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The anti-seizure racetams may provide novel molecular insights into neuropathic pain due to their unique mechanism involving synaptic vesicle glycoprotein 2A (SV2A). Anti-allodynic effects of levetiracetam (LEV) have been shown in animal models of neuropathic pain. Here, we studied the effect of brivaracetam (BRV), which binds to SV2A with 20-fold greater affinity, and has fewer off-target effects.
Learn More >The interaction between the immune system and the nervous system has been at the centre of multiple research studies in recent years. While the role played by cytokines as neuronal mediators is no longer contested, the mechanisms by which cytokines modulate pain processing remain to be elucidated. In this study, we have analysed the involvement of Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF) in nociceptor activation in male and female mice. Previous studies have suggested GM-CSF might directly activate neurons. However, here we established the absence of a functional GM-CSF receptor in murine nociceptors, and suggest an indirect mechanism of action, via immune cells. We report that GM-CSF applied directly to magnetically purified nociceptors does not induce any transcriptional changes in nociceptive genes. In contrast, conditioned medium from GM-CSF-treated murine macrophages was able to drive nociceptor transcription. We also found that conditioned medium from nociceptors treated with the well-established pain mediator, Nerve Growth Factor (NGF), could also modify macrophage gene transcription, providing further evidence for a bidirectional crosstalk.The interaction of the immune system and the nervous system is known to play an important role in the development and maintenance of chronic pain disorders. Elucidating the mechanisms of these interactions is an important step towards understanding, and therefore treating, chronic pain disorders. This study provides evidence for a two-way cross talk between macrophages and nociceptors in the peripheral nervous system which may contribute to the sensitization of nociceptors by cytokines in pain development.
Learn More >Emotional disorders are common comorbid conditions that further exacerbate the severity and chronicity of chronic pain. However, individuals show considerable vulnerability to developing chronic pain under similar pain conditions. In this study on male rat and mouse models of chronic neuropathic pain, we identify the histone deacetylase SIRT1 in central amygdala as a key epigenetic regulator that controls the development of comorbid emotional disorders underlying the individual vulnerability to chronic pain. We found that animals that were vulnerable to developing behaviors of anxiety and depression under the pain condition displayed reduced SIRT1 protein in central amygdala, but not those animals resistant to the emotional disorders. Viral overexpression of local SIRT1 reversed this vulnerability, but viral knockdown of local SIRT1 mimicked the pain effect, eliciting the pain vulnerability in pain-free animals. The SIRT1 action was associated with CaMKIIα downregulation and deacetylation of histone H3 lysine 9 at the promoter. These results suggest that, by transcriptional repression of in central amygdala, SIRT1 functions to guard against the emotional pain vulnerability under chronic pain conditions. This study indicates that SIRT1 may serve as a potential therapeutic molecule for individualized treatment of chronic pain with vulnerable emotional disorders.Chronic pain is a prevalent neurological disease with no effective treatment at present. Pain patients display considerably variable vulnerability to developing chronic pain, indicating individual-based molecular mechanisms underlying the pain vulnerability, which is hardly addressed in current preclinical research. In this study, we have identified the histone deacetylase Sirtuin 1 (SIRT1) as a key regulator that controls this pain vulnerability. This study reveals that the SIRT1–CaMKIIaα pathway in central amygdala acts as an epigenetic mechanism that guards against the development of comorbid emotional disorders under chronic pain, and that its dysfunction causes increased vulnerability to developing chronic pain. These findings suggest that SIRT1 activators may be used in a novel therapeutic approach for individual-based treatment of chronic pain.
Learn More >The chronic pain disorder, fibromyalgia, is associated with sleep disturbance, typically sleep maintenance. No studies have evaluated the effect of sleep medication on pain sensitivity in this population. Suvorexant, an orexin antagonist, approved for treatment of insomnia was evaluated for effects on both the sleep and pain of fibromyalgia.
Learn More >Mood disorders such as depression and anxiety are frequently observed in patients suffering from chronic pain. Over time, different tests and models have been developed in rodents to study the anxiodepressive-like consequences of chronic pain. This review describes these pre-clinical tools (models and tests) used for studying behavioural aspects of the comorbid relationship between chronic pain and anxiety and/or major depressive disorder (MDD). Three major types of chronic pain strongly associated with anxiodepressive-like comorbidity as well as their animal models are presented: neuropathic pain, inflammatory pain and fibromyalgia. After a description of chronic pain animal models and of the tests that allows determining nociceptive responses, this review presents and discusses the various behavioural tests that have been used to assess anxiety and depressive-like behaviours in these models of chronic pain. Finally, this review highlights the progress that remains to be made to homogenize the results in the field of pain-induced mood disorders and summarizes the recent advances achieved through these tests and models.
Learn More >Chronic neuropathic pain (NEP) is associated with growing therapeutic cannabis use. To promote quality of life without psychotropic effects, cannabinoids other than Δ9-tetrahydrocannabidiol, including cannabidiol and its precursor cannabidiolic acid (CBDA), are being evaluated. Due to its instability, CBDA has been understudied, particularly as an anti-nociceptive agent. Adding a methyl ester group (CBDA-ME) significantly enhances its stability, facilitating analyses of its analgesic effects in vivo. This study examines early treatment efficacy of CBDA-ME in a rat model of peripherally induced NEP and evaluates sex as a biological variable.
Learn More >Pain problems tend to run in families and children of individuals with chronic pain (ICPs) have been found to report lower functioning. Drawing upon a social learning perspective, the current study examined how diverse maternal pain coping responses (i.e., pain catastrophizing and distraction) may, via corresponding child pain coping responses, act as a vulnerability or protective factor for child functioning in the context of parental chronic pain (CP).
Learn More >Although astrocytes are known to regulate synaptic transmission and affect new memory formation by influencing long-term potentiation and functional synaptic plasticity, their role in pain modulation is poorly understood. Motor cortex stimulation (MCS) has been used to reduce neuropathic pain through the incertothalamic pathway, including the primary motor cortex (M1) and the zona incerta (ZI). However, there has been no in-depth study of these modulatory effects and region-specific changes in neural plasticity. In this study, we investigated the effects of MCS-induced pain modulation as well as the relationship between the ZI neuroplasticity and MCS-induced pain alleviation in neuropathic pain (NP). MCS-induced threshold changes were evaluated after daily MCS. Then, the morphological changes of glial cells were compared by tissue staining. In order to quantify the neuroplasticity, MAP2, PSD95, and synapsin in the ZI and M1 were measured and analyzed with western blot. In behavioral test, repetitive MCS reduced NP in nerve-injured rats. We also observed recovered GFAP expression in the NP with MCS rats. In the NP with sham MCS rats, increased CD68 level was observed. In the NP with MCS group, increased mGluR1 expression was observed. Analysis of synaptogenesis-related molecules in the M1 and ZI revealed that synaptic changes occured in the M1, and increased astrocytes in the ZI were more closely associated with pain alleviation after MCS. Our findings suggest that MCS may modulate the astrocyte activities in the ZI and synaptic changes in the M1. Our results may provide new insight into the important and numerous roles of astrocytes in the formation and function.
Learn More >Nearly 100 000 primary total knee replacements (TKR) are performed in the UK annually. The primary aim of TKR is pain relief, but 10%-34% of patients report chronic pain. The aim of this systematic review was to evaluate the effectiveness of presurgical interventions in preventing chronic pain after TKR.
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