  
Yao Liu ◽  
Fumiya Kano ◽  
Noboru Hashimoto ◽  
Linze Xia ◽  
Hideharu Hibi ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Stem Cells ◽  
Neuropathic Pain ◽  
Sciatic Nerve ◽  
Dental Pulp ◽  
Dorsal Root ◽  
Antinociceptive Effect ◽  
Deciduous Teeth ◽  
M2 Macrophages ◽  
Partial Sciatic Nerve Ligation

Abstract BackgroundAlthough recent studies have revealed the powerful antinociceptive effect of human dental pulp stem cells in an animal model for diabetes and osteoarthritis, its analgesic mechanisms are still largely elusive. We have previously reported that conditioned medium (CM) from dental pulp stem cells of deciduous teeth (SHED-CM) or its components, monocyte chemoattractant protein-1 (MCP-1) and the secreted ectodomain of sialic acid-binding Ig-like lectin-9 (sSiglec-9), directly induces anti-inflammatory M2 macrophages, however the antinociceptive activity of induced M2 is unknown. In this study, we investigated the antinociceptive effect of SHED-CM, MCP-1, and sSiglec-9 or secretome from M2-induced by SHED-CM (M2-CM) against neuropathic pain (NP) using a partial sciatic nerve ligation (PSL) mouse model and analyzed the mechanical bases of their antinociceptive effects. MethodsPSL mice were treated using SHED-CM with or without mannosylated-Clodrosome, specifically depleting M2 macrophages, recombinant MCP-1 and sSiglec-9 protein, M2-CM, or fibroblast-CM. Human Schwann cells activated by TNF-α in vitro were treated with M2-CM. The expression of pro-inflammatory mediators, neuroprotective factors, the nociceptive receptor, and markers for M1, M2, and activated glial cells in injured sciatic nerve (SCN), dorsal root ganglion, or spinal cord were evaluated by RT-PCR and immunohistochemistry. Mechanical allodynia of PSL mice was analyzed via von Frey test. ResultsIn the behavioral test, intravenous administration of SHED-CM greatly improved the PSL-induced hypersensitivity. SHED-CM treatment recruited M2 macrophages in the injured SCN and ipsilateral L4/L5 dorsal root ganglion and suppressed microglial activation in the spinal cord. Specific depletion of the M2 by mannosylated-Clodrosome markedly reduced the antinociceptive effect of SHED-CM. Intravenous administration of both MCP-1/sSiglec-9 and M2-CM ameliorated the PSL-induced hypersensitivity. We found that M2-CM directly suppressed the expression of nociceptive receptors as well as proinflammatory mediators in Schwann cells. ConclusionTaken together, our data suggest that SHED-CM ameliorates NP through the induction of the analgesic anti-inflammatory M2 macrophages. Thus, SHED-CM may present as a potential novel therapeutic candidate for NP.

scholarly journals Conditioned Medium of Bone Marrow-Derived Mesenchymal Stromal Cells as a Therapeutic Approach to Neuropathic Pain: A Preclinical Evaluation

2018 ◽  
Vol 2018 ◽  
pp. 1-12 ◽  
Author(s):  
Kelly Barbosa Gama ◽  
Dourivaldo Silva Santos ◽  
Afrânio Ferreira Evangelista ◽  
Daniela Nascimento Silva ◽  
Adriano Costa de Alcântara ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Neuropathic Pain ◽  
Sciatic Nerve ◽  
Conditioned Medium ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Therapeutic Potential ◽  
Antinociceptive Effect ◽  
Live Cells ◽  
Reference Drug

Neuropathic pain is a type of chronic pain caused by injury or dysfunction of the nervous system, without effective therapeutic approaches. Mesenchymal stromal cells (MSCs), through their paracrine action, have great potential in the treatment of this syndrome. In the present study, the therapeutic potential of MSC-derived conditioned medium (CM) was investigated in a mouse model of neuropathic pain induced by partial sciatic nerve ligation (PSL). PSL mice were treated by endovenous route with bone marrow-derived MSCs (1 × 106), CM, or vehicle. Gabapentin was the reference drug. Twelve hours after administration, neuropathic mice treated with CM exhibited an antinociceptive effect that was maintained throughout the evaluation period. MSCs also induced nonreversed antinociception, while gabapentin induced short-lasting antinociception. The levels of IL-1β, TNF-α, and IL-6 were reduced, while IL-10 was enhanced on sciatic nerve and spinal cord by treatment with CM and MSCs. Preliminary analysis of the CM secretome revealed the presence of growth factors and cytokines likely involved in the antinociception. In conclusion, the CM, similar to injection of live cells, produces a powerful and long-lasting antinociceptive effect on neuropathic pain, which is related with modulatory properties on peripheral and central levels of cytokines involved with the maintenance of this syndrome.

Functional interaction between N-methyl-D-aspartate receptor and ascorbic acid during neuropathic pain induced by chronic constriction injury of the sciatic nerve

2017 ◽  
Vol 28 (6) ◽  
Author(s):  
Sepideh Saffarpour ◽  
Farinaz Nasirinezhad
Keyword(s):  
Ascorbic Acid ◽  
Neuropathic Pain ◽  
Sciatic Nerve ◽  
Nmda Receptors ◽  
Pain Threshold ◽  
Chronic Constriction Injury ◽  
Single Injection ◽  
Antinociceptive Effect ◽  
Pain Condition

AbstractBackground:Neuropathic pain is a chronic pain condition, which is resistant to therapy. Ascorbate was released because of the activation of glutaminergic neurons. Due to the important role of N-methyl-D-aspartate (NMDA) receptors in the pathophysiology of neuropathic pain, this study investigated the analgesic efficacy of ascorbic acid (AA) in neuropathic pain condition and the role of NMDA receptors in this effect.Methods:For this purpose, adult male rats were randomly allocated to experimental groups (n=8 in each group). Neuropathic pain was induced by chronic constriction injury (CCI) of the sciatic nerve. During the second week after CCI, animals received a single injection of 1, 3, 5, or 10 mg/kg of AA intraperitoneally and pain threshold was determined 15 and 60 min later. The antinociceptive effect of chronic administration was also evaluated by intraperitoneal injection (IP) of 3 mg/kg AA for 3 weeks. To determine the role of NMDA receptors, separate groups of animals 30 min after single injection of AA (1 mg/kg) animals received i.p. injection of ketamine (5 mg/kg), MK-801 (0.01 mg/kg), or glutamate (1000 nmol) and were tested 20 min afterwards. Data analyzed by ANOVA and Newman-Keuls tests and p<0.05 were considered as significant.Results:IP of 3, 5 and 10 mg/kg increased the pain threshold during the second week after CCI (p<0.05,Conclusions:The results indicated that AA produced a dose-dependent antinociceptive effect that seems to mediate through its interaction with NMDA receptors.

scholarly journals Role of the galanin N-terminal fragment (1-15) in anhedonia: Involvement of the dopaminergic mesolimbic system

2019 ◽  
Vol 33 (6) ◽  
pp. 737-747 ◽  
Author(s):  
Carmelo Millón ◽  
Antonio Flores-Burgess ◽  
Belén Gago ◽  
Francisco Alén ◽  
Laura Orio ◽  
...  
Keyword(s):  
Positron Emission Tomography ◽  
Nucleus Accumbens ◽  
Ventral Tegmental Area ◽  
Emission Tomography ◽  
Galanin Receptor ◽  
Mesolimbic System ◽  
Mediated Effects ◽  
Terminal Fragment ◽  
Positron Emission ◽  
Galanin Receptors

Background: Anhedonia is a core feature of depressive disorders. The galanin N-terminal fragment (1-15) plays a role in mood regulation since it induces depression and anxiogenic-like effects in rats. In this study, we analysed galanin N-terminal fragment (1-15) actions in anhedonic-like behaviours in rats using operant and non-operant tests and the areas involved with these effects. Methods: Galanin N-terminal fragment (1-15) effects were analysed in saccharin self-administration, sucrose preference, novelty-suppressed feeding and female urine sniffing tests. The areas involved in galanin N-terminal fragment (1-15)-mediated effects were studied with positron emission tomography for in vivo imaging, and we analysed the ventral tegmental area and nucleus accumbens. Galanin N-terminal fragment (1-15) had effects on the mRNA expression of the dopamine transporters Dat and Vmat2; the C-Fos gene; the dopamine receptors D1, D2, D3, D5; and the galanin receptors 1 and 2. Results: Galanin N-terminal fragment (1-15) at a concentration of 3 nmol induced a strong anhedonia-like phenotype in all tests. The involvement of galanin receptor 2 was demonstrated with the galanin receptor 2 antagonist M871 (3 nmol). The 18F-fluorodeoxyglucose positron emission tomography images indicated the action of galanin N-terminal fragment (1-15) over several nuclei of the limbic system. Galanin N-terminal fragment (1-15)-mediated effects also involved changes in the expression of Dat, Vmat2, D3 and galanin receptors in the ventral tegmental area as well as the expression of C-Fos, D1, D2 and D3 and TH immunoreactivity in the nucleus accumbens. Conclusions: Our results indicated that galanin N-terminal fragment (1-15) exerts strong anhedonic-like effects and that this effect was accompanied by changes in the dopaminergic mesolimbic system. These results may provide a basis for the development of novel therapeutic strategies using galanin N-terminal fragment (1-15) analogues for the treatment of depression and reward-related diseases.

Sign in / Sign up

Export Citation Format

Share Document