Dataset Information

Repeated Sigma-1 Receptor Antagonist MR309 Administration Modulates Central Neuropathic Pain Development After Spinal Cord Injury in Mice.

ABSTRACT: Up to two-thirds of patients affected by spinal cord injury (SCI) develop central neuropathic pain (CNP), which has a high impact on their quality of life. Most of the patients are largely refractory to current treatments, and new pharmacological strategies are needed. Recently, it has been shown that the acute administration of the ?1R antagonist MR309 (previously developed as E-52862) at 28 days after spinal cord contusion results in a dose-dependent suppression of both mechanical allodynia and thermal hyperalgesia in wild-type CD-1 Swiss female mice. The present work was addressed to determine whether MR309 might exert preventive effects on CNP development by repeated administration during the first week after SCI in mice. To this end, the MR309 (16 or 32 mg/kg i.p.) modulation on both thermal hyperalgesia and mechanical allodynia development were evaluated weekly up to 28 days post-injury. In addition, changes in pro-inflammatory cytokine (TNF-?, IL-1?) expression and both the expression and activation (phosphorylation) of the N-methyl-D-aspartate receptor subunit 2B (NR2B-NMDA) and extracellular signal-regulated kinases (ERK1/2) were analyzed. The repeated treatment of SCI-mice with MR309 resulted in significant pain behavior attenuation beyond the end of the administration period, accompanied by reduced expression of central sensitization-related mechanistic correlates, including extracellular mediators (TNF-? and IL-1?), membrane receptors/channels (NR2B-NMDA) and intracellular signaling cascades (ERK/pERK). These findings suggest that repeated MR309 treatment after SCI may be a suitable pharmacologic strategy to modulate SCI-induced CNP development.

SUBMITTER: Castany S

PROVIDER: S-EPMC6439356 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Repeated Sigma-1 Receptor Antagonist MR309 Administration Modulates Central Neuropathic Pain Development After Spinal Cord Injury in Mice.

Castany Sílvia S Codony Xavier X Zamanillo Daniel D Merlos Manuel M Verdú Enrique E Boadas-Vaello Pere P

Frontiers in pharmacology 20190322

Up to two-thirds of patients affected by spinal cord injury (SCI) develop central neuropathic pain (CNP), which has a high impact on their quality of life. Most of the patients are largely refractory to current treatments, and new pharmacological strategies are needed. Recently, it has been shown that the acute administration of the σ1R antagonist MR309 (previously developed as E-52862) at 28 days after spinal cord contusion results in a dose-dependent suppression of both mechanical allodynia an ...[more]

PMID: 30967775

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Project description:BackgroundCentral sensitization is considered a key mechanism underlying neuropathic pain (NP) after spinal cord injury (SCI).MethodsTwo novel proxies for central sensitization were investigated in thoracic SCI subjects with (SCI-NP) and without NP (SCI-nonNP) compared to healthy controls (HC). Specifically, temporal summation of pain (TSP) was investigated by examining pain ratings during a 2-min tonic heat application to the volar forearm. Additionally, palmar heat-induced sympathetic skin responses (SSR) were recorded in order to reveal changes in pain-autonomic interaction above the lesion level. Pain extent was assessed as the percentage of the body area and the number of body regions being affected by NP.ResultsEnhanced TSP was observed in SCI-NP (+66%) compared to SCI-nonNP (-75%, p = 0.009) and HC (-59%, p = 0.021). In contrast, no group differences were found (p = 0.685) for SSR habituation. However, pain extent in SCI-NP was positively correlated with deficient SSR habituation (body area: r = 0.561, p = 0.024; body regions: r = 0.564, p = 0.023).ConclusionsThese results support the value of TSP and heat-induced SSRs as proxies for central sensitization in widespread neuropathic pain syndromes after SCI. Measures of pain-autonomic interaction emerged as a promising tool for the objective investigation of sensitized neuronal states in chronic pain conditions.SignificanceWe present two surrogate readouts for central sensitization in neuropathic pain following SCI. On the one hand, temporal summation of tonic heat pain is enhanced in subjects with neuropathic pain. On the other hand, pain-autonomic interaction reveals potential advanced measures in chronic pain, as subjects with a high extent of neuropathic pain showed diminished habituation of pain-induced sympathetic measures. A possible implication for clinical practice is constituted by an improved assessment of neuronal hyperexcitability potentially enabling mechanism-based treatment.

Project description:Background:Neurofeedback (NFB) is a neuromodulatory technique that enables voluntary modulation of brain activity in order to treat neurological condition, such as central neuropathic pain (CNP). A distinctive feature of this technique is that it actively involves participants in the therapy. In this feasibility study, we present results of participant self-managed NFB treatment of CNP. Methods:Fifteen chronic spinal cord injured (SCI) participants (13M, 2F), with chronic CNP equal or greater than 4 on the Visual Numeric Scale, took part in the study. After initial training in hospital (up to 4 sessions), they practiced NF at home, on average 2-3 times a week, over a period of several weeks (min 4, max 20). The NFB protocol consisted of upregulating the alpha (9-12 Hz) and downregulating the theta (4-8 Hz) and the higher beta band (20-30 Hz) power from electrode location C4, for 30 min. The output measures were pain before and after NFB, EEG before and during NFB and pain questionnaires. We analyzed EEG results and show NFB strategies based on the Power Spectrum Density of each single participant. Results:Twelve participants achieved statistically significant reduction in pain and in eight participants this reduction was clinically significant (larger than 30%). The most successfully regulated frequency band during NFB was alpha. However, most participants upregulated their individual alpha band, that had an average dominant frequency at ?p = 7.6 ± 0.8 Hz (median 8 Hz) that is lower than the average of the general population, which is around 10 Hz. Ten out of fifteen participants significantly upregulated their individual alpha power (?p ± 2 Hz) as compared to 4 participants who upregulated the power in the fixed alpha band (8-12 Hz). Eight out of the twelve participants who achieved a significant reduction of pain, significantly upregulated their individual alpha band power. There was a significantly larger increase in alpha power (p < 0.0001) and decrease of theta power (p < 0.04) in participant specific rather than in fixed frequency bands. Conclusion:Neurofeedback is a neuromodulatory technique that gives participants control over their pain and can be self-administered at home. Regulation of individual frequency band was related to a significant reduction in pain.

Dataset Information

Repeated Sigma-1 Receptor Antagonist MR309 Administration Modulates Central Neuropathic Pain Development After Spinal Cord Injury in Mice.

Publications

Repeated Sigma-1 Receptor Antagonist MR309 Administration Modulates Central Neuropathic Pain Development After Spinal Cord Injury in Mice.

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