NMDA Antagonist Peptide Supplementation Enhances Pain Alleviation by Adrenal Medullary Transplants

Spinal transplantation of adrenal medullary chromaffin cells has been shown to decrease pain responses in several animal models. Improved potency may be possible by engineering cells to produce greater levels of naturally derived analgesics. As an initial screen for potential candidates, adrenal medullary transplants were evaluated in combination with exogenously administered neuropeptides in rodent pain models. Histogranin is a 15-amino acid peptide that exhibits NMDA receptor antagonist activity. The stable derivative [Ser1]histogranin (SHG) can attenuate pain symptoms in some animal models. The formalin model for neurogenic inflammatory pain and the chronic constriction injury (CCI) model for neuropathic pain were used to evaluate the combined effects of chromaffin cell transplantation and intrathecal (IT) SHG injections. Animals were implanted with either adrenal medullary or control striated muscle tissue in the spinal subarachnoid space. For evaluation of formalin responses, animals were pretreated with SHG (0.5, 1.0, 3.0 μg) followed by an intraplantar injection of formalin, and flinching responses were quantified. Pretreatment with SHG had no significant effect on flinching behavior in control animals at lower doses, with incomplete attenuation only at the highest dose. In contrast, 0.5 μg SHG significantly reduced flinching responses in animals with adrenal medullary transplants, and 1.0 μg nearly completely eliminated flinching in these animals in the tonic phase. For evaluation of effects on neuropathic pain, animals received transplants 1 week following CCI, and were tested for thermal and mechanical hyperalgesia and cold allodynia before and following SHG treatment. The addition of low doses of SHG nearly completely eliminated neuropathic pain symptoms in adrenal medullary transplanted animals, while in control transplanted animals only thermal hyperalgesia was attenuated, at the highest dose of SHG. These results suggest that SHG can augment adrenal medullary transplants, and the combination may result in improved effectiveness and range in the treatment of chronic pain syndromes.

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The terpenes camphene and alpha-bisabolol inhibit inflammatory and neuropathic pain via Cav3.2 T-type calcium channels

Molecular Brain ◽

10.1186/s13041-021-00876-6 ◽

2021 ◽

Vol 14 (1) ◽

Author(s):

Vinicius M. Gadotti ◽

Sun Huang ◽

Gerald W. Zamponi

Keyword(s):

Neuropathic Pain ◽

Calcium Channels ◽

Wide Spectrum ◽

Thermal Hyperalgesia ◽

Significant Inhibition ◽

Dorsal Root Ganglion Neurons ◽

Intraplantar Injection ◽

Mouse Dorsal Root Ganglion ◽

Ganglion Neurons ◽

Micromolar Range

AbstractT-type calcium channels are known molecular targets of certain phytocannabinoids and endocannabinoids. Here we explored the modulation of Cav3.2 T-type calcium channels by terpenes derived from cannabis plants. A screen of eight commercially available terpenes revealed that camphene and alpha-bisabolol mediated partial, but significant inhibition of Cav3.2 channels expressed in tsA-201 cells, as well as native T-type channels in mouse dorsal root ganglion neurons. Both compounds inhibited peak current amplitude with IC50s in the low micromolar range, and mediated an additional small hyperpolarizing shift in half-inactivation voltage. When delivered intrathecally, both terpenes inhibited nocifensive responses in mice that had received an intraplantar injection of formalin, with alpha-bisabolol showing greater efficacy. Both terpenes reduced thermal hyperalgesia in mice injected with Complete Freund’s adjuvant. This effect was independent of sex, and absent in Cav3.2 null mice, indicating that these compounds mediate their analgesic properties by acting on Cav3.2 channels. Both compounds also inhibited mechanical hypersensitivity in a mouse model of neuropathic pain. Hence, camphene and alpha-bisabolol have a wide spectrum of analgesic action by virtue of inhibiting Cav3.2 T-type calcium channels.

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Zerumbone Ameliorates Neuropathic Pain Symptoms via Cannabinoid and PPAR Receptors Using In Vivo and In Silico Models

Molecules ◽

10.3390/molecules26133849 ◽

2021 ◽

Vol 26 (13) ◽

pp. 3849

Author(s):

Jasmine Siew Min Chia ◽

Ahmad Akira Omar Farouk ◽

Tengku Azam Shah Tengku Mohamad ◽

Mohd Roslan Sulaiman ◽

Hanis Zakaria ◽

...

Keyword(s):

Neuropathic Pain ◽

Mechanical Allodynia ◽

Thermal Hyperalgesia ◽

Docking Studies ◽

Peroxisome Proliferator ◽

Chronic Pain Condition ◽

Peroxisome Proliferator Activated Receptors ◽

Pain Symptoms ◽

In Silico Models

Neuropathic pain is a chronic pain condition persisting past the presence of any noxious stimulus or inflammation. Zerumbone, of the Zingiber zerumbet ginger plant, has exhibited anti-allodynic and antihyperalgesic effects in a neuropathic pain animal model, amongst other pharmacological properties. This study was conducted to further elucidate the mechanisms underlying zerumbone’s antineuropathic actions. Research on therapeutic agents involving cannabinoid (CB) and peroxisome proliferator-activated receptors (PPARs) is rising. These receptor systems have shown importance in causing a synergistic effect in suppressing nociceptive processing. Behavioural responses were assessed using the von Frey filament test (mechanical allodynia) and Hargreaves plantar test (thermal hyperalgesia), in chronic constriction injury (CCI) neuropathic pain mice. Antagonists SR141716 (CB1 receptor), SR144528 (CB2 receptor), GW6471 (PPARα receptor) and GW9662 (PPARγ receptor) were pre-administered before the zerumbone treatment. Our findings indicated the involvement of CB1, PPARα and PPARγ in zerumbone’s action against mechanical allodynia, whereas only CB1 and PPARα were involved against thermal hyperalgesia. Molecular docking studies also suggest that zerumbone has a comparable and favourable binding affinity against the respective agonist on the CB and PPAR receptors studied. This finding will contribute to advance our knowledge on zerumbone and its significance in treating neuropathic pain.

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Alleviation of neuropathic pain symptoms by xenogeneic chromaffin cell grafts in the spinal subarachnoid space

Brain Research ◽

10.1016/0006-8993(94)90696-3 ◽

1994 ◽

Vol 651 (1-2) ◽

pp. 183-193 ◽

Cited By ~ 51

Author(s):

Aldric T. Hama ◽

Jacqueline Sagen

Keyword(s):

Neuropathic Pain ◽

Subarachnoid Space ◽

Chromaffin Cell ◽

Spinal Subarachnoid Space ◽

Pain Symptoms

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Novel agonist of GDNF family ligand receptor RET for the treatment of experimental neuropathy

10.1101/061820 ◽

2016 ◽

Cited By ~ 3

Author(s):

Maxim M. Bespalov ◽

Yulia A. Sidorova ◽

Ilida Suleymanova ◽

James Thompson ◽

Oleg Kambur ◽

...

Keyword(s):

Neuropathic Pain ◽

Animal Models ◽

Cell Line ◽

Glial Cell ◽

Sensory Neurons ◽

Neurotrophic Factor ◽

Somatosensory System ◽

Pain Symptoms ◽

First Time

AbstractNeuropathic pain is a chronic pain condition caused by lesion or disease affecting the somatosensory system. The glial cell line-derived neurotrophic factor (GDNF) family ligands (GFLs) alleviate symptoms of NP and stimulate regeneration of sensory neurons in vivo. Here we report the development of the compound BT18 that selectively activates GFLreceptors, alleviates pain and restores damaged dorsal root ganglion (DRG) neurons in rat models of NP.Significance statementNeuropathic pain (NP) is a chronic syndrome caused by different diseases and lesions affecting nervous system. Earlier studies demonstrated that neurotrophic factors - the glial cell line-derived neurotrophic factor (GDNF) and artemin - could reverse the damage done by lesions in animal models of NP. We demonstrate for the first time that a small molecule can activate receptor of GDNF and artemin, it alleviates pain symptoms in vivo in two animal models of NP and restores to normal the molecular markers expressed in sensory neurons. This compound, termed BT18, can pave way for creating novel disease modifying therapies for NP.

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Anti-Neuropathic Pain Activity of Ageratum conyzoides L due to The Essential Oil Components

CNS & Neurological Disorders - Drug Targets ◽

10.2174/1871527319666201120144228 ◽

2020 ◽

Vol 19 ◽

Author(s):

Yedy Purwandi Sukmawan ◽

Kusnandar Anggadiredja ◽

I Ketut Adnyana

Keyword(s):

Neuropathic Pain ◽

Essential Oil ◽

Opioid Receptor ◽

Steam Distillation ◽

Chronic Constriction Injury ◽

Thermal Hyperalgesia ◽

Ageratum Conyzoides ◽

Safety And Efficacy ◽

Activity Test ◽

Oil Components

Background: Neuropathic pain is one of the contributors to the global burdens of illness. At present many patients do not achieve satisfactory pain relief even with synthetic pain-killers. Taking this into consideration, it is necessary to search for natural product-derived alternative treatment with confirmed safety and efficacy. Ageratum conyzoides L is a plant often used as analgesic in Indonesia, however, anti-neuropathic pain activity of this plant is still unknown. Objective: To determine the anti-neuropathic pain activity of the essential oil and non-essential oil component (distillation residue) of A. conyzoides L. Methods: We conducted separation of the essential oil component from other secondary metabolites through steam distillation. Both components were tested for anti-neuropathic pain activity using chronic constriction injury animal models with thermal hyperalgesia and allodynia tests. The animals were divided into 7 test groups namely normal, sham, negative, positive (pregabalin at 0.195 mg/20 g BW of mice), essential oil component (100 mg/kg BW), and non-essential oil component (100 mg/kg BW). Naloxone was tested against the most potent anti-neuropathic pain component (essential oil or nonessential oil) to investigate the involvement of opioid receptor. Results: The GC-MS of the essential oil component indicated the presence of 60 compounds. Meanwhile, non-essential oil components contained alkaloid, flavonoid, polyphenol, quinone, steroid, and triterpenoid. This non-essential oil component contained a total flavonoid equivalent to 248.89 ppm quercetin. The anti-neuropathic pain activity test showed significantly higher activity of the essential oil component compared to the non-essential oil component and negative groups (p<0.05). Furthermore, the essential oil component showed equal activity to pregabalin (p>0.05). However, this activity was abolished by naloxone, indicating the involvement of opioid receptor in the action of the essential oil component. Conclusion: The essential oil component of A. conyzoides L is a potential novel substance for use as anti-neuropathic pain.

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

Clinical Phytoscience ◽

10.1186/s40816-021-00263-7 ◽

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.

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Incidence, Aetiology, and Associated Fracture Patterns of Infraorbital Nerve Injuries Following Zygomaticomaxillary Complex Fractures: A Retrospective Analysis of 272 Patients

Craniomaxillofacial Trauma & Reconstruction ◽

10.1177/19433875211022569 ◽

2021 ◽

pp. 194338752110225

Author(s):

Kathia Dubron ◽

Maarten Verbist ◽

Eman Shaheen ◽

Titiaan Jacob Dormaar ◽

Reinhilde Jacobs ◽

...

Keyword(s):

Neuropathic Pain ◽

Interpersonal Violence ◽

Fracture Line ◽

Infraorbital Nerve ◽

Type B ◽

Treatment Methods ◽

Infraorbital Canal ◽

Pain Symptoms ◽

Fracture Types ◽

Zygomaticomaxillary Complex

Study Design: Retrospective study. Objective: Zygomaticomaxillary complex (ZMC) fractures are common facial injuries with heterogeneity regarding aetiologies, fracture types, infraorbital nerve (ION) involvement, and treatment methods. The aim of this study was to identify associations between aetiologies, fracture types, and neurological complications. Additionally, treatment methods and recovery time were investigated. Methods: Medical files of 272 patients with unilateral and bilateral ZMC fractures were reviewed, whose cases were managed from January 2014 to January 2019 at the Department of Oral and Maxillofacial Surgery, University hospitals Leuven, Belgium. History of ION sensory dysfunction and facial nerve motoric dysfunction were noted during follow-up. Results: ION hypoaesthesia incidence was 37.3%, with the main causes being fall accidents, road traffic accidents, and interpersonal violence. Significant predictors of ION hypoaesthesia were Zingg type B fractures ( P = 0.003), fracture line course through the infraorbital canal ( P < .001), orbital floor fracture ( P < 0.001), and ZMC dislocation or mobility ( P = 0.001). Conclusion: Of all ZMC fractures, 37.3% exhibited ION hypoaesthesia. Only ZMC Zingg type B fractures (74.0%) were significantly more associated with ION hypoaesthesia. ION hypoesthesia was more likely (OR = 2.707) when the fracture line course ran through the infraorbital canal, and was less dependent on the degree of displacement. Neuropathic pain symptoms developed after ZMC fractures in 2.2% patients, posing a treatment challenge. Neuropathic pain symptoms were slightly more common among women, and were associated only with type B or C fractures. No other parameters were found to predict the outcome of this post-traumatic neuropathic pain condition.

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Short-chain fatty acids contribute to neuropathic pain via regulating microglia activation and polarization

Molecular Pain ◽

10.1177/1744806921996520 ◽

2021 ◽

Vol 17 ◽

pp. 174480692199652

Author(s):

Feng Zhou ◽

Xian Wang ◽

Baoyu Han ◽

Xiaohui Tang ◽

Ru Liu ◽

...

Keyword(s):

Spinal Cord ◽

Neuropathic Pain ◽

Thermal Hyperalgesia ◽

Short Chain Fatty Acids ◽

Antibiotic Administration ◽

Tnf Α ◽

Microglia Polarization ◽

Inflammatory Phenotype ◽

Phenotype Markers ◽

Anti Inflammatory

Microglia activation and subsequent pro-inflammatory responses play a key role in the development of neuropathic pain. The process of microglia polarization towards pro-inflammatory phenotype often occurs during neuroinflammation. Recent studies have demonstrated an active role for the gut microbiota in promoting microglial full maturation and inflammatory capabilities via the production of Short-Chain Fatty Acids (SCFAs). However, it remains unclear whether SCFAs is involved in pro-inflammatory/anti-inflammatory phenotypes microglia polarization in the neuropathic pain. In the present study, chronic constriction injury (CCI) was used to induce neuropathic pain in mice, the mechanical withdrawal threshold, thermal hyperalgesia were accomplished. The levels of microglia markers including ionized calcium-binding adaptor molecule 1 (Iba1), cluster of differentiation 11b (CD11b), pro-inflammatory phenotype markers including CD68, interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and anti-inflammatory phenotype markers including CD206, IL-4 in the hippocampus and spinal cord were determined on day 21 after CCI. The results showed that CCI produced mechanical allodynia and thermal hyperalgesia, and also increased the expressions of microglia markers (Iba1, CD11b) and pro-inflammatory phenotype markers (CD68, IL-1β, and TNF-α), but not anti-inflammatory phenotype marker (CD206, IL-4) in the hippocampus and spinal cord, accompanied by increased SCFAs in the gut. Notably, antibiotic administration reversed these abnormalities, and its effects was also bloked by SCFAs administration. In conclusion, data from our study suggest that CCI can lead to mechanical and thermal hyperalgesia, while SCFAs play a key role in the pathogenesis of neuropathic pain by regulating microglial activation and subsequent pro-inflammatory phenotype polarization. Antibiotic administration may be a new treatment for neuropathic pain by reducing the production of SCFAs and further inhibiting the process of microglia polarization.

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Impaired discrimination of a subanesthetic dose of ketamine in a maternal immune activation model of schizophrenia risk

Journal of Psychopharmacology ◽

10.1177/02698811211029739 ◽

2021 ◽

pp. 026988112110297

Author(s):

Wayne Meighan ◽

Thomas W Elston ◽

David Bilkey ◽

Ryan D Ward

Keyword(s):

Animal Models ◽

Drug Discrimination ◽

Immune Activation ◽

Internal State ◽

Nmda Receptor Antagonist ◽

Activation Model ◽

Data Link ◽

Maternal Immune Activation ◽

Internal States ◽

Reliable Methods

Background: Animal models of psychiatric diseases suffer from a lack of reliable methods for accurate assessment of subjective internal states in nonhumans. This gap makes translation of results from animal models to patients particularly challenging. Aims/methods: Here, we used the drug-discrimination paradigm to allow rats that model a risk factor for schizophrenia (maternal immune activation, MIA) to report on the subjective internal state produced by a subanesthetic dose of the N-methyl-D-aspartate (NMDA) receptor antagonist ketamine. Results/outcomes: The MIA rats’ discrimination of ketamine was impaired relative to controls, both in the total number of rats that acquired and the asymptotic level of discrimination accuracy. This deficit was not due to a general inability to learn to discriminate an internal drug cue or internal state generally, as MIA rats were unimpaired in the learning and acquisition of a morphine drug discrimination and were as sensitive to the internal state of satiety as controls. Furthermore, the deficit was not due to a decreased sensitivity to the physiological effects of ketamine, as MIA rats showed increased ketamine-induced locomotor activity. Finally, impaired discrimination of ketamine was only seen at subanesthetic doses which functionally correspond to psychotomimetic doses in humans. Conclusion: These data link changes in NMDA responses to the MIA model. Furthermore, they confirm the utility of the drug-discrimination paradigm for future inquiries into the subjective internal state produced in models of schizophrenia and other developmental diseases.

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