scholarly journals Nonselective and NR2B-selective N -methyl-d-aspartic Acid Receptor Antagonists Produce Antinociception and Long-term Relief of Allodynia in Acute and Neuropathic Pain

2011 ◽  
Vol 115 (1) ◽  
pp. 165-174 ◽  
Author(s):  
Maarten Swartjes ◽  
Aurora Morariu ◽  
Marieke Niesters ◽  
Leon Aarts ◽  
Albert Dahan

Background At low dose, the nonselective N-methyl-D-aspartate receptor antagonist ketamine produces potent analgesia. In humans, psychedelic side effects limit its use. To assess whether other N-methyl-D-aspartate receptor antagonist have an improved therapeutic utility index, we compared antinociceptive, side effect, and locomotor activity of three N-methyl-D-aspartate receptor antagonists. Methods Ketamine, its active metabolite norketamine, and the NR2B-selective antagonist traxoprodil (CP-101,606) were tested in rat models of acute antinociception (paw-withdrawal response to heat) and chronic neuropathic pain (spared nerve injury). Side effects (stereotypical behavior, activity level) were scored and locomotor function of the nerve-injured paw was assessed using computerized gait analysis. In the chronic pain model, treatment was given 7 days after surgery, for 3 h on 5 consecutive days. Results All three N-methyl-D-aspartate receptor antagonists caused dose-dependent antinociception in the acute pain model and relief of mechanical and cold allodynia for 3-6 weeks after treatment in the chronic pain model (P < 0.05 vs. saline). In both tests, ketamine was most potent. Norketamine was as much as two times less potent and traxoprodil was up to 8 times less potent than ketamine (based on area under the curve measures). Nerve injury caused an inability to use the affected paw that either did not improve after treatment (ketamine, traxoprodil) or showed only a limited effect (norketamine). Traxoprodil, but not ketamine or norketamine, showed clear separation between effect and side effect. Conclusions The observation that traxoprodil causes relief of chronic pain outlasting the treatment period with no side effects makes it an attractive alternative to ketamine in the treatment of chronic neuropathic pain.

2019 ◽  
Vol 20 (1) ◽  
pp. 95-108
Author(s):  
Adriana Miclescu ◽  
Antje Straatmann ◽  
Panagiota Gkatziani ◽  
Stephen Butler ◽  
Rolf Karlsten ◽  
...  

AbstractBackground and aimsAside from the long term side effects of a nerve injury in the upper extremity with devastating consequences there is often the problem of chronic neuropathic pain. The studies concerning the prevalence of persistent pain of neuropathic origin after peripheral nerve injuries are sparse. The prevalence and risk factors associated with chronic neuropathic pain after nerve injuries in the upper extremity were assessed.MethodsA standardized data collection template was employed prospectively and retrospectively for all patients with traumatic nerve injuries accepted at the Hand Surgery Department, Uppsala, Sweden between 2010 and 2018. The template included demographic data, pain diagnosis, type of injured nerve, level of injury, date of the lesion and repair, type of procedure, reoperation, time since the procedure, S-LANSS questionnaire (Self report-Leeds Assessment of Neuropathic Symptoms and Signs), RAND-36 (Item short form health survey), QuickDASH (Disability of Shoulder, Arm and Hand) and additional questionnaires concerned medication, pain intensity were sent to 1,051 patients with nerve injuries. Partial proportional odds models were used to investigate the association between persistent pain and potential predictors.ResultsMore than half of the patients undergoing a surgical procedure developed persistent pain. Prevalence of neuropathic pain was 73% of the patients with pain (S-LANSS ≥ 12 or more). Multivariate analysis indicated that injury of a major nerve OR 1.6 (p = 0.013), years from surgery OR 0.91 (p = 0.01), younger age OR 0.7 (p < 0.001), were the main factors for predicting pain after surgery. The type of the nerve injured was the strongest predictor for chronic pain with major nerves associated with more pain (p = 0.019).ConclusionsA high prevalence of chronic pain and neuropathic pain with a negative impact on quality of life and disability were found in patients after traumatic nerve injury. Major nerve injury, younger age and less time from surgery were predictors for chronic pain.


2018 ◽  
Vol 18 (4) ◽  
pp. 687-693 ◽  
Author(s):  
Tiansheng Shi ◽  
Jing-Xia Hao ◽  
Zsuzsanna Wiesenfeld-Hallin ◽  
Xiao-Jun Xu

Abstract Background and aims The clinical management of neuropathic pain remains a challenge. We examined the interaction between gabapentin and NMDA receptor antagonists dextromethrophan and MK-801 in alleviating neuropathic pain-like behaviors in rats after spinal cord or sciatic nerve injury. Methods Female and male rats were produced with Ischemic spinal cord injury and sciatic nerve injury. Gabapentin, dextromethorphan, MK-801 or drug combinations were injected with increasing doses. Mechanical response thresholds were tested with von Frey hairs to graded mechanical touch/pressure, and ethyl chloride spray was applied to assess the cold sensitivity before and after injuries. Results In spinally injured rats, gabapentin and dextromethorphan did not affect allodynia-like behaviors at doses of 30 and 20 mg/kg, respectively. In contrast, combination of 15 or 30 mg/kg gabapentin with dextromethorphan at 10 mg/kg produced total alleviation of allodynia to mechanical or cold stimulation. Further reducing the dose of gapapentin to 7.5 mg/kg and dextromethorphan to 5 mg/kg still produced significant effect. MK-801, another NMDA receptor antagonist, also enhanced the effect of gabapentin in spinally injured rats. Similar synergistic anti-allodynic effect between dextromethorphan and gabapentin was also observed in a rat model of partial sciatic nerve injury. No increased side effect was seen following the combination between gabapentin and dextromethorphan. Conclusions In conclusion, the present study suggested that combining NMDA receptor antagonists with gabapentin could provide synergistic effect to alleviate neuropathic pain and reduced side effects. Implications Combining NMDA receptor antagonists with gabapentin may provide a new approach in alleviating neuropathic pain with increased efficacy and reduced side effects.


2020 ◽  
Vol 48 (5) ◽  
pp. 030006052090365
Author(s):  
Razia Abdool Gafaar Khammissa ◽  
Raoul Ballyram ◽  
Jeanine Fourie ◽  
Michael Bouckaert ◽  
Johan Lemmer ◽  
...  

Pain induced by inflammation and nerve injury arises from abnormal neural activity of primary afferent nociceptors in response to tissue damage, which causes long-term elevation of the sensitivity and responsiveness of spinal cord neurons. Inflammatory pain typically resolves following resolution of inflammation; however, nerve injury—either peripheral or central—may cause persistent neuropathic pain, which frequently manifests as hyperalgesia or allodynia. Neuralgias, malignant metastatic bone disease, and diabetic neuropathy are some of the conditions associated with severe, often unremitting chronic pain that is both physically and psychologically debilitating or disabling. Therefore, optimal pain management for patients with chronic neuropathic pain requires a multimodal approach that comprises pharmacological and psychological interventions. Non-opioid analgesics (e.g., paracetamol, aspirin, or other non-steroidal anti-inflammatory drugs) are first-line agents used in the treatment of mild-to-moderate acute pain, while opioids of increasing potency are indicated for the treatment of persistent, moderate-to-severe inflammatory pain. N-methyl D-aspartate receptor antagonists, antidepressants, anticonvulsants, or a combination of these should be considered for the treatment of chronic neuropathic pain. This review discusses the various neural signals that mediate acute and chronic pain, as well as the general principles of pain management.


Biomolecules ◽  
2021 ◽  
Vol 11 (6) ◽  
pp. 816
Author(s):  
Rosmara Infantino ◽  
Consalvo Mattia ◽  
Pamela Locarini ◽  
Antonio Luigi Pastore ◽  
Sabatino Maione ◽  
...  

Chronic pain, including neuropathic pain, represents an untreated disease with important repercussions on the quality of life and huge costs on the national health system. It is well known that opioids are the most powerful analgesic drugs, but they represent the second or third line in neuropathic pain, that remain difficult to manage. Moreover, these drugs show several side effects that limit their use. In addition, opioids possess addictive properties that are associated with misuse and drug abuse. Among available opioids compounds, buprenorphine has been suggested advantageous for a series of clinical reasons, including the effectiveness in neuropathic pain. Some properties are partly explained by its unique pharmacological characteristics. However, questions on the dynamic profile remain to be answered. Pharmacokinetics optimization strategies, and additional potentialities, are still to be explored. In this paper, we attempt to conceptualize the potential undiscovered dynamic profile of buprenorphine.


2019 ◽  
Vol 20 (1) ◽  
pp. 33-37 ◽  
Author(s):  
Marzia Malcangio

AbstractBackgroundAcute pain is a warning mechanism that exists to prevent tissue damage, however pain can outlast its protective purpose and persist beyond injury, becoming chronic. Chronic Pain is maladaptive and needs addressing as available medicines are only partially effective and cause severe side effects. There are profound differences between acute and chronic pain. Dramatic changes occur in both peripheral and central pathways resulting in the pain system being sensitised, thereby leading to exaggerated responses to noxious stimuli (hyperalgesia) and responses to non-noxious stimuli (allodynia).Critical role for immune system cells in chronic painPreclinical models of neuropathic pain provide evidence for a critical mechanistic role for immune cells in the chronicity of pain. Importantly, human imaging studies are consistent with preclinical findings, with glial activation evident in the brain of patients experiencing chronic pain. Indeed, immune cells are no longer considered to be passive bystanders in the nervous system; a consensus is emerging that, through their communication with neurons, they can both propagate and maintain disease states, including neuropathic pain. The focus of this review is on the plastic changes that occur under neuropathic pain conditions at the site of nerve injury, the dorsal root ganglia (DRG) and the dorsal horn of the spinal cord. At these sites both endothelial damage and increased neuronal activity result in recruitment of monocytes/macrophages (peripherally) and activation of microglia (centrally), which release mediators that lead to sensitisation of neurons thereby enabling positive feedback that sustains chronic pain.Immune system reactions to peripheral nerve injuriesAt the site of peripheral nerve injury following chemotherapy treatment for cancer for example, the occurrence of endothelial activation results in recruitment of CX3C chemokine receptor 1 (CX3CR1)-expressing monocytes/macrophages, which sensitise nociceptive neurons through the release of reactive oxygen species (ROS) that activate transient receptor potential ankyrin 1 (TRPA1) channels to evoke a pain response. In the DRG, neuro-immune cross talk following peripheral nerve injury is accomplished through the release of extracellular vesicles by neurons, which are engulfed by nearby macrophages. These vesicles deliver several determinants including microRNAs (miRs), with the potential to afford long-term alterations in macrophages that impact pain mechanisms. On one hand the delivery of neuron-derived miR-21 to macrophages for example, polarises these cells towards a pro-inflammatory/pro-nociceptive phenotype; on the other hand, silencing miR-21 expression in sensory neurons prevents both development of neuropathic allodynia and recruitment of macrophages in the DRG.Immune system mechanisms in the central nervous systemIn the dorsal horn of the spinal cord, growing evidence over the last two decades has delineated signalling pathways that mediate neuron-microglia communication such as P2X4/BDNF/GABAA, P2X7/Cathepsin S/Fractalkine/CX3CR1, and CSF-1/CSF-1R/DAP12 pathway-dependent mechanisms.Conclusions and implicationsDefinition of the modalities by which neuron and immune cells communicate at different locations of the pain pathway under neuropathic pain states constitutes innovative biology that takes the pain field in a different direction and provides opportunities for novel approaches for the treatment of chronic pain.


2015 ◽  
Vol 2015 ◽  
pp. 1-10 ◽  
Author(s):  
Jeongsoo Han ◽  
Minjee Kwon ◽  
Myeounghoon Cha ◽  
Motomasa Tanioka ◽  
Seong-Karp Hong ◽  
...  

The insular cortex (IC) is associated with important functions linked with pain and emotions. According to recent reports, neural plasticity in the brain including the IC can be induced by nerve injury and may contribute to chronic pain. Continuous active kinase, protein kinase Mζ(PKMζ), has been known to maintain the long-term potentiation. This study was conducted to determine the role of PKMζin the IC, which may be involved in the modulation of neuropathic pain. Mechanical allodynia test and immunohistochemistry (IHC) of zif268, an activity-dependent transcription factor required for neuronal plasticity, were performed after nerve injury. Afterζ-pseudosubstrate inhibitory peptide (ZIP, a selective inhibitor of PKMζ) injection, mechanical allodynia test and immunoblotting of PKMζ, phospho-PKMζ(p-PKMζ), and GluR1 and GluR2 were observed. IHC demonstrated that zif268 expression significantly increased in the IC after nerve injury. Mechanical allodynia was significantly decreased by ZIP microinjection into the IC. The analgesic effect lasted for 12 hours. Moreover, the levels of GluR1, GluR2, and p-PKMζwere decreased after ZIP microinjection. These results suggest that peripheral nerve injury induces neural plasticity related to PKMζand that ZIP has potential applications for relieving chronic pain.


2021 ◽  
Author(s):  
Hisakatsu Ito ◽  
Hiroshi Tusneki ◽  
Toshiyasu Sasaoka ◽  
Naoki Toyooka ◽  
Mitsuaki Yamazaki

Abstract Chronic pain and sleep disorders are independently associated with a reduction in the quality of life. They can be both a cause and consequence of each other; therefore, they should be treated simultaneously. However, optimal treatments for chronic pain-related sleep disorders are not well established. Here, we aimed to investigate the effects of suvorexant, a novel sleep drug, and mirtazapine, a noradrenergic and specific serotonergic antidepressant, on pain-related sleep disorders in a preclinical neuropathic pain mouse model, which was produced by partial sciatic nerve ligation. We calculated the quantity, duration, and depth of sleep by analyzing the electroencephalogram. Voluntary activity was also evaluated by counting the number of wheel rotations with special cages. Daily administration of suvorexant and mirtazapine normalized the reduced rapid eye movement (REM) and non-REM sleep and improved the fragmented sleep, further regaining the depth of sleep at sleep onset in the chronic pain state. Suvorexant decreased voluntary activity, which was prolonged after the end of administration; however, mirtazapine did not decrease it. Both suvorexant and mirtazapine could be potential therapeutic agents for chronic pain-related sleep disorders.


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