Associations between institutional-social-ecological factors and COVID -19 case-fatality: Evidence from 134 countries using multiscale geographically weighted regression (MGWR).

During the period in which the Omicron coronavirus variant was rapidly spreading, the impact of the institutional-social-ecological dimensions on the case-fatality rate was rarely afforded attention. By adopting the diagnostic social-ecological system (SES) framework, the present paper aims to identify the impact of institutional-social-ecological factors on the case-fatality rate of COVID-19 in 134 countries and regions and test their spatial heterogeneity. Using statistical data from the Our World In Data website, the present study collected the cumulative case-fatality rate from 9 November 2021 to 23 June 2022, along with 11 country-level institutional-social-ecological factors. By comparing the goodness of fit of the multiple linear regression model and the multiscale geographically weighted regression (MGWR) model, the study demonstrated that the effects of SES factors exhibit significant spatial heterogeneity in relation to the case-fatality rate of COVID-19. After substituting the data into the MGWR model, six SES factors were identified with an R square of 0.470 based on the ascending effect size: COVID-19 vaccination policy, age dependency ratio, press freedom, gross domestic product (GDP), COVID-19 testing policy, and population density. The GWR model was used to test and confirm the robustness of the research results. Based on the analysis results, it is suggested that the world needs to meet four conditions to restore normal economic activity in the wake of the COVID-19 pandemic: (i) Countries should increase their COVID-19 vaccination coverage and maximize COVID-19 testing expansion. (ii) Countries should increase public health facilities available to provide COVID-19 treatment and subsidize the medical costs of COVID-19 patients. (iii) Countries should strictly review COVID-19 news reports and actively publicize COVID-19 pandemic prevention knowledge to the public through a range of media. (iv) Countries should adopt an internationalist spirit of cooperation and help each other to navigate the COVID-19 pandemic. The study further tests the applicability of the SES framework to the field of COVID-19 prevention and control based on the existing research, offering novel policy insights to cope with the COVID-19 pandemic that coexists with long-term human production and life for a long time.

Mechanisms of adsorption and diffusion of Na on a VSe2 monolayer with engineering-induced vacancies.

Although research on vacancy engineering of anode materials has sufficiently advanced to obtain heightened battery capacity, the effect on the diffusion barrier underlying the mechanism remains to be elucidated. Herein, we investigated the effect of vacancy engineering on Na adsorption and diffusion on a vanadium diselenide (VSe2) monolayer using first-principles calculations to reveal the underlying physics behind the performance optimization of anode materials in a sodium-ion battery. The results demonstrate that the structure of the substrate is responsible for the difference between the adsorption energy and diffusion barrier that resulted from cation and anion vacancies. As there is an absent Se atom (VSe) on the surface layer of the substrate, diffusion of Na on the surface could become pressurized with a high diffusion barrier up to 0.33 eV and a high adsorption energy (-1.92 eV) to capture additional Na atoms. However, because the V layer is sandwiched between two Se layers, there is less interaction with Na, and the adsorption energy and diffusion barrier are -1.58 and 0.13 eV, respectively, when a V atom is nonexistent (VV). Moreover, the defective VSe2 increased the battery capacity, with little impact on open-circuit voltage. In this work, we analyzed the effect of vacancy engineering on VSe2 monolayer material, which provides theoretical clues for the design of efficient sodium-ion batteries with heightened capacity.

An IL-6/STAT3/MR/FGF21 axis mediates heart-liver cross-talk after myocardial infarction.

The liver plays a protective role in myocardial infarction (MI). However, very little is known about the mechanisms. Here, we identify mineralocorticoid receptor (MR) as a pivotal nexus that conveys communications between the liver and the heart during MI. Hepatocyte MR deficiency and MR antagonist spironolactone both improve cardiac repair after MI through regulation on hepatic fibroblast growth factor 21 (FGF21), illustrating an MR/FGF21 axis that underlies the liver-to-heart protection against MI. In addition, an upstreaming acute interleukin-6 (IL-6)/signal transducer and activator of transcription 3 (STAT3) pathway transmits the heart-to-liver signal to suppress MR expression after MI. Hepatocyte Il6 receptor deficiency and Stat3 deficiency both aggravate cardiac injury through their regulation on the MR/FGF21 axis. Therefore, we have unveiled an IL-6/STAT3/MR/FGF21 signaling axis that mediates heart-liver cross-talk during MI. Targeting the signaling axis and the cross-talk could provide new strategies to treat MI and heart failure.

Osteoblast MR deficiency protects against adverse ventricular remodeling after myocardial infarction.

RATIONALE: Mineralocorticoid receptor (MR) antagonists have been clinically used to treat heart failure. However, the underlying cellular and molecular mechanisms remain incompletely understood. METHODS AND RESULTS: Using osteoblast MR knockout (MRobko) mouse in combination with myocardial infarction (MI) model, we demonstrated that MR deficiency in osteoblasts significantly improved cardiac function, promoted myocardial healing, as well as attenuated cardiac hypertrophy, fibrosis and inflammatory response after MI. Gene expression profiling using RNA sequencing revealed suppressed expression of osteocalcin (OCN) in calvaria from MRobko mice compared to littermate control (MRfl/fl) mice with or without MI. Plasma levels of undercarboxylated OCN (ucOCN) were also markedly decreased in MRobko mice compared to MRfl/fl mice. Administration of ucOCN abolished the protective effects of osteoblast MR deficiency on infarcted hearts. Mechanistically, ucOCN treatment promoted proliferation and inflammatory cytokine secretion in macrophages. Spironolactone, an MR antagonist, significantly inhibited the expression and secretion of OCN in post-MI mice. More importantly, spironolactone decreased plasma levels of ucOCN and inflammatory cytokines in heart failure patients. CONCLUSIONS: MR deficiency in osteoblasts alleviates pathological ventricular remodeling after MI, likely through its regulation on OCN. Spironolactone may work through osteoblast MR/OCN axis to exert its therapeutic effects on pathological ventricular remodeling and heart failure in mice and human patients.

Macrophage Nuclear Receptor Corepressor 1 Deficiency Protects Against Ischemic Stroke in Mice.

Microglia/macrophage activation plays an essential role in Ischemic stroke (IS). Nuclear receptor corepressor 1 (NCoR1) has been identified as a vital regulator in macrophages. The present study aims to explore the functions of macrophage NCoR1 in IS. Macrophage NCoR1 knockout (MNKO) mice and littermate control mice were subjected to middle cerebral artery occlusion (MCAO). Our data showed that macrophage NCoR1 deficiency significantly reduced the infarct size and infarct volume as well as brain edema after MCAO. Additionally, MNKO induced less microglia/macrophage infiltration and activation, neuroinflammation, apoptosis of neuronal cells, and BBB disruption in brains after IS. Mechanistic studies revealed that NCoR1 interacted with LXRß in microglia and MNKO impaired the activation of the Nuclear factor-κB signaling pathway in brains after IS. Our data demonstrated that macrophage NCoR1 deficiency inhibited microglia/macrophage activation and protected against IS. Targeting NCoR1 in microglia/macrophage may be a potential approach for IS treatment.

Development of Multifunctional and Orally Active Cyclic Peptide Agonists of Opioid/Neuropeptide FF Receptors that Produce Potent, Long-Lasting, and Peripherally Restricted Antinociception with Diminished Side Effects.

We previously reported that a multifunctional opioid/neuropeptide FF receptor agonist, DN-9, achieved peripherally restricted analgesia with reduced side effects. To develop stable and orally bioavailable analogues of DN-9, eight lactam-bridged cyclic analogues of DN-9 between positions 2 and 5 were designed, synthesized, and biologically evaluated. In vitro cAMP assays revealed that these analogues, except 7, were multifunctional ligands that activated opioid and neuropeptide FF receptors. Analogue 1 exhibited improved potency for κ-opioid and NPFF2 receptors. All analogues exhibited potent, long-lasting, and peripherally restricted antinociception in the tail-flick test without tolerance development after subcutaneous administration and produced oral analgesia. Oral administration of the optimized compound analogue 1 exhibited powerful, peripherally restricted antinociceptive effects in mouse models of acute, inflammatory, and neuropathic pain. Remarkably, orally administered analogue 1 had no significant side effects, such as tolerance, dependence, constipation, or respiratory depression, at effective analgesic doses.

Microbiota in Gut, Oral Cavity, and Mitral Valves Are Associated With Rheumatic Heart Disease.

Rheumatic heart disease refers to the long-term damage of heart valves and results from an autoimmune response to group A Streptococcus infection. This study aimed to analyze the microbiota composition of patients with rheumatic heart disease and explore potential function of microbiota in this disease. First, we revealed significant alterations of microbiota in feces, subgingival plaques, and saliva of the patients compared to control subjects using 16S rRNA gene sequencing. Significantly different microbial diversity was observed in all three types of samples between the patients and control subjects. In the gut, the patients possessed higher levels of genera including Bifidobacterium and Eubacterium, and lower levels of genera including Lachnospira, Bacteroides, and Faecalibacterium. Coprococcus was identified as a super-generalist in fecal samples of the patients. Significant alterations were also observed in microbiota of subgingival plaques and saliva of the patients compared to control subjects. Second, we analyzed microbiota in mitral valves of the patients and identified microbes that could potentially transmit from the gut or oral cavity to heart valves, including Streptococcus. Third, we further analyzed the data using random forest model and demonstrated that microbiota in the gut, subgingival plaque or saliva could distinguish the patients from control subjects. Finally, we identified gut/oral microbes that significantly correlated with clinical indices of rheumatic heart disease. In conclusion, patients with rheumatic heart disease manifested important alterations in microbiota that might distinguish the patients from control subjects and correlated with severity of this disease.

Synthesis and Biological Characterization of Cyclic Disulfide-Containing Peptide Analogs of the Multifunctional Opioid/Neuropeptide FF Receptor Agonists That Produce Long-Lasting and Nontolerant Antinociception.

In a previously described chimeric peptide, we reported that the multifunctional opioid/neuropeptide FF (NPFF) receptor agonist 0 (BN-9) produced antinociception for 1.5 h after supraspinal administration. Herein, four cyclic disulfide analogs containing l- and/or d-type cysteine at positions 2 and 5 were synthesized. The cyclized analogs and their linear counterparts behaved as multifunctional agonists at both opioid and NPFF receptors in vitro and produced potent analgesia without tolerance development. In comparison to 0, cyclized peptide 6 exhibited sevenfold more potent µ-opioid receptor agonistic activity in vitro. Interestingly, the cyclized analog 6 possessed an improved stability in the brain and an increased blood-brain barrier permeability compared to the parent peptide 0 and produced more potent analgesia after supraspinal or subcutaneous administration with improved duration of action of 4 h. In addition, antinociceptive tolerance of analog 6 was greatly reduced after subcutaneous injection compared to fentanyl, as was the rewarding effect, withdrawal reaction, and gastrointestinal inhibition.

Two Pyrophosphates with Large Birefringences and Second-Harmonic Responses as Ultraviolet Nonlinear Optical Materials.

Two new pyrophosphates nonlinear optical (NLO) materials, Rb3 PbBi(P2 O7 )2 (I) and Cs3 PbBi(P2 O7 )2 (II), were successfully designed and synthesized. Both compounds exhibit large NLO effects and birefringences. Material I presents the scarce case of possessing the coexistence of large birefringence (0.031 at 1064 nm and 0.037 at 532 nm) and second harmonic generation (SHG) response (2.8× potassium dihydrogen phosphate (KDP)) in ultraviolet NLO phosphates and its SHG is the largest in the phase-matching (PM) pyrophosphates. Both I and II have three-dimensional (3D) crystal structures composed of corner-shared RbO12 (CsO11 ), RbO10 (CsO10 ), BiO6 , PbO7 (PbO6 ) and P2 O7 groups, in which P2 O7 and PbO7 (PbO6 ) units form an alveolate [PbPO]∞ skeleton frame. Theoretical calculations reveal that the P-O, Bi-O and Pb-O units are mainly responsible for the moderate birefringence and large SHG efficiency of I.

Tellurium-oxygen group enhanced birefringence in tellurium phosphates: a first-principles investigation.

Phosphates possess a relatively large UV/DUV cutoff edge, but these compounds usually have very small birefringence. Recently the Te2P2O9 crystal was synthesized and its birefringence was reported to be as large as 0.106 at 1013.98 nm. Herein, we investigated the electronic structure and optical properties of Te2P2O9 using the first-principles method. The obtained results are in good agreement with the experimental values. The Born effective charges and SHG density of Te2P2O9 show that the contribution to the birefringence and SHG response mainly originates from the TeO5 group. The electronic structures and optical response of Ba2TeO(PO4)2 and Te3O3(PO4)2 were also investigated for comparison. The results show that these two tellurium phosphates also possess a large birefringence similar to Te2P2O9. Also, the birefringence originates from the TeO x polyhedrons, which was confirmed by the real-space atom-cutting results and distortion indices.

The multifunctional peptide DN-9 produced peripherally acting antinociception in inflammatory and neuropathic pain via µ- and κ-opioid receptors.

BACKGROUND AND PURPOSE: Considerable effort has recently been directed at developing multifunctional opioid drugs to minimize the unwanted side effects of opioid analgesics. We have developed a novel multifunctional opioid agonist, DN-9. Here, we studied the analgesic profiles and related side effects of peripheral DN-9 in various pain models. EXPERIMENTAL APPROACH: Antinociceptive effects of DN-9 were assessed in nociceptive, inflammatory, and neuropathic pain. Whole-cell patch-clamp and calcium imaging assays were used to evaluate the inhibitory effects of DN-9 to calcium current and high-K+ -induced intracellular calcium ([Ca2+ ]i ) on dorsal root ganglion (DRG) neurons respectively. Side effects of DN-9 were evaluated in antinociceptive tolerance, abuse, gastrointestinal transit, and rotarod tests. KEY RESULTS: DN-9, given subcutaneously, dose-dependently produced antinociception via peripheral opioid receptors in different pain models without sex difference. In addition, DN-9 exhibited more potent ability than morphine to inhibit calcium current and high-K+ -induced [Ca2+ ]i in DRG neurons. Repeated treatment with DN-9 produced equivalent antinociception for 8 days in multiple pain models, and DN-9 also maintained potent analgesia in morphine-tolerant mice. Furthermore, chronic DN-9 administration had no apparent effect on the microglial activation of spinal cord. After subcutaneous injection, DN-9 exhibited less abuse potential than morphine, as was gastroparesis and effects on motor coordination. CONCLUSIONS AND IMPLICATIONS: DN-9 produces potent analgesia with minimal side effects, which strengthen the candidacy of peripherally acting opioids with multifunctional agonistic properties to enter human studies to alleviate the current highly problematic misuse of classic opioids on a large scale.

Nuclear receptor corepressor 1 represses cardiac hypertrophy.

The function of nuclear receptor corepressor 1 (NCoR1) in cardiomyocytes is unclear, and its physiological and pathological implications are unknown. Here, we found that cardiomyocyte-specific NCoR1 knockout (CMNKO) mice manifested cardiac hypertrophy at baseline and had more severe cardiac hypertrophy and dysfunction after pressure overload. Knockdown of NCoR1 exacerbated whereas overexpression mitigated phenylephrine-induced cardiomyocyte hypertrophy. Mechanistic studies revealed that myocyte enhancer factor 2a (MEF2a) and MEF2d mediated the effects of NCoR1 on cardiomyocyte hypertrophy. The receptor interaction domains (RIDs) of NCoR1 interacted with MEF2a to repress its transcriptional activity. Furthermore, NCoR1 formed a complex with MEF2a and class IIa histone deacetylases (HDACs) to suppress hypertrophy-related genes. Finally, overexpression of RIDs of NCoR1 in the heart attenuated cardiac hypertrophy and dysfunction induced by pressure overload. In conclusion, NCoR1 cooperates with MEF2 and HDACs to repress cardiac hypertrophy. Targeting NCoR1 and the MEF2/HDACs complex may be an attractive therapeutic strategy to tackle pathological cardiac hypertrophy.

Cardiac resynchronization therapy by left bundle branch area pacing in patients with heart failure and left bundle branch block.

BACKGROUND: Cardiac resynchronization therapy (CRT) via biventricular pacing has demonstrated clinical benefits in patients with heart failure (HF) and ventricular dyssynchrony. Other approaches of CRT is little known. OBJECTIVE: The purpose of this study was to assess the feasibility, safety, and efficacy of left bundle branch area pacing (LBBAP) in patients with HF and left bundle branch block (LBBB). METHODS: Eleven consecutive patients with HF, reduced left ventricular ejection fraction and LBBB and indicated for CRT were recruited. LBBAP was achieved via transventricular septal approach and characterized by narrower QRS duration, shortened peak left ventricular activation time, and right bundle branch conduction delay on the electrocardiogram. Electrocardiogram, echocardiogram, and cardiac function were evaluated at baseline and follow-up. Interventricular mechanical delay and 3-dimensional tissue synchronization imaging during LBBAP and intrinsic LBBB status were measured by echocardiography at follow-up. RESULTS: LBBAP significantly shortened QRS duration (from baseline 180.00 ± 15.86 ms to 129.09 ± 15.94 ms; P < .01) and left ventricular activation time (from baseline 108.18 ± 15.54 ms to 80.91 ± 9.95 ms; P < .01). Interventricular mechanical delay and the standard deviation of tissue synchronization imaging of 12 left ventricular (LV) segments were significantly shorter during LBBAP than in intrinsic LBBB status (both with P < .01). At a mean follow-up period of 6.7 months, New York Heart Association functional class, plasma level of B-type natriuretic peptide, LV end-systolic diameter, and left ventricular ejection fraction were significantly improved (all with P < .05 vs baseline). CONCLUSION: The study demonstrates that LBBAP is clinically feasible in patients with systolic HF and LBBB. LBBAP can be a new CRT technique to correct LBBB, provide ventricular synchrony, and improve clinical symptoms with LV reverse remodeling.

Discovery of two novel branched peptidomimetics containing endomorphin-2 and RF9 pharmacophores: Synthesis and neuropharmacological evaluation.

It is well known that opioid analgesics produce side effects including tolerance and constipation. Since neuropeptide FF (NPFF) receptor antagonists reversed opioid-induced hyperalgesia and analgesic tolerance, the present work was performed to synthetize two branched peptidomimetics, EKR and RKE, containing the opioid peptide endomorphin-2 (EM-2) and the NPFF receptor antagonist RF9. Our data obtained from the in vitro cyclic adenosine monophosphate experiment demonstrated that EKR functioned as a mixed mu-, delta-opioid receptors agonist and NPFF1 receptor antagonist/NPFF2 receptor partial agonist, whereas RKE acted as a multi-functional peptidomimetic with the mu-opioid agonism and the NPFF1 antagonism/NPFF2 partial agonism. Furthermore, EKR and RKE completely blocked the NPFF2 receptor-mediated neurite outgrowth of Neuro 2A cells. In vivo antinociception studies found that supraspinal administration of EKR and RKE dose-dependently produced potent antinociception via the mu-opioid receptor in the tail-flick test. In carrageenan inflammatory pain model, spinal administration of EKR and RKE induced dose-related analgesia, which was significantly reduced by the opioid antagonist naloxone and the NPFF antagonist RF9. Notably, compared with morphine, intracerebroventricular repeated administration of EKR and RKE maintained prolonged antinociceptive effectiveness. In addition, at the antinociceptive doses, these two branched peptidomimetics did not significantly inhibit gastrointestinal transit. Taken together, the present work suggest that EKR and RKE behave as multi-functional ligands with the opioid agonism and the NPFF1 antagonism/NPFF2 partial agonism, and produce prolonged antinociception with limited side effects. Moreover, our results imply that EKR and RKE might be interesting pharmacological tools for further investigating the biological function of the NPFF and opioid systems.

Left Bundle Branch Conduction Recovery Following Left Bundle Branch Pacing in a Heart Failure Patient.

This report presents the application of left bundle branch pacing as a cardiac resynchronization therapy in a patient with systolic heart failure and complete left bundle branch block. At the 3-month follow-up, the patient had significant improvement in cardiac function accompanied by the recovery of left bundle branch conduction. (Level of Difficulty: Intermediate.).

Preemptive intrathecal administration of endomorphins relieves inflammatory pain in male mice via inhibition of p38 MAPK signaling and regulation of inflammatory cytokines.

BACKGROUND: Preemptive administration of analgesic drugs reduces perceived pain and prolongs duration of antinociceptive action. Whereas several lines of evidence suggest that endomorphins, the endogenous mu-opioid agonists, attenuate acute and chronic pain at the spinal level, their preemptive analgesic effects remain to be determined. In this study, we evaluated the anti-allodynic activities of endomorphins and explored their mechanisms of action after preemptive administration in a mouse model of inflammatory pain. METHODS: The anti-allodynic activities of preemptive intrathecal administration of endomorphin-1 and endomorphin-2 were investigated in complete Freund's adjuvant (CFA)-induced inflammatory pain model and paw incision-induced postoperative pain model. The modulating effects of endomorphins on the expression of p38 mitogen-activated protein kinase (p38 MAPK) and inflammatory mediators in dorsal root ganglion (DRG) of CFA-treated mice were assayed by real-time reverse transcription-polymerase chain reaction (RT-PCR), Western blotting, or immunofluorescence staining. RESULTS: Preemptive intrathecal injection of endomorphins dose-dependently attenuated CFA-induced mechanical allodynia via the mu-opioid receptor and significantly reversed paw incision-induced allodynia. In addition, CFA-caused increase of phosphorylated p38 MAPK in DRG was dramatically reduced by preemptive administration of endomorphins. Repeated intrathecal application of the specific p38 MAPK inhibitor SB203580 reduced CFA-induced mechanical allodynia as well. Further RT-PCR assay showed that endomorphins regulated the mRNA expression of inflammatory cytokines in DRGs induced by peripheral inflammation. CONCLUSIONS: Our findings reveal a novel mechanism by which preemptive treatment of endomorphins attenuates inflammatory pain through regulating the production of inflammatory cytokines in DRG neurons via inhibition of p38 MAPK phosphorylation.

Analgesic activities of the mixed opioid and NPFF receptors agonist DN-9 in a mouse model of formalin-induced orofacial inflammatory pain.

Orofacial pain is one of the most common pain conditions and compromises the quality of life of the sufferer. Several studies have shown that opioid agonists produced significant analgesia in the orofacial pain, and combination of opioids with drugs belonging to other classes induced synergism in the orofacial pain. However, combination therapy of different analgesic drugs improves the risk of drug-drug interactions. Against this background, we sought to investigate the analgesic effects of the multi-functional opioid peptide DN-9, a mixed opioid and NPFF receptors agonist that produced robust analgesia in acute and inflammatory pain models, on formalin-induced orofacial pain. Our results showed that formalin injection caused significant spontaneous pain behaviors and increased the expressions of the mu-opioid receptor, c-Fos and phosphorylated extracellular signal-regulated kinase (p-ERK1/2) in the ipsilateral trigeminal ganglion (TG). In mice pretreated with DN-9, there was a significant reduction in nociceptive behaviors, which was selectively mediated by the mu- and kappa-opioid receptors, independently of the NPFF system. Four hours after formalin injection, the level of c-Fos immunoreactivity in the ipsilateral TG neurons was much lower in mice pretreated with DN-9 or morphine. In addition, DN-9 exhibited a significant inhibition in the expression of p-ERK1/2, which was reversed by the selective antagonists of the mu- and kappa-opioid receptors. In conclusion, our present results demonstrate that central administration of DN-9 produces potential antinociceptive effects via the mu- and kappa-opioid receptors, independently of the NPFF system, and this antinociceptive action is tightly linked with the intracellular ERK activation in TG neurons.

Systemic administration of the bifunctional opioid/neuropeptide FF receptors agonist BN-9 produced peripheral antinociception in preclinical mouse models of pain.

We recently characterized a novel bifunctional agonist for opioid and neuropeptide FF receptors, named BN-9, which exhibited potent analgesia in the mouse tail-flick test when given centrally. To further evaluate its potential therapeutic efficacy for translational-medical development, the current work was performed to explore the antinociceptive activities of intraperitoneal (i.p.) administration of BN-9 in mouse models of tail-flick assay, formalin pain, visceral pain and post-operative pain. In the tail-flick test, BN-9 induced a dose-related antinociceptive effect, which was fully blocked by systemic pretreatment with the peripheral acting opioid receptor antagonist naloxone methiodide, but not supraspinal naloxone methiodide, implying the involvement of the peripheral opioid receptors. In addition, the systemic antinociception of BN-9 was antagonized by the selective antagonists of the µ- and κ-opioid receptors, independently of the δ-opioid and neuropeptide FF receptors. Similarly, dose-dependent analgesia was also produced by systemic BN-9 in different pain models via the peripheral opioid receptors, independently of the neuropeptide FF receptors. Furthermore, the side-effects of systemic BN-9 on motor performance, tolerance development and gastrointestinal transit inhibition were also evaluated. Repeated systemic injection of BN-9 produced non-tolerance analgesia over 8 days. Compared with morphine, intraperitoneal administration of BN-9 exerted less inhibition of gastrointestinal transit. These data show that BN-9 induced systemic analgesia with reduced side-effects on tolerance and constipation. This article suggests that systemic injection of BN-9 causes effective antinociception in different preclinical pain models via the peripheral opioid receptors, providing an attractive approach to develop peripherally acting opioid analgesics with multiple targeting properties.

GpTx-1 and [Ala5 , Phe6 , Leu26 , Arg28 ]GpTx-1, two peptide NaV 1.7 inhibitors: analgesic and tolerance properties at the spinal level.

BACKGROUND AND PURPOSE: The voltage-gated sodium channel NaV 1.7 is considered a therapeutic target for pain treatment based on human genetic evidence. GpTx-1 and its potent analogue [Ala5 , Phe6 , Leu26 , Arg28 ]GpTx-1 (GpTx-1-71) were recently characterized as NaV 1.7 inhibitors in vitro. Furthermore, the present work was conducted to investigate the analgesic properties of these two peptides in different pain models after spinal administration. EXPERIMENTAL APPROACH: The antinociceptive activities of both GpTx-1 and GpTx-1-71 were investigated in mouse models of acute, visceral, inflammatory and neuropathic pain. Furthermore, the side effects of GpTx-1 and GpTx-1-71 were evaluated in rotarod, antinociceptive tolerance, acute hyperlocomotion and gastrointestinal transit tests. KEY RESULTS: The i.t. administration of both GpTx-1 and GpTx-1-71 dose-dependently produced powerful antinociception in the different pain models. This effect was attenuated by the opioid receptor antagonist naloxone, suggesting the involvement of the opioid system. In this study, repeated administration of these two_peptides produced spinal analgesia without a loss of potency over 8 days in mouse models of acute, inflammatory and neuropathic pain. Moreover, spinal administration of GpTx-1 and GpTx-1-71 did not induce significant effects on motor coordination, evoke acute hyperlocomotion or increase gastrointestinal transit time. CONCLUSIONS AND IMPLICATIONS: Our data indicate that the NaV 1.7 peptide inhibitors GpTx-1 and GpTx-1-71 produce powerful, nontolerance-forming analgesia in preclinical pain models, which might be dependent on the endogenous opioid system. In addition, at the spinal level, the limited side effects imply that these NaV 1.7 peptide inhibitors could be potentially developed as GpTx-1-based drugs for pain relief.

Antinociceptive effects of the endogenous cannabinoid peptide agonist VD-hemopressin(ß) in mice.

Cannabinoids (CBs) play important roles in pain modulation. Recently, VD-hemopressin(ß) [VD-Hpß], a 12-residue ß-hemoglobin-derived peptide, was reported to activate both CB1 and CB2 receptors in vitro. To further characterize in vivo actions of VD-Hpß, its antinociceptive activity and site(s) were evaluated in the mouse tail-flick test, and supraspinal antinociception of VD-Hpß was further assessed in the writhing test. Our results demonstrated that supraspinal, intrathecal, subcutaneous and intraperitoneal administrations of VD-Hpß produced analgesia in the tail-flick test. When given at the same levels, the CB1 antagonist AM251, rather than the CB2 antagonist AM630 diminished VD-Hpß-induced antinociception. Furthermore, our results indicated that supraspinal, intrathecal or subcutaneous pretreatment with AM251 significantly inhibited VD-Hpß-induced systemic antinociception. In the writhing test, supraspinal VD-Hpß inhibited pain-related behaviors, which was partially prevented by AM251. Notably, supraspinal administration of VD-Hpß failed to affect motor function at the antinociceptive doses. These findings suggest that VD-Hpß induces CB1 receptor-mediated antinociception in tail-flick test in various routes of administration, and its systemic antinociception is mediated by both central and peripheral CB1 receptor. In addition, VD-Hpß produces analgesic activity in the writhing test, which is at least partially mediated by CB1 receptor. Therefore, our present animal models show a CB1 agonistic character of VD-Hpß, an endogenous cannabinoid peptide.