scholarly journals GPR55 and GPR119 Receptors Contribute to the Processing of Neuropathic Pain in Rats

2022 ◽  
Vol 15 (1) ◽  
pp. 67
Author(s):  
Ángel Zúñiga-Romero ◽  
Quetzali Rivera-Plata ◽  
Jesús Arrieta ◽  
Francisco Javier Flores-Murrieta ◽  
Juan Rodríguez-Silverio ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
G Protein ◽  
Protein Localization ◽  
Intrathecal Administration ◽  
Spinal Nerve ◽  
Spinal Cord Dorsal ◽  
Gpr119 Agonist ◽  
G Protein Coupled ◽  
Dose Dependent ◽  
Antiallodynic Effect

Orphan G-protein-coupled receptors (GPCR) comprise a large number of receptors which are widely distributed in the nervous system and represent an opportunity to identify new molecular targets in pain medicine. GPR55 and GPR119 are two orphan GPCR receptors whose physiological function is unclear. The aim was to explore the participation of spinal GPR55 and GPR119 in the processing of neuropathic pain in rats. Mechanical allodynia was evaluated using von Frey filaments. Protein localization and modulation were measured by immunohistochemistry and western blotting, respectively. Intrathecal administration of CID16020046 (selective GPR55 antagonist) or AS1269574 (selective GPR119 agonist) produced a dose-dependent antiallodynic effect, whereas O1062 (GPR55 agonist) and G-protein antagonist peptide dose-dependently prevented the antiallodynic effect of CID16020046 and AS1269574, respectively. Both GPR55 and GPR119 receptors were expressed in spinal cord, dorsal root ganglia and sciatic nerve, but only GPR119 was downregulated after 14 days of spinal nerve ligation. Data suggest that GPR55 and GPR119 participate in the processing of neuropathic pain and could be useful targets to manage neuropathic pain disorders.

Intrathecal Clonidine Alleviates Allodynia in Neuropathic Rats 

1999 ◽  
Vol 90 (2) ◽  
pp. 509-514 ◽  
Author(s):  
Hui-Lin Pan ◽  
Shao-Rui Chen ◽  
James C. Eisenach
Keyword(s):  
Neuropathic Pain ◽  
Nicotinic Receptor ◽  
Nicotinic Receptors ◽  
Intrathecal Injection ◽  
Intrathecal Administration ◽  
Spinal Nerve ◽  
Dependent Manner ◽  
Receptor Antagonists ◽  
Muscarinic And Nicotinic Receptors ◽  
Antiallodynic Effect

Background Intrathecally administered clonidine increases release of spinal acetylcholine, which may be related to its analgesic action in neuropathic pain. The current study determined the role of spinal muscarinic and nicotinic receptors in the antiallodynic effect of intrathecally administered clonidine in spinal nerve-ligated rats. Methods Allodynia was produced in rats by ligation of the left L5-L6 spinal nerves. Mechanical allodynia was determined by application of von Frey filaments to the left hindpaw. The effect of intrathecal injection of saline, two muscarinic receptor antagonists (atropine and scopolamine), and two nicotinic receptor antagonists (mecamylamine and hexamethonium) on the antiallodynic action produced by intrathecal administration of 20 microg clonidine was assessed in six groups of animals. Each group consisted of six to eight rats. Results Intrathecal injection of saline or muscarinic or nicotinic receptor antagonists did not alter the withdrawal thresholds. The antiallodynic effect produced by intrathecally administered clonidine was attenuated in a dose-dependent manner by intrathecal treatment with muscarinic and nicotinic antagonists. Although nicotinic receptor antagonists only partially attenuated the effect of clonidine, blockade of spinal muscarinic receptors almost abolished the antiallodynic effect of clonidine. Conclusions These results demonstrate that the analgesic effect of intrathecally administered clonidine on neuropathic pain is mediated by spinal muscarinic and nicotinic receptors. Therefore, this study provides functional evidence that spinally released acetylcholine plays a role in the antiallodynic effect of intrathecally administered clonidine in neuropathic pain.

scholarly journals Dose-dependent transduction of Hedgehog relies on phosphorylation-based feedback between the G-protein-coupled receptor Smoothened and the kinase Fused

Development ◽  
2017 ◽  
Vol 144 (10) ◽  
pp. 1841-1850 ◽  
Author(s):  
Matthieu Sanial ◽  
Isabelle Bécam ◽  
Line Hofmann ◽  
Julien Behague ◽  
Camilla Argüelles ◽  
...  
Keyword(s):  
G Protein ◽  
G Protein Coupled Receptor ◽  
G Protein Coupled ◽  
Dose Dependent

Gabapentin Activates Spinal Noradrenergic Activity in Rats and Humans and Reduces Hypersensitivity after Surgery

2007 ◽  
Vol 106 (3) ◽  
pp. 557-562 ◽  
Author(s):  
Ken-ichiro Hayashida ◽  
Sophia DeGoes ◽  
Regina Curry ◽  
James C. Eisenach
Keyword(s):  
Cerebrospinal Fluid ◽  
Postoperative Pain ◽  
G Protein ◽  
Intrathecal Administration ◽  
Noradrenergic System ◽  
Dependent Manner ◽  
Norepinephrine Release ◽  
Inwardly Rectifying ◽  
G Protein Coupled

Background Gabapentin has been reported to inhibit various acute and chronic pain conditions in animals and humans. Although the efficacy of gabapentin depends on the alpha2delta subunit of voltage-gated calcium channels, its analgesic mechanisms in vivo are still unknown. Here, the authors tested the role of spinal noradrenergic inhibition in gabapentin's analgesia for postoperative pain. Methods Gabapentin was administered orally and intracerebroventricularly to rats on the day after paw incision, and withdrawal threshold to paw pressure was measured. The authors also measured cerebrospinal fluid concentration of norepinephrine and postoperative morphine use after surgery in patients who received oral placebo or gabapentin. Results Both oral and intracerebroventricular gabapentin attenuated postoperative hypersensitivity in rats in a dose-dependent manner. This effect of gabapentin was blocked by intrathecal administration of the alpha2-adrenergic receptor antagonist idazoxan and the G protein-coupled inwardly rectifying potassium channel antagonist tertiapin-Q, but not by atropine. In humans, preoperative gabapentin, 1,200 mg, significantly increased norepinephrine concentration in cerebrospinal fluid and decreased morphine requirements. Conclusions These data suggest that gabapentin activates the descending noradrenergic system and induces spinal norepinephrine release, which produces analgesia via spinal alpha2-adrenoceptor stimulation, followed by activation of G protein-coupled inwardly rectifying potassium channels. The authors' clinical data suggest that gabapentin activates the descending noradrenergic system after preoperative oral administration at the time of surgery. These data support a central mechanism of oral gabapentin to reduce postoperative pain and suggest that this effect could be magnified by treatments that augment the effect of norepinephrine release.

scholarly journals A new synthetic protectin D1 analog 3-oxa-PD1n-3 DPA reduces neuropathic pain and chronic itch in mice

2021 ◽  
Author(s):  
Jannicke Irina Nesman ◽  
Ouyang Chen ◽  
Xin Luo ◽  
Ru-Rong Ji ◽  
Charles Nicholas Serhan ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Neuropathic Pain ◽  
Polyunsaturated Fatty Acids ◽  
Signaling Pathways ◽  
G Protein ◽  
Receptor Signaling ◽  
Active Process ◽  
Resolution Of Inflammation ◽  
Chronic Itch ◽  
G Protein Coupled

The resolution of inflammation is a biosynthetically active process controlled by the interplay between oxygenated polyunsaturated mediators and G-protein coupled receptor-signaling pathways. These oxygenated polyunsaturated fatty acids belong to distinct...

scholarly journals Spinal Cord is the Primary Site of Action of the Cannabinoid CB2 Receptor Agonist JWH133 that Suppresses Neuropathic Pain: Possible Involvement of Microglia

2014 ◽  
Vol 7 (1) ◽  
pp. 1-8
Author(s):  
Hiroshi Shimoyama ◽  
Makoto Tsuda ◽  
Takahiro Masuda ◽  
Ryohei Yoshinaga ◽  
Keiko Tsukamoto ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Neuropathic Pain ◽  
Nerve Injury ◽  
Intrathecal Administration ◽  
Tactile Allodynia ◽  
Cb2 Receptor ◽  
Analgesic Agents ◽  
Inflammatory Drugs ◽  
Antiallodynic Effect

Neuropathic pain, a highly debilitating condition that commonly occurs after damage to the nervous system, is often resistant to commonly used analgesic agents such as non-steroidal anti-inflammatory drugs and even opioids.Several studies using rodent models reported that cannabinoid CB2 receptor (CB2R) agonists are effective for treating chronic pain. However, the analgesic mechanism of CB2R agonists in neuropathic pain states is not fully understood. In this study, we investigated the role of CB2Rs in the development and maintenance phases of neuropathic pain, and the mechanism of the CB2R-mediated analgesic effect on neuropathic pain. In a rat model of neuropathic pain, systemic administration of JWH133, a CB2R agonist, markedly improved tactile allodynia, and this effect was prevented by intrathecal pretreatment with AM630, a CB2R antagonist. The antiallodynic effect of intrathecally administered JWH133 was inhibited by intrathecal pretreatment with pertussis toxin or forskolin. In the spinal cord, CB2R expression was significantly increased on post-operative day 3, and persisted for 2 weeks. Furthermore, repeated intrathecal administration of JWH133 notably attenuated the development of tactile allodynia after peripheral nerve injury. In a culture of microglia activated by overexpressing interferon regulatory factor 8, a transcription factor crucial for neuropathic pain, JWH133 treatment suppressed the increased expression of interleukin-1β. Our findings suggest that activation of CB2Rs upregulated in the spinal cord after nerve injury alleviates existing tactile allodynia through the Gi/oadenylate cyclase signaling pathway and suppresses the development of allodynia. This process may reduce the inflammatory response of microglia. Therefore, spinal CB2Rs may be a therapeutic target for the treatment of neuropathic pain.

scholarly journals Gαi-derived peptide binds the µ-opioid receptor

2019 ◽  
Author(s):  
Piotr Kosson ◽  
Jolanta Dyniewicz ◽  
Piotr F. J. Lipiński ◽  
Joanna Matalinska ◽  
Aleksandra Misicka ◽  
...  
Keyword(s):  
G Protein ◽  
Opioid Receptor ◽  
Protein Complexes ◽  
Active Form ◽  
Peptide Modification ◽  
C Terminus ◽  
External Stimuli ◽  
G Protein Coupled ◽  
Dose Dependent ◽  
Peptide Interaction

G protein-coupled receptors (GPCRs) transduce external stimuli into the cell by G proteins via an allosteric mechanism. Agonist binding to the receptor stimulates GDP/GTP exchange within the heterotrimeric G protein complex. Whereas recent structures of GPCR-G protein complexes revealed that the H5, S1 and S2 domains of Gα are involved in binding the active receptor, earlier studies showed that a short peptide analogue derived from the C-terminus (H5) of the G protein transducin (Gt) is sufficient to stabilize rhodopsin in an active form. Here, we show that a Gαi-derived peptide of 12 amino acids binds the µ-opioid receptor (µOR) and acts as an allosteric modulator. The Gαi-derived peptide increases µOR affinity for its agonist morphine in a dose-dependent way. These results indicate that the GPCR-Gα peptide interaction observed so far for only rhodopsin can be extrapolated to µOR. In addition, we show that the C-terminal peptide of the Gαi subunit is sufficient to stabilize the active conformation of the receptor. Our approach opens the possibility to investigate the GPCR-G protein interface with peptide modification.

Opioid Self-administration in the Nerve-injured Rat

2007 ◽  
Vol 106 (2) ◽  
pp. 312-322 ◽  
Author(s):  
Thomas J. Martin ◽  
Susy A. Kim ◽  
Nancy L. Buechler ◽  
Frank Porreca ◽  
James C. Eisenach
Keyword(s):  
Neuropathic Pain ◽  
Nerve Injury ◽  
Intrathecal Administration ◽  
Spinal Nerve ◽  
Spinal Nerve Ligation ◽  
Drug Intake ◽  
Spontaneous Pain ◽  
Self Administration ◽  
Mechanical Hypersensitivity ◽  
Opioid Sparing

Background Neuropathic pain is associated with several sensory abnormalities, including allodynia as well as spontaneous pain. Opioid intake in neuropathic pain patients is motivated by alleviation of both pain and allodynia. However, laboratory animal studies rely almost exclusively on reflexive withdrawal measures of allodynia. The authors examined the pharmacology of self-regulated intake of opioids in rats with or without nerve injury and compared the rate of drug intake to reversal of allodynia. Methods Rats were implanted with intravenous catheters, and the L5 and L6 spinal nerves were ligated in half of these animals. Rats were then trained to self-administer a commonly abused opioid (heroin) and commonly prescribed opioids (morphine, fentanyl, hydromorphone, and methadone). In addition, rats trained to self-administer heroin were given either clonidine or adenosine spinally before self-administration sessions to assess opioid-sparing effects. Results Nerve injury significantly decreased the reinforcing effects of low doses of opioids, and only doses of each opioid that reduced mechanical hypersensitivity maintained self-administration after spinal nerve ligation. The rate of drug consumption was correlated with the duration of the antiallodynic effect for each dose of opioid. Intrathecal administration of clonidine or adenosine reversed mechanical hypersensitivity, but only clonidine reduced heroin self-administration in rats with spinal nerve ligation. Conclusion Opioid self-administration is significantly altered by nerve injury, with rate of drug intake being correlated with reversal of allodynia. Intrathecal clonidine, but not adenosine, produces opioid-sparing effects in self-administering rats. The neurobiologic mechanisms that regulate opioid consumption in rats therefore seem to be altered after nerve injury.

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