Molecular Pain最新文献

Pain stands as one of the main factors related to human disability and suffering, with different classifications (e.g., acute/chronic, somatic/visceral, and malignant/non-malignant). The management of this factor is of great importance during the lifespan; however, the current suggested medications have not yet reflected sufficient effectiveness with minimum side effects. Therefore, applying an ideal strategy against conditions accompanied by pain is urgent. A growing body of evidence has recently highlighted that alkaloids as bioactive compounds with analgesic capacity can be effective in these conditions. Regarding this matter, dehydrocorydaline, a bioactive alkaloid derived from the tubers of Rhizoma Corydalis, has shown promising results in pain management in diseases, including Chronic constriction injury, bone cancer, sleep deprivation, and inflammatory pain. Also, dehydrocorydaline has been shown to exert different biological and pharmacological benefits, like anti-tumor, anti-inflammatory, anti-microbial, anti-viral, anti-nociceptive, and cardioprotective. Hence, in this literature review, we aimed to explore the potential of this alkaloid agent in these conditions with a mechanistic insight.

Pain is an unfavorable subjective sensation influencing 20% of the public population, giving rise to substantial health and economic issues. Several categories of pain, such as acute and chronic pain, have been determined according to factors like pathophysiological mechanism, etiology, and anatomical locations. The current analgesic drugs are the cornerstone of pain management; however, some challenges, such as short-term relief and concerns about addiction, dependence, and side effects, warrant alternative choices for pain alleviation. In the recent decade, the importance of polyphenolic compounds, particularly honokiol, has increased due to their diverse therapeutic and biological features like anti-cancer, anti-inflammatory, anti-oxidative, anti-bacterial, anti-viral, and immune regulatory properties. Also, some documents have accentuated the striking role of honokiol in exerting analgesic effects in conditions such as inflammatory pain, neuropathic pain, and gouty arthritis. Ergo, the current literature review aimed to discuss the analgesic potential of honokiol in the mentioned conditions with a mechanistic insight.

Neuropathic pain is still a clinical challenge. Inflammatory responses and autophagy in the spinal cord are important mechanisms for the occurrence and maintain of neuropathic pain. PDCD4 is an important molecule that regulates inflammation and autophagy. However, the regulatory role of PDCD4 is unknown in pain modulation. In this study we found that the expression of PDCD4 in the spinal cord of CCI mice was increased. Inhibition of PDCD4 by intrathecal injection of adeno-associated virus alleviated neuropathic pain hypersensitivity and enhanced autophagy in CCI mice, and inhibited the activation of MAPKs, as well as the expression of inflammatory factors. Intrathecal injection of autophagy inhibitor 3-MA reversed PDCD4 inhibition induced pain relief and change of autophagy. Our results indicate that spinal cord inhibition of PDCD4 alleviates pain sensitization in neuropathic pain mice through MAPKs and autophagy, and PDCD4 may be developed into a therapeutic target of neuropathic pain treatment.

Preclinical studies addressing the peripheral effects of cancer perineural invasion report severe neuronal availability and excitability changes. Oral cell squamous cell carcinoma perineural invasion (MOC2-PNI) shows similar effects, modulating the afferent's sensibility (tactile desensitization with concurrent nociceptive sensitization) and demyelination without inducing spontaneous activity (see Part 1.). The current study addresses the electrical status (normal or abnormal) of both active (low threshold mechano receptors (LT) and high threshold mechano receptors (HT)) and inactive (F-type and S-type) afferents. Concurrently, we have also evaluated changes in the genetic landscape that may help to understand the physiological dynamics behind MOC2-PNI-induced functional disruption of the peripheral sensory system. We have observed that the altered cell distribution and mechanical sensibility of the animal's somatosensory system cannot be explained by cellular electrical dysfunction or MOC2-PNI-induced apoptosis. Although PNI does modify the expression of several genes related to cellular hypersensitivity, these changes are insufficient to explain the MOC2-PNI-induced aberrant neuronal excitability state. Our results indicate that genetic markers provide limited information about the functional hyperexcitable state of the peripheral system. Importantly, our results also highlight the emerging role of plasma membrane Ca²⁺-ATPase activity (PMCA) in explaining several aspects of the observed gender-specific neuronal plasticity and the reported cellular distribution switch generated by MOC2-PNI.

Chronic pain affects nearly 100 million adults in the U.S., yet few novel therapeutics have emerged in recent decades. P2X4 receptor (P2X4R), implicated in pain signaling, represents a promising target. We evaluated a humanized single-chain variable fragment (hscFv) targeting P2X4R for its ability to reduce ATP-induced currents and modulate excitability in human dorsal root ganglion (hDRG) neurons. Voltage-clamp recordings confirmed that human P2X4R (hP2X4R) hscFv significantly reduced ATP-evoked currents in HEK-293T cells expressing human P2X4, likely by relocalization of the receptor to the perinuclear region after hscFv treatment. Immunohistochemistry and transcriptomic analyses demonstrated widespread P2X4R (P2RX4) expression across hDRG neuronal subtypes in both male and female donors. Current-clamp recordings revealed that hP2X4R hscFv selectively increased action potential (AP) threshold in multi-firing hDRG neurons, without affecting single-firing neurons. Spontaneous activity at rest and depolarizing spontaneous fluctuation (DSF) amplitude were also reduced. Analysis confirmed consistent effects of hP2X4R hscFv on excitability parameters. These findings suggest that hP2X4 hscFv exerts modest but targeted effects on human sensory neurons, supporting its potential as a novel therapeutic for chronic pain.

Pain is an unpleasant sensory and emotional sensation about actual or possible tissue damage that can cause remarkable health and economic problems. For pain relief, analgesic drugs are commonly utilized; however, their prolonged use can cause different side effects from mild to severe stages. Therefore, discovering new and alternative choices for analgesic purposes is of importance. Hopeful evidence has shown that flavonoid compounds have various therapeutic and pharmacological potentials. Among these, silymarin, obtained from the milk thistle plant Silybum marianum, has addressed its competence in medicine, as demonstrated by its capacity against metabolic diseases, malignancies, inflammatory-related disorders, and organ toxicities. In the recent decade, some documents have stated the analgesic influences of silymarin, especially in some pathological situations like rheumatoid arthritis and neuropathic pain. Also, there is promising information regarding the possible synergistic effects of silymarin and some pharmacological or bioactive compounds. For these reasons, this narrative literature review aims to summarize and discuss the analgesic abilities of this flavonoid agent in pathological and nonpathological conditions and its interactions with other drugs with a focus on the involved mechanisms.

Background: Pancreatic neuropathy occurs during the development of pancreatic ductal adenocarcinoma (PDAC), with changes correlating to pancreatic neuropathic pain and increased expression of nociceptive genes in sensory ganglia. Emerging evidence suggests that sphingosine-1-phosphate receptor 1 (S1PR1) plays critical roles in the onset and maintenance of pain. However, whether S1PR1 in sensory ganglia contributes to PDAC-associated neuropathic pain remains unclear.

Methods: We collected histopathological sections and pain-related data from patients who underwent surgical resection and were pathologically confirmed as having PDAC. S1PR1 levels in intrapancreatic nerves were measured using immunohistochemistry. A mouse model of PDAC-associated pain was established in C57BL/6J mice via orthotopic transplantation of MT5 cells. Pain behaviors were evaluated through abdominal mechanical hyperalgesia, hunch score, and open-field tests. The changes and subcellular localization of S1PR1 in dorsal root ganglia (DRGs) were observed. Subsequently, the S1PR1 antagonists W146 and FTY720 were administered to investigate the underlying molecular mechanisms. We further assessed the analgesic efficacy and its impact on tumor progression of the S1PR1 antagonist FTY720.

Results: S1PR1 levels in nerves from PDAC patients experiencing cancer-associated pain were significantly higher compared to those without such pain. In the DRGs of a PDAC mouse model, S1PR1 expression was upregulated and colocalized with neurons and satellite glial cells. Intrathecal injection of S1PR1 antagonists W146 and FTY720 effectively alleviated PDAC-induced neuropathic pain hypersensitivity and suppressed the upregulation of transient receptor potential vanilloid 1 (TRPV1) and calcitonin gene-related peptide (CGRP). Additionally, FTY720 alleviated pancreatic cancer-related neuropathic pain and demonstrated partial anti-tumor effects.

Conclusions: Our findings indicate that S1PR1 in DRGs plays a pivotal role in PDAC-associated neuropathic pain. Inhibition of S1PR1 signaling may alleviate PDAC-related neuropathic pain, and targeting S1PR1 represents a promising strategy for adjuvant management of pancreatic cancer-related pain.

Across mammalian evolution, chronic pain has no adaptive value, and in the wild, there's no evidence of its existence. Since rodents are often used to model chronic pain in humans, the question of how the peripheral somatosensory system of these animals responds to injury becomes critical to our overall translatability efforts. Over a decade of intensive work on this question has led to the discovery of the primordial systemic process that protects the mammalian peripheral somatosensory system against uncontrolled hyperexcitability, as well as its underlying electrical mechanism. Named the "butterfly effect," this two-stage process enables the appropriate animal behavioral response to injury (first stage) while evading pathology by deactivating hyperactive nociceptive neurons (second stage). This deactivation process involves the generation of subthreshold membrane sawtooth oscillations, which, rather than producing ectopic discharges, lead the cells to a quiescent state. The complex nature of this phenomenon challenges any simplistic approach to modeling and translating animal pain physiology directly into human pain pathology.

EA effectively treats gastrointestinal diseases, pain symptoms, and emotional disorder. Furthermore, vHPC and mPFC are two of the crucial nuclei involved in controlling chronic pain and anxiety-like behaviors. In the present study, it is investigated whether EA may reduce visceral pain and anxiety associated with inflammatory bowel disease (IBD) by inhibition of vHPC-to-mPFC pathway. We found that EA alleviated visceral hyperalgesia and anxiety in TNBS-treated IBD mice. EA decreased the numbers of c-Fos and neurogranin (labeled glutamatergic neurons) co-labeled neurons in both vHPC and mPFC. EA suppressed the activation of vHPC and mPFC pyramidal neurons associated with anxiety-like behaviors and EA suppressed the activation of vHPC neuronal response to von Frey filament. In addition, chemogenetic inhibition of the vHPC-to-mPFC pathway alleviated mechanical allodynia, visceral hyperalgesia and anxiety in IBD mice. However, chemogenetic activation of vHPC-to-mPFC pathway antagonized the effect of EA on anxiety and visceral hyperalgesia, but not on mechanical allodynia in IBD mice. In conclusion, our findings revealed that vHPC-to-mPFC pathway is involved in the inhibitory effect of EA on anxiety and pain sensitivity in IBD mice. EA may exert anti-anxiety effect via inhibition of vHPC-to-mPFC pathway. Thus, our study provides new information about the cellular circuits mechanisms of the therapeutic effect of EA on the comorbidity of visceral pain and anxiety induced by IBD.

The downregulation of mu-opioid receptor (MOR) expression in dorsal root ganglia (DRG) following peripheral nerve injury plays a pivotal role in neuropathic pain development and contributes to the reduced efficacy of morphine analgesia. The molecular mechanisms underlying this transcriptional silencing remain poorly understood. In this study, we demonstrate that peripheral nerve injury induces upregulation of methyl-CpG-binding domain protein 1 (MBD1) and histone lysine methyltransferase SUV39H1, leading to increased trimethylation of histone H3 at lysine 9 (H3K9me3) at the Oprm1 gene locus in injured DRG neurons. Genetic ablation of MBD1 reversed injury-induced MOR downregulation at both mRNA and protein levels, attenuated H3K9me3 enrichment at the Oprm1 promoter, and alleviated neuropathic pain behaviors, despite persistent SUV39H1 upregulation. Mechanistic studies revealed that nerve injury enhances the recruitment of SUV39H1 and H3K9me3 to the Oprm1 promoter, which is dependent on MBD1. Our findings establish a novel epigenetic mechanism wherein MBD1-mediated recruitment of SUV39H1 promotes H3K9me3-dependent transcriptional silencing of Oprm1 in DRG neurons following peripheral nerve injury.