scholarly journals The σ1 Receptor and the HINT1 Protein Control α2δ1 Binding to Glutamate NMDA Receptors: Implications in Neuropathic Pain

Biomolecules ◽  
2021 ◽  
Vol 11 (11) ◽  
pp. 1681
Author(s):  
María Rodríguez-Muñoz ◽  
Elsa Cortés-Montero ◽  
Yara Onetti ◽  
Pilar Sánchez-Blázquez ◽  
Javier Garzón-Niño
Keyword(s):  
Neuropathic Pain ◽  
Sciatic Nerve ◽  
Mechanical Allodynia ◽  
Chronic Constriction Injury ◽  
Intracerebroventricular Injection ◽  
Sigma 1 Receptor ◽  
Targeted Deletion ◽  
Σ1 Receptor ◽  
Sigma 1 ◽  
Glutamate Nmda Receptors

Nerve injury produces neuropathic pain through the binding of α2δ1 proteins to glutamate N-methyl-D-aspartate receptors (NMDARs). Notably, mice with a targeted deletion of the sigma 1 receptor (σ1R) gene do not develop neuropathy, whereas mice lacking the histidine triad nucleotide-binding protein 1 (Hint1) gene exhibit exacerbated allodynia. σ1R antagonists more effectively diminish neuropathic pain of spinal origin when administered by intracerebroventricular injection than systemically. Thus, in mice subjected to unilateral sciatic nerve chronic constriction injury (CCI), we studied the participation of σ1Rs and HINT1 proteins in the formation of α2δ1-NMDAR complexes within the supraspinal periaqueductal gray (PAG). We found that δ1 peptides required σ1Rs in order to interact with the NMDAR NR1 variant that contains the cytosolic C1 segment. σ1R antagonists or low calcium levels provoke the dissociation of σ1R-NR1 C1 dimers, while they barely affect the integrity of δ1-σ1R-NR1 C1 trimers. However, HINT1 does remove δ1 peptides from the trimer, thereby facilitating the subsequent dissociation of σ1Rs from NMDARs. In σ1R-/- mice, CCI does not promote the formation of NMDAR-α2δ1 complexes and allodynia does not develop. The levels of α2δ1-σ1R-NMDAR complexes increase in HINT1-/- mice and after inducing CCI, degradation of α2δ1 proteins is observed. Notably, σ1R antagonists but not gabapentinoids alleviate neuropathic pain in these mice. During severe neuropathy, the metabolism of α2δ1 proteins may account for the failure of many patients to respond to gabapentinoids. Therefore, σ1Rs promote and HINT1 proteins hinder the formation α2δ1-NMDAR complexes in the PAG, and hence, the appearance of mechanical allodynia depends on the interplay between these proteins.

Sigma‐1 receptor antagonist ( BD ‐1063) potentiates the antinociceptive effect of quercetin in neuropathic pain induced by chronic constriction injury

2020 ◽  
Author(s):  
Josué Vidal Espinosa‐Juárez ◽  
Osmar Antonio Jaramillo‐Morales ◽  
Myrna Déciga‐Campos ◽  
Luis Alfonso Moreno‐Rocha ◽  
Francisco Javier López‐Muñoz
Keyword(s):  
Neuropathic Pain ◽  
Receptor Antagonist ◽  
Chronic Constriction Injury ◽  
Antinociceptive Effect ◽  
Sigma 1 Receptor ◽  
Sigma 1

scholarly journals An Adapted Chronic Constriction Injury of the Sciatic Nerve Produces Sensory, Affective, and Cognitive Impairments: A Peripheral Mononeuropathy Model for the Study of Comorbid Neuropsychiatric Disorders Associated with Neuropathic Pain in Rats

Pain Medicine ◽  
2020 ◽  
Author(s):  
Priscila Medeiros ◽  
Ieda Regina dos Santos ◽  
Ivair Matias Júnior ◽  
Enza Palazzo ◽  
José Aparecido da Silva ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Sciatic Nerve ◽  
Mechanical Allodynia ◽  
Chronic Constriction Injury ◽  
Anxiety And Depression ◽  
Novel Object Recognition ◽  
Walking Test ◽  
Cci Model ◽  
Underlying Mechanisms ◽  
Motor Alterations

Abstract Background Chronic constriction injury (CCI) is a model of neuropathic pain induced by four loose ligatures around the sciatic nerve. This work aimed to investigate the sensory, affective, cognitive, and motor changes induced by an adaptation of the CCI model by applying a single ligature around the sciatic nerve. Methods Mechanical allodynia was measured from day 1 to day 28 postsurgery by the von Frey test. The beam walking test (BWT) was conducted weekly until 28 days after surgery. Anxiety- and depression-like behaviors, and cognitive performance were assessed through the open field (OF), forced swimming (FS), and novel object recognition (NOR) tests, respectively, 21 days after surgery. Results The two CCI models, both Bennett and Xie’s model (four ligatures of the sciatic nerve) and a modification of it (one ligature), induced mechanical allodynia, increased immobility in the FS, and reduced recognition index in the NOR. The exploratory behavior and time spent in the central part of the arena decreased, while the defensive behavior increased in the OF. The animals subjected to the two CCI models showed motor alterations in the BWT; however, autotomy was observed only in the group with four ligatures and not in the group with a single ligature. Conclusions Overall these results demonstrate that our adapted CCI model, using a single ligature around the sciatic nerve, induces sensory, affective, cognitive, and motor alterations comparable to the CCI model with four ligatures without generating autotomy. This adaptation to the CCI model may therefore represent an appropriate and more easily performed model for inducing neuropathic pain and study underlying mechanisms and effective treatments.

scholarly journals Hypoalgesic effect of Spirulina platensis on the sciatic neuropathic pain induced by chronic constriction injury in male rats

2018 ◽  
Vol 5 (9) ◽  
pp. 2671-2679 ◽  
Author(s):  
Hossein Ali Safakhah ◽  
Farzaneh Tamimi ◽  
Nasroallah Moradi kor ◽  
Ahmad Reza Bandegi ◽  
Ali Ghanbari
Keyword(s):  
Neuropathic Pain ◽  
Sciatic Nerve ◽  
Spirulina Platensis ◽  
Mechanical Allodynia ◽  
Chronic Constriction Injury ◽  
Thermal Hyperalgesia ◽  
Male Rats ◽  
Intragastric Administration ◽  
Post Surgery ◽  
Reducing Ability

Background: It has been revealed that herbal medicines have a palliative effect on pain. In the present study, the hypoalgesic effect of Spirulina platensis (microalgae) on the neuropathic pain induced by chronic constriction injury (CCI) was investigated. Methods: In the present study, 74 adult male Wistar rats weighing 200-220 grams were used. For inducing neuropathic pain, CCI was performed on the left sciatic nerve. Spirulina platensis was intragastrically administered daily for 3 weeks. Mechanical allodynia and thermal hyperalgesia were assessed by Von Frey hairs and plantar test device, respectively. Malondialdehyde (MDA) and total antioxidant capacity (TOC) were detected in the serum using thiobarbituric acid and ferric reducing ability of plasma (FRAP), respectively. Results: CCI of the sciatic nerve led to mechanical allodynia and thermal hyperalgesia at three weeks as well as two weeks post surgery. Three weeks of Spirulina therapy significantly (P<0.05) decreased paw withdrawal response to mechanical and thermal stimulations, compared to control. FRAP, but not MDA, significantly decreased three weeks after CCI, and Spirulina therapy significantly reversed its level towards control. Conclusion: Chronic intragastric administration of Spirulina platensis alleviates CCI-induced neuropathic pain by modulating oxidative stress through increasing FRAP levels in male rats.

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 Alpha lipoic acid attenuated neuropathic pain induced by chronic constriction Injury of sciatic nerve in rats

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Prasad Neerati ◽  
Harika Prathapagiri
Keyword(s):  
Neuropathic Pain ◽  
Peripheral Neuropathy ◽  
Sciatic Nerve ◽  
Lipoic Acid ◽  
Normal Saline ◽  
Chronic Constriction Injury ◽  
Thermal Hyperalgesia ◽  
Alpha Lipoic Acid ◽  
Chronic Neuropathic Pain ◽  
Neuropathic Pain Syndrome

Abstract Background Chronic neuropathic pain syndrome is associated with impaired quality of life and is poorly manageable. Alpha lipoic acid (ALA) is a powerful antioxidant and showed its effectiveness on diabetic neuropathy and other acute peripheral nerve injuries but it was not evaluated in the chronic neuropathic pain, chronic constriction injury (CCI) in rat model by using duloxetine (DLX) as standard. Methodology The main objective of the study was to expedite ALA effect on chronic peripheral neuropathy induced by CCI of sciatic nerve in rats. In this study, male Wister rats were randomly divided into six groups (n = 8) including, normal saline, sham operated, surgery control, DLX 30mg/kg treated, ALA treated 25mg/kg, and ALA+DLX. The CCI of sciatic nerve was conducted on all animals except normal saline group and studied for 21 days (i.e. 14 days treatment period & 7 days treatment free period) by using different behavioral, biochemical and, histopathology studies. Results ALA showed minor but significant decrease of thermal hyperalgesia, cold allodynia, malondialdehyde (MDA), total protein, lipid peroxidation, and nitric oxide levels and significant increase of motor coordination, glutathione level and decreased axonal degeneration significantly. These effects sustained even during treatment free period. ALA enhanced the effect of DLX when given in combination by showing sustained effect. In conclusion, ALA acted as potent antioxidant may be this activity is responsible for the potent neuroprotective effect. Conclusion Hence, ALA attenuated the nueroinflammation mediated by chronic peripheral neuropathy. Further studies are warranted with ALA to develop as a clinically relevant therapeutic agent for the treatment of neuropathic pain.

scholarly journals Tongluo Zhitong Prescription Alleviates Allodynia, Hyperalgesia, and Dyskinesia in the Chronic Constriction Injury Model of Rats

2017 ◽  
Vol 2017 ◽  
pp. 1-6 ◽  
Author(s):  
Zhiyong Wang ◽  
Jianwei Wang ◽  
Lihua Qin ◽  
Weiguang Zhang
Keyword(s):  
Neuropathic Pain ◽  
Mechanical Allodynia ◽  
Chronic Constriction Injury ◽  
Catgut Suture ◽  
Cold Allodynia ◽  
Injury Model ◽  
Neuropathic Pain Model ◽  
Gait Function ◽  
Chronic Constriction Injury Model ◽  
Heat Hyperalgesia

Neuropathic pain is common in clinical practice. Exploration of new drug therapeutics has always been carried out for more satisfactory effects and fewer side-effects. In the present study, we aimed to investigate effects of Tongluo Zhitong Prescription (TZP), a compounded Chinese medicine description, on neuropathic pain model of rats with chronic constriction injury (CCI). The CCI model was established by loosely ligating sciatic nerve with catgut suture, proximal to its trifurcation. The static and dynamic allodynia, heat hyperalgesia, mechanical allodynia, cold allodynia, and gait were assessed. Our results showed that TZP alleviated CCI-induced static and dynamic allodynia, suppressed heat hyperalgesia and cold and mechanical allodynia, and improved gait function. These results suggest that TZP could alleviate neuropathic pain. Further experiments are needed to explore its mechanisms.

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