Histone deacetylase as emerging pharmacological therapeutic target for neuropathic pain: From epigenetic to selective drugs.

BACKGROUND: Neuropathic pain remains a formidable challenge for modern medicine. The first-line pharmacological therapies exhibit limited efficacy and unfavorable side effect profiles, highlighting an unmet need for effective therapeutic medications. The past decades have witnessed an explosion in efforts to translate epigenetic concepts into pain therapy and shed light on epigenetics as a promising avenue for pain research. Recently, the aberrant activity of histone deacetylase (HDAC) has emerged as a key mechanism contributing to the development and maintenance of neuropathic pain. AIMS: In this review, we highlight the distinctive role of specific HDAC subtypes in a cell-specific manner in pain nociception, and outline the recent experimental evidence supporting the therapeutic potential of HDACi in neuropathic pain. METHODS: We have summarized studies of HDAC in neuropathic pain in Pubmed. RESULTS: HDACs, widely distributed in the neuronal and non-neuronal cells of the dorsal root ganglion and spinal cord, regulate gene expression by deacetylation of histone or non-histone proteins and involving in increased neuronal excitability and neuroinflammation, thus promoting peripheral and central sensitization. Importantly, pharmacological manipulation of aberrant acetylation using HDAC-targeted inhibitors (HDACi) has shown promising pain-relieving properties in various preclinical models of neuropathic pain. Yet, many of which exhibit low-specificity that may induce off-target toxicities, underscoring the necessity for the development of isoform-selective HDACi in pain management. CONCLUSIONS: Abnormally elevated HDACs promote neuronal excitability and neuroinflammation by epigenetically modulating pivotal gene expression in neuronal and immune cells, contributing to peripheral and central sensitization in the progression of neuropathic pain, and HDACi showed significant efficacy and great potential for alleviating neuropathic pain.

Efficacy and safety of patient-controlled intravenous analgesia after APS team standardized postoperative pain management: A 6-year experience of an acute pain service in 107802 Chinese patients.

There are few studies on the impact of postoperative pain management (such as Acute Pain Service, APS) on the prognosis of patients, especially the research on large samples, even less data on Chinese patients. It is reported that only 25.12 % of hospitals in China have established APS or similar teams, and less than 10 % of them are responsible for the whole process of postoperative analgesia services. Tongji Hospital affiliated to Tongji Medical College of Huazhong University of Science and Technology has established a professional APS team led by anesthesiologists (TJ-APS), and has a standardized workflow and management system. Based on the TJ-APS standardized postoperative pain management, the incidence and adverse effects of postoperative pain in different types of surgical patients were analyzed. In total, 107,802 patients receiving intravenous PCA from the Tongji Hospital affiliated to Tongji Medical College of Huazhong University of Science and Technology were selected between January 2016 and December 2021, which were under TJ-APS standardized postoperative analgesia process, postoperative analgesia strategy based on the principle of "low opioid, multimodal, specialization and individualization", as well as regular ward rounds and 24-h on call on-duty system. We assessed the incidence and adverse effects of postoperative pain in different types of surgical patients. Based on the TJ-APS standardized postoperative pain management, the incidence of poor postoperative analgesia in patients with intravenous PCA is significantly lower than that reported in the current literature (20 %), and mainly occurs in biliary-pancreatic surgery, extrahepatic surgery and gastrointestinal surgery. The overall incidence of adverse effects was 5.52 %, of which nausea and vomiting was the highest, especially among gynecological tumors and gynecological patients, which were 10.75 % and 8.68 % respectively, but both were lower than the level reported in the current literature (20 %). This APS multimodal management and analgesia process can provide reference and guidance for PCA management of postoperative acute pain.

A novel co-target of ACY1 governing plasma membrane translocation of SphK1 contributes to inflammatory and neuropathic pain.

Previous studies validate that inhibiting sodium channel 1.8 (Nav1.8) effectively relieves inflammatory and neuropathic pain. However, Nav1.8 blockers have cardiac side effects in addition to analgesic effects. Here, we constructed a spinal differential protein expression profile using Nav1.8 knockout mice to screen common downstream proteins of Nav1.8 in inflammatory and neuropathic pain. We found that aminoacylase 1 (ACY1) expression was increased in wild-type mice compared to Nav1.8 knockout mice in both pain models. Moreover, spinal ACY1 overexpression induced mechanical allodynia in naive mice, while ACY1 suppression alleviated inflammatory and neuropathic pain. Further, ACY1 could interact with sphingosine kinase 1 and promote its membrane translocation, resulting in sphingosine-1-phosphate upregulation and the activation of glutamatergic neurons and astrocytes. In conclusion, ACY1 acts as a common downstream effector protein of Nav1.8 in inflammatory and neuropathic pain and could be a new and precise therapeutic target for chronic pain.

Transcriptomics reveals the effects of NTRK1 on endoplasmic reticulum stress response-associated genes in human neuronal cell lines.

Background: NTRK1 gene, encoding TrkA, is essential for the nervous system and drives a variety of biological processes, including pain. Given the unsatisfied analgesic effects of some new drugs targeting NTRK1 in clinic, a deeper understanding for the mechanism of NTRK1 in neurons is crucial. Methods: We assessed the transcriptional responses in SH-SY5Y cells with NTRK1 overexpression using bioinformatics analysis. GO and KEGG analyses were performed, PPI networks were constructed, and the functional modules and top 10 genes were screened. Subsequently, hub genes were validated using RT-qPCR. Results: A total of 419 DEGs were identified, including 193 upregulated and 226 downregulated genes. GO showed that upregulated genes were mainly enriched in response to endoplasmic reticulum (ER) stress, protein folding in ER, etc., and downregulated genes were highly enriched in a series of cellular parts and cellular processes. KEGG showed DEGs were enriched in protein processing in ER and pathways associated with cell proliferation and migration. The finest module was dramatically enriched in the ER stress response-related biological process. The verified seven hub genes consisted of five upregulated genes (COL1A1, P4HB, HSPA5, THBS1, and XBP1) and two downregulated genes (CCND1 and COL3A1), and almost all were correlated with response to ER stress. Conclusion: Our data demonstrated that NTRK1 significantly influenced the gene transcription of ER stress response in SH-SY5Y cells. It indicated that ER stress response could contribute to various functions of NTRK1-dependent neurons, and therefore, ER stress response-associated genes need further study for neurological dysfunction implicated in NTRK1.

Pivotal role of the gut microbiota in congenital insensitivity to pain with anhidrosis.

BACKGROUND: Increasing evidence has shown that the occurrence and development of various human diseases are closely related to the gut microbiota. We compared the gut microbial communities of human subjects with congenital insensitivity to pain with anhidrosis (CIPA) and healthy controls (HCs) to assess whether fecal microbiota transplantation (FMT) into germ-free mice and mice in acute pain influenced the behaviors of the host. METHODS: We utilized 16 s rRNA analysis to compare the gut microbial communities of CIPA subjects and HCs and assessed whether FMT into germ-free mice and mice in acute pain influenced the behaviors of the host. RESULTS: In a 16 s RNA analysis, the CIPA group had significant decreases in the relative abundance of 11 bacteria, whereas 7 bacteria were significantly increased. In further animal experiments, the transplantation of fecal samples from CIPA patients to healthy mice significantly increased their scores on both the mechanical withdrawal test and the tail flick test; in an acute plantar incision model, scores were also significantly increased on the mechanical withdrawal test at 4 and 5 days after the operation. Moreover, pseudo-germ-free mice receiving fecal bacteria from patients with CIPA took significantly longer to escape and had a significantly longer path length on training days 1, 2, and 5 and also had fewer platform crossings and spent less time in the target quadrant in the probe trial. CONCLUSIONS: Our results suggest that the gut microbiota in CIPA subjects plays a key role in behaviors. Therapeutic strategies for improving the gut microbiota might alleviate CIPA symptoms.

The Potential Effect of Na v 1.8 in Autism Spectrum Disorder: Evidence From a Congenital Case With Compound Heterozygous SCN10A Mutations.

Apart from the most prominent symptoms in Autism spectrum disorder (ASD), namely deficits in social interaction, communication and repetitive behavior, patients often show abnormal sensory reactivity to environmental stimuli. Especially potentially painful stimuli are reported to be experienced in a different way compared to healthy persons. In our present study, we identified an ASD patient carrying compound heterozygous mutations in the voltage-gated sodium channel (VGSC) Na v 1.8, which is preferentially expressed in sensory neurons. We expressed both mutations, p.I1511M and p.R512∗, in a heterologous expression system and investigated their biophysical properties using patch-clamp recordings. The results of these experiments reveal that the p.R512∗ mutation renders the channel non-functional, while the p.I1511M mutation showed only minor effects on the channel's function. Behavioral experiments in a Na v 1.8 loss-of-function mouse model additionally revealed that Na v 1.8 may play a role in autism-like symptomatology. Our results present Na v 1.8 as a protein potentially involved in ASD pathophysiology and may therefore offer new insights into the genetic basis of this disease.

Emerging Role of Serum Glucocorticoid-Regulated Kinase 1 in Pathological Pain.

Currently, the management of acute and chronic pain in clinical practice remains unsatisfactory due to the existence of limited effective treatments, and novel therapeutic strategies for pathological pain are urgently needed. In the past few decades, the role of serum and glucocorticoid-inducible kinase 1 (SGK1) in the development of pain and diurnal rhythms has been implicated in numerous studies. The expression levels of SGK1 mRNA and protein were found to be elevated in the spinal cord and brain in various pathological pain models. Blocking SGK1 significantly attenuated pain-like responses and the development of pathological pain. These studies provide strong evidence that SGK1 plays a role in the development of various types of pathological pain and that targeting SGK1 may be a novel therapeutic strategy for pain management. In this review article, we provide evidence from animal models for the potential role of SGK1 in the regulation of pathological pain caused by inflammation, nerve injury, psychiatric disorders, and chronic opioid exposure.

The Role of Gut Microbiota in Chronic Itch-Evoked Novel Object Recognition-Related Cognitive Dysfunction in Mice.

The high incidence of patients with chronic itch highlights the importance of fundamental research. Recent advances in the interface of gut microbiota have shed new light into exploring this phenomenon. However, it is unknown whether gut microbiota plays a role in chronic itch in rodents with or without cognitive dysfunction. In this study, the role of gut microbiota in diphenylcyclopropenone (DCP)-evoked chronic itch was investigated in mice and hierarchical cluster analysis of novel object recognition test (ORT) results were used to classify DCP-evoked itch model in mice with or without cognitive dysfunction (CD)-like phenotype and 16S ribosomal RNA (rRNA) gene sequencing was used to compare gut bacterial composition between CD (Susceptible) and Non-CD phenotypes (Unsusceptible) in chronic itch mice. Results showed that the microbiota composition was significantly altered by DCP-evoked chronic itch and chronic itch induced novel object recognition-related CD. However, abnormal gut microbiota composition induced by chronic itch may not be correlated with novel object recognition-related CD.

NGF-Induced Nav1.7 Upregulation Contributes to Chronic Post-surgical Pain by Activating SGK1-Dependent Nedd4-2 Phosphorylation.

At present, chronic post-surgical pain (CPSP) is difficult to prevent and cure clinically because of our lack of understanding of its mechanisms. Surgical injury induces the upregulation of voltage-gated sodium channel Nav1.7 in dorsal root ganglion (DRG) neurons, suggesting that Nav1.7 is involved in the development of CPSP. However, the mechanism leading to persistent dysregulation of Nav1.7 is largely unknown. Given that nerve growth factor (NGF) induces a long-term increase in the neuronal hyperexcitability after injury, we hypothesized that NGF might cause the long-term dysregulation of Nav1.7. In this study, we aimed to investigate whether Nav1.7 regulation by NGF is involved in CPSP and thus contributes to the specific mechanisms involved in the development of CPSP. Using conditional nociceptor-specific Nav1.7 knockout mice, we confirmed the involvement of Nav1.7 in NGF-induced pain and identified its role in the maintenance of pain behavior during long-term observations (up to 14 days). Using western blot analyses and immunostaining, we showed that NGF could trigger the upregulation of Nav1.7 expression and thus support the development of CPSP in rats. Using pharmacological approaches, we showed that the increase of Nav1.7 might be partly regulated by an NGF/TrkA-SGK1-Nedd4-2-mediated pathway. Furthermore, reversing the upregulation of Nav1.7 in DRG could alleviate spinal sensitization. Our results suggest that the maintained upregulation of Nav1.7 triggered by NGF contributes to the development of CPSP. Attenuating the dysregulation of Nav1.7 in peripheral nociceptors may be a strategy to prevent the transition from acute post-surgical pain to CPSP.

The Role of Voltage-Gated Sodium Channel 1.8 in the Effect of Atropine on Heart Rate: Evidence From a Retrospective Clinical Study and Mouse Model.

Atropine is commonly used to counter the effects of the parasympathetic neurotransmitter acetylcholine on heart rate in clinical practice, such as in the perioperative period; however, individual differences in the response to atropine are huge. The association between SCN10A/voltage-gated sodium channel 1.8 (NaV1.8) and cardiac conduction has been demonstrated; however, the exact role of SCN10A/NaV1.8 in the heart rate response to atropine remains unclear. To identify the role of SCN10A variants that influence the heart rate responses to atropine, we carried out a retrospective study in 1,005 Han Chinese subjects. Our results showed that rs6795970 was associated with the heart rate response to atropine. The heart rate responses to atropine and methoctramine in NaV1.8 knockout mice were lower, whereas the heart rate response to isoproterenol was like those in wild type mice. Furthermore, we observed that the NaV1.8 blocker A-803467 alleviated the heart rate response to atropine in wild type mice. The retrospective study revealed a previously unknown role of NaV1.8 in controlling the heart rate response to atropine, as shown by the animal study, a speculative mechanism that may involve the cardiac muscarinic acetylcholine receptor M2.

Upregulation of transcription factor 4 downregulates NaV1.8 expression in DRG neurons and prevents the development of rat inflammatory and neuropathic hypersensitivity.

The voltage sodium channel 1.8 (NaV1.8) in the dorsal root ganglion (DRG) neurons contributes to the initiation and development of chronic inflammatory and neuropathic pain. However, an effective intervention on NaV1.8 remains to be studied in pre-clinical research and clinical trials. In this study, we aimed to investigate whether transcription factor 4 (TCF4) overexpression represses NaV1.8 expression in DRG neurons, thus preventing the development of chronic pain. Using chromatin immunoprecipitation (CHIP), we verified the interaction of TCF4 and sodium voltage-gated channel alpha subunit 10A (SCN10A) enhancer in HEK293 cells and rat DRG neurons. Using a dual luciferase reporter assay, we confirmed the transcriptional inhibition of TCF4 on SCN10A promoter in vitro. To investigate the regulation of TCF4 on Nav1.8, we then upregulated TCF4 expression by intrathecally delivering an overexpression of recombinant adeno-associated virus (rAAV) in the Complete Freund's adjuvant (CFA)-induced inflammatory pain model and spared nerve injury (SNI)-induced neuropathic pain model. By using a quantitative polymerase chain reaction (qPCR), western blot, and immunostaining, we evaluated NaV1.8 expression after a noxious stimulation and the application of the TCF4 overexpression virus. We showed that the intrathecal delivery of TCF4 overexpression virus significantly repressed the increase of NaV1.8 and prevented the development of hyperalgesia in rats. Moreover, we confirmed the efficient role of an overexpressed TCF4 in preventing the CFA- and SNI-induced neuronal hyperexcitability by calcium imaging. Our results suggest that attenuating the dysregulation of NaV1.8 by targeting TCF4 may be a novel therapeutic strategy for chronic inflammatory and neuropathic pain.

Altered expression of itch­related mediators in the lower cervical spinal cord in mouse models of two types of chronic itch.

In this study, we focused on several itch­related molecules and receptors in the spinal cord with the goal of clarifying the specific mediators that regulate itch sensation. We investigated the involvement of serotonin receptors, opioid receptors, glia cell markers and chemokines (ligands and receptors) in models of acetone/ether/water (AEW)­ and diphenylcyclopropenone (DCP)­induced chronic itch. Using reverse transcription­quantitative polymerase chain reaction, we examined the expression profiles of these mediators in the lower cervical spinal cord (C5­8) of two models of chronic itch. We found that the gene expression levels of opioid receptor mu 1 (Oprm1), 5­hydroxytryptamine receptor 1A (Htr1a) and 5­hydroxytryptamine receptor 6 (Htr6) were upregulated. Among the chemokines, the expression levels of C­C motif chemokine ligand (Ccl)21, Cxcl3 and Cxcl16 and their receptors, Ccr7, Cxcr2 and Cxcr6, were simultaneously upregulated in the spinal cords of the mice in both models of chronic itch. By contrast, the expression levels of Ccl2, Ccl3, Ccl4 and Ccl22 were downregulated. These findings indicate that multiple mediators, such as chemokines in the spinal cord, are altered and may be central candidates in further research into the mechanisms involved in the development of chronic itch.

Oxycodone regulates incision-induced activation of neurotrophic factors and receptors in an acute post-surgery pain rat model.

BACKGROUND: Oxycodone, which is one of the most commonly used opiates in postoperative pain management, has a different affinity for µ-opioid receptors (MOR), κ-opioid receptors (KOR), and δ-opioid receptors (DOR). Accumulating research has suggested that neurotrophins (NTs) are involved in opioid analgesia. In the current exploratory study, we aimed to investigate the underlying mechanisms of the analgesic effects of oxycodone on post-surgery pain in rats and to determine whether neurotrophic factors and receptors were involved in these effects. METHODS: Mechanical and thermal sensitivity tests were used to evaluate the validity of the postoperative pain rat model and to determine the analgesic effect of oxycodone. Quantitative PCR and Western blot analysis were used to detect the changes in the expression of three types of opioid receptors and NTs and their high-affinity receptors in the spinal cord after surgery and oxycodone administration. RESULTS: Oxycodone showed an analgesic effect on plantar incision (PI)-induced hyperalgesia, especially thermal hyperalgesia. We detected an obvious increase in MOR expression levels but insignificant changes in KOR and DOR levels in the spinal cord after PI. Moreover, we found that oxycodone was able to reverse the increased expression of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), tyrosine kinase receptor (TrK) A, and TrkB and the decreased expression of NT-3 and TrkC, after PI. Pretreatment with oxycodone also altered the expression of these mediators. CONCLUSION: Based on the results, possible underlying mechanisms for the antinociceptive properties of oxycodone in acute postoperative pain include the activation of MOR downstream signaling and the regulation of NTs and receptor expression through attenuation of glial activation and fortification of antinociceptive mediators in the spinal cord. This study may provide new insights into the molecular mechanisms underlying the analgesic action of oxycodone.

Altered expression of differential gene and lncRNA in the lower thoracic spinal cord on different time courses of experimental obstructive jaundice model accompanied with altered peripheral nociception in rats.

The spinal origin of jaundice-induced altered peripheral nociceptive response poorly understood. In the current study, we aimed to first validate rats with bile duct ligation (BDL) as a jaundice model accompanied by altered peripheral nociceptive response, and then to analyze differential gene and lncRNA expression patterns in the lower thoracic spinal cord on different time courses after BDL operation by using high-throughput RNA sequencing. The differentially expressed genes (DEGs) identified using reverse transcription-quantitative polymerase chain reaction (RT-qPCR) analysis, followed by clustering analysis, Gene Ontology analysis and pathway analysis. As a result, a total of 2033 lncRNAs were differentially expressed 28d after BDL, in which 1545 probe sets were up-regulated and 488 probe sets were down-regulated, whereas a total of 2800 mRNAs were differentially expressed, in which 1548 probe sets were up-regulated and 1252 probe sets were down-regulated. The RNAseq data of select mRNAs and lncRNAs was validated by RT-qPCR. 28d after BDL, the expressions of lncRNA NONRATT002335 and NONRATT018085 were significantly up-regulated whereas the expression of lncRNA NONRATT025415, NONRATT025388 and NONRATT025409 was significantly down-regulated. 14d after BDL, the expressions of lncRNA NONRATT002335 and NONRATT018085 were significantly up-regulated; the expression of lncRNA NONRATT025415, NONRATT025388 and NONRATT025409 was significantly down-regulated. In conclusion, the present study showed that jaundice accompanied with decreased peripheral nociception involved in the changes of gene and lncRNA expression profiles in spinal cord. These findings extend current understanding of spinal mechanism for obstructive jaundice accompanied by decreased peripheral nociception.

Altered expression of target genes of spinal cord in different itch models compared with capsaicin assessed by RT-qPCR validation.

Spinal cord plays a central role in the development and progression of pathogenesis of obstinate pruritus. In the current study, four groups of adult male C57Bl/6 mice were investigated; one group treated with saline, while the other groups intradermally injected with compound 48/80, histamine, α-Me-5-HT and capsaicin (algogenic substance), respectively. The intradermal microinjection of pruritic and algogenic compound resulted in a dramatic increase in the itch/algogenic behavior. Analysis of the microarray data showed that 15 genes in spinal cord (C5-C8) were differentially expressed between control group and 48/80 group, in which 9 genes were up-regulated and 6 genes were down-regulated. Furthermore, the results of RT-qPCR validation studies in C5-C8 spinal cord revealed that the 9 mRNA (Sgk1, Bag4, Fos, Ehd2, Edn3, Wdfy, Corin, 4921511E18Rik and 4930423020Rik) showed very different patterns for these different drugs, especially when comparing α-Me-5-HT and capsaicin. In three itch models, Fos and Ehd2 were up-regulated whereas Corin, 4921511E18Rik and 4930423020Rik were down-regulated. Furthermore, Corin and 4930423020Rik were down-regulated in itch model group compared to capsaicin group. Thus the application of microarray technique, coupled with RT-qPCR validation, further explain the mechanism behind itching evoked by pruritic compounds. It can contribute to our understanding of pharmacological methods for prevention or treatment of obstinate pruritus.

The caudal pedunculopontine tegmental nucleus may be involved in the regulation of skeletal muscle activity by melanocortin-sympathetic pathway: a virally mediated trans-synaptic tracing study in spinally transected transgenic mice.

Understanding neuroanatomical sympathetic circuitry and neuronal connections from the caudal pedunculopontine tegmental nucleus to skeletal muscle is important to the study of possible mechanisms of pedunculopontine tegmental nucleus (PPTg) and cuneiform nucleus (CnF) that are involved in the regulation of skeletal muscle activity of the sympathetic pathway. The aim of this study was to use virus PRV-614 to trace the melanocortin-sympathetic neural pathways from PPTg and CnF to a hindlimb muscle (gastrocnemius) in spinally transected MC4R-GFP transgenic mice. PRV-614 was injected into the gastrocnemius muscle after receiving a complete spinal cord transection below the L2 level. PRV-614/MC4R-GFP and PRV-614/TPH dual-labeled neurons were found in the dissipated parts of PPTg (dpPPTg), but not between the compact parts of PPTg (cpPPTg) and CnF. It is proposed that a hierarchical pathway of neurons within the caudal pedunculopontine tegmental nucleus sends projections to the RVLM, which in turn projects onto the IML sympathetic preganglionic neurons that regulate muscle blood flow through melanocortin-sympathetic signals. Our results collectively indicate that MC4Rs expressed in caudal pedunculopontine tegmental nucleus may be involved in skeletal muscle activity of melanocortin-sympathetic pathways.

Differential gene and lncRNA expression in the lower thoracic spinal cord following ischemia/reperfusion-induced acute kidney injury in rats.

We used high-throughput RNA sequencing to analyze differential gene and lncRNA expression patterns in the lower thoracic spinal cord during ischemia/reperfusion (I/R)-induced acute kidney injury (AKI) in rats. We observed that of 32662 mRNAs, 4296 out were differentially expressed in the T8-12 segments of the spinal cord upon I/R-induced AKI. Among these, 62 were upregulated and 34 were downregulated in response to I/R (FDR < 0.05, |log2FC| > 1). Further, 52 differentially expressed lncRNAs (35 upregulated and 17 downregulated) were identified among 3849 lncRNA transcripts. The differentially expressed mRNAs were annotated as "biological process," "cellular components" and "molecular functions" through gene ontology enrichment analysis. KEGG pathway enrichment analysis showed that cell cycle and renin-angiotensin pathways were upregulated in response to I/R, while protein digestion and absorption, hedgehog, neurotrophin, MAPK, and PI3K-Akt signaling were downregulated. The RNA-seq data was validated by qRT-PCR and western blot analyses of select mRNAs and lncRNAs. We observed that Bax, Caspase-3 and phospho-AKT were upregulated and Bcl-2 was downregulated in the spinal cord in response to renal injury. We also found negative correlations between three lncRNAs (TCONS_00042175, TCONS_00058568 and TCONS_00047728) and the degree of renal injury. These findings provide evidence for differential expression of lncRNAs and mRNAs in the lower thoracic spinal cord following I/R-induced AKI in rats and suggest potential clinical applicability.

Melanocortin-4 receptor regulation of pain.

An increasingly high occurrence of chronic pain in patients highlights the importance of fundamental research. The melanocortin-4 receptor (MC4R) regulation of pain has attracted much attention in recent years due to its high expression in the mammalian brain regions related to nociception and pain. This review is devoted to anatomic distribution of MC4R in the brain and interaction between MC4R and other pathways for pain modulation. The experimental evidence available at present had expanded our understanding of melanocortin-4 receptor regulation of pain. This article is part of a Special Issue entitled: Melanocortin Receptors - edited by Ya-Xiong Tao.

Consciousness loss during epileptogenesis: implication for VLPO-PnO circuits.

There is a growing concern about consciousness loss during epileptic seizures. Understanding neural mechanisms could lead to a better comprehension of cerebral circuit function in the control of consciousness loss in intractable epilepsy. We propose that ventrolateral preoptic area (VLPO)- PnO (nucleus pontis oralis) circuits may serve a major role in the loss of consciousness in drug-refractory epilepsy. Future behavioural and neuroimaging studies are clearly needed to understand the functional connectivity between the VLPO and PnO during loss of consciousness in drug-refractory epilepsy, to greatly prevent unconsciousness in this disorder and improve the quality of life in patients with intractable epilepsy.