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Bone cancer pain (BCP) caused by primary or metastatic bone tumours significantly interferes with the quality of life of patients. However, the relief of BCP remains a major challenge. Our previous study demonstrated that intrathecal administration of the Sirtuin 1 (SIRT1) activator SRT1720 attenuated BCP in a murine model. Nevertheless, the underlying mechanisms have not been fully clarified. Previous studies demonstrated that the activation of the cAMP response element binding (CREB) protein played a critical role in BCP. Furthermore, SIRT1 can also regulate the balance between glucose and lipid metabolism through CREB deacetylation. In this study, we measured the analgesic effects of different intrathecal doses of SRT1720 on BCP in a murine model and further examined whether SRT1720 attenuated BCP by suppressing CREB/CREB-regulated transcription coactivator 1 (CRTC1) signalling pathway. Our results demonstrated that the BCP mice developed significant mechanical allodynia and spontaneous flinching, which were accompanied by the upregulation of phospho-Ser133 CREB (p-CREB) and CRTC1 expression in the spinal cord. SRT1720 treatment produced a dose-dependent analgesic effect on the BCP mice and downregulated the expression of p-CREB and CRTC1. These results suggest that intrathecal administration of SRT1720 reverses BCP likely by inhibiting the CREB/CRTC1 signalling pathway.
Learn More >Synaptosomal associated proteins of 25 kDa (SNAP-25), as a member of stable soluble N-ethylmaleimide-sensitive factor attachment protein receptor complex, is critical for membrane fusion and required for the release of neurotransmitters. The α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor is implicated in pathologic pain. This study aimed to investigate whether and how SNAP-25 regulated AMPA receptors in neuropathic pain.
Learn More >Gut-innervating nociceptor sensory neurons respond to noxious stimuli by initiating protective responses including pain and inflammation; however, their role in enteric infections is unclear. Here, we find that nociceptor neurons critically mediate host defense against the bacterial pathogen Salmonella enterica serovar Typhimurium (STm). Dorsal root ganglia nociceptors protect against STm colonization, invasion, and dissemination from the gut. Nociceptors regulate the density of microfold (M) cells in ileum Peyer's patch (PP) follicle-associated epithelia (FAE) to limit entry points for STm invasion. Downstream of M cells, nociceptors maintain levels of segmentous filamentous bacteria (SFB), a gut microbe residing on ileum villi and PP FAE that mediates resistance to STm infection. TRPV1+ nociceptors directly respond to STm by releasing calcitonin gene-related peptide (CGRP), a neuropeptide that modulates M cells and SFB levels to protect against Salmonella infection. These findings reveal a major role for nociceptor neurons in sensing and defending against enteric pathogens.
Learn More >Paradoxically, some TRPV1 agonists are, at the organismal level, both non-pungent and clinically useful as topical analgesics. Here, we describe the scaled-up synthesis and characterization in mouse models of a novel, non-pungent vanilloid. Potent analgesic ac-tivity was observed in models of neuropathic pain, and the compound blocked capsaicin induced allodynia, showing dermal accu-mulation with little transdermal absorption. Finally, it displayed much weaker systemic toxicity compared to capsaicin and was negative in assays of genotoxicity.
Learn More >The United States is experiencing an epidemic of opioid use disorder (OUD) and overdose-related deaths. However, the genetic basis for the ability to discontinue opioid use has not been investigated. We performed a genome-wide association study (GWAS) of opioid cessation (defined as abstinence from illicit opioids for >1 year or <6 months before the interview date) in 1130 African American (AA) and 2919 European ancestry (EA) participants recruited for genetic studies of substance use disorders and who met lifetime Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) criteria for OUD. Association tests performed separately within each ethnic group were combined by meta-analysis with results obtained from the Comorbidity and Trauma Study. Although there were no genome-wide significant associations, we found suggestive associations with nine independent loci, including three which are biologically relevant: rs4740988 in ( = 2.24 × 10), rs36098404 in ( = 2.24 × 10), and rs592026 in ( = 6.53 × 10). Significant pathways identified in persons of European ancestry (EA) are related to vitamin D metabolism ( = 3.79 × 10) and fibroblast growth factor (FGF) signaling ( = 2.39 × 10). UK Biobank traits including smoking and drinking cessation and chronic back pain were significantly associated with opioid cessation using GWAS-derived polygenic risk scores. These results provide evidence for genetic influences on opioid cessation, suggest genetic overlap with other relevant traits, and may indicate potential novel therapeutic targets for OUD.
Learn More >Stress-induced analgesia (SIA) is an evolutionarily conserved phenomenon during stress. Neuropeptide S (NPS), orexins, substance P, glutamate and endocannabinoids are known to be involved in stress and/or SIA, however their causal links remain unclear. Here, we reveal an unprecedented sequential cascade involving these mediators in the lateral hypothalamus (LH) and ventrolateral periaqueductal gray (vlPAG) using a restraint stress-induced SIA model.
Learn More >Expectation interacting with nociceptive input can shape the perception of pain. It has been suggested that reward-related expectations are associated with the activation of the ventral tegmental area (VTA), which projects to the striatum (e.g., nucleus accumbens [NAc]) and prefrontal cortex (e.g., rostral anterior cingulate cortex [rACC]). However, the role of these projection pathways in encoding expectancy effects on pain remains unclear. In this study, we leveraged a visual cue conditioning paradigm with a long pain anticipation period and collected magnetic resonance imaging (MRI) data from 30 healthy human subjects (14 females). At the within-subject level, whole brain functional connectivity (FC) analyses showed that the mesocortical pathway (VTA-rACC FC) and the mesolimbic pathway (VTA-NAc FC) were enhanced with positive expectation but inhibited with negative expectation during pain anticipation period. Mediation analyses revealed that cue-based expectancy effects on pain were mainly mediated by the VTA-NAc FC, and structural equation modeling showed that VTA-based FC influenced pain perception by modulating pain-evoked brain responses. At the between-subject level, multivariate pattern analyses demonstrated that gray matter volumes in the VTA, NAc, and rACC were able to predict the magnitudes of conditioned pain responses associated with positive and/or negative expectations across subjects. Our results therefore advance the current understanding of how the reward system is linked to the interaction between expectation and pain. Furthermore, they provide precise functional and structural information on mesocorticolimibic pathways that encode within-subject and between-subject variability of expectancy effects on pain.Studies have suggested that reward-related expectation is associated with the activation of the ventral tegmental area (VTA), which projects to the striatum and prefrontal cortex. However, the role of these projection pathways in encoding expectancy effects on pain remains unclear. Using multi-modality MRI and a visual cue conditioning paradigm, we found that the functional connectivity and gray matter volumes in key regions (the VTA, nucleus accumbens, and rostral anterior cingulate cortex) within the mesocorticolimbic pathways encoded expectancy effects on pain. Our results advance the current understanding of how the reward system is linked to the interaction between expectation and pain, and provide precise functional and structural information on mesocorticolimbic pathways that encode expectancy effects on pain.
Learn More >: Prurigo nodularis (PN) is an intensely pruritic skin condition of considerable morbidity. However, the pathogenesis of PN and its association with underlying neuropathy is unclear. : We sought to investigate the association between PN and etiologies of peripheral neuropathy. : A cross-sectional analysis of adult patients (≥18-year-old) with PN, AD, and Psoriasis at the Johns Hopkins Health System over a six-year period (January 2013-January 2019) was performed. The strength of association with etiologies of peripheral neuropathy were compared to a control cohort of individuals without PN, as well as those with AD or psoriasis. : A total of 1122 patients with PN were compared to 10,390 AD patients, 15,056 patients with psoriasis, and a control cohort of 4,949,017 individuals without PN, with respect to 25 comorbidities associated with peripheral neuropathies. : Comparisons between peripheral neuropathies and PN represent associations but are not causal relationships. : Prurigo nodularis is strongly associated with peripheral neuropathies, suggesting a role for neural dysregulation in pathogenesis.
Learn More >Pancreatitis-associated proteins (PAPs) display multiple functions in visceral diseases. Previous studies showed that the expression level of PAP-I was low in the dorsal root ganglion (DRG) of naïve rats but was expressed after peripheral nerve injury. However, its role in neuropathic pain remains unknown. We found that PAP-I expression was continuously up-regulated in the DRG neurons from rat spared nerve injury (SNI) models, and transported towards the spinal dorsal horn to act as a pro-inflammatory factor. Intrathecal delivery of PAP-I enhanced sensory hyperalgesia, whereas PAP-I deficiency by either gene knockout or antibody application alleviated tactile allodynia at the maintenance phase after SNI. Furthermore, PAP-I functioned by activating the spinal microglia via C-C chemokine receptor type 2 (CCR2) that participated in neuropathic pain. Inhibition of either microglial activation or CCR2 abolished the PAP-I-induced hyperalgesia. Thus, PAP-I mediates the neuron-microglial crosstalk after peripheral nerve injury, and contributes to the maintenance of neuropathic pain.Neuropathic pain is maladaptive pain condition and the maintaining mechanism is largely unclear. Here we reveal that after peripheral nerve injury, PAP-I can be transported to the spinal dorsal horn and is crucial in the progression of neuropathic pain. Importantly, we prove that PAP-I mainly functions through activating the spinal microglia via CCR2-p38 MAPK pathway. Furthermore, we confirm that the pro-inflammatory effect of PAP-I is more prominent after the establishment of neuropathic pain, thus indicating that microglia also participates in the maintenance phase of neuropathic pain.
Learn More >Voltage-gated T-type Ca (Cav3) channels regulate diverse physiological events including neuronal excitability and have been linked to several pathological conditions such as absence epilepsy, cardiovascular diseases, and neuropathic pain. It is also acknowledged that Ca/Calmodulin-dependent protein kinase II (CaMKII) and protein kinases A and C (PKA and PKC) regulate the activity of T-type channels. Interestingly, peripheral nerve injury induces tactile allodynia and up-regulates Cav3.2 channels and Cdk5 in dorsal root ganglia (DRG) and spinal dorsal horn (SDH). Here, we report that recombinant Cav3.2 channels expressed in HEK-293 cells are regulatory targets of cyclin-dependent kinase 5 (Cdk5). Site-directed mutagenesis showed that the relevant sites for this regulation are residues S561 and S1987. We also found that Cdk5 may regulate Cav3.2 channel functional expression in rats with mechanical allodynia induced by spinal nerve ligation (SNL). Consequently, the Cdk5 inhibitor olomoucine affected the compound action potential (cAP) recorded in the spinal nerves, as well as the paw withdrawal threshold. Likewise, Cdk5 expression was upregulated after SNL in the DRGs. These findings unveil a novel mechanism for how phosphorylation may regulate Cav3.2 channels and suggest that increased channel activity by Cdk5-mediated phosphorylation after SNL contributes nerve injury-induced tactile allodynia.Neuropathic pain is a current public health challenge. It can develop as a result of injury or nerve illness. It is acknowledged that the expression of various ion channels can be altered in neuropathic pain, including T-type Ca channels that are expressed in sensory neurons where they play a role in the regulation of cellular excitability. The present work shows that the exacerbated expression of Cdk5 in a preclinical model of neuropathic pain increases the functional expression of Cav3.2 channels. This finding is relevant for the understanding of the molecular pathophysiology of the disease. Additionally, this work may have a substantial translational impact, since it describes a novel molecular pathway that could represent an interesting therapeutic alternative for neuropathic pain.
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