Effects of administration of α2 adrenergic receptor agonist into psoas major muscle on inflammatory pain induced by injection of complete Freund's adjuvant in rats.

α2 adrenergic agonists are widely used in clinical anesthesia and ICU sedation owing to their effective sedative and analgesic effects. Lumbago and leg pain is the most common clinical pain disease. Studies have reported that lumbago and leg pain is associated with dysregulation of paravertebral muscles, especially psoas major muscles. In the present study, a unilateral lower extremity chronic inflammation and pain model was established by subcutaneous administration of low-dose complete Fredrin's adjuvant (CFA) into the posterior paw of rats. α2 adrenalin receptor agonist was then injected into the psoas major muscle. Behavioral tests were conducted for 21 days. Psoas major muscle tissue was harvested for evaluation of biochemical indexes related to pain. The effect of α2 adrenergic receptor agonist injected into psoas major muscle on chronic inflammatory pain of lower extremities in rats was explored. The results showed that injection of α2 adrenergic receptor agonist into the psoas major muscle relieved CFA-induced mechanical hyperalgesia. Administration of α2 adrenergic receptor antagonist yohimbine reversed the analgesic effect of α2 adrenergic receptor agonists. Administration of dexmedetomidine into psoas major muscle downregulated the levels of norepinephrine, interleukin-6 and tumor necrosis factor-α in tissues. The findings of the present study show that administration of α2 adrenoceptor agonists into the psoas major muscle relieves chronic inflammatory pain induced by CFA. Local injection of dexmedetomidine also exerted anti-inflammatory and anti-sympathetic effect by activating α2-adrenoceptor in the psoas major muscle.

Evaluating the effect of anti-nausea drugs in IDO enzyme gene expression and preventing postoperative vomiting and nausea in patients undergoing general anesthesia: A Meta-analysis.

Nausea and vomiting are known as side effects after surgery. Since serotonin antagonist drugs are widely used to prevent nausea and vomiting after surgery, the present study was conducted to compare the effectiveness of this group's drugs, namely, ondansetron and palonosetron. On the other hand, recent studies have shown that the metabolites of the kynurenine pathway in the Suppression of the immune response play a role. Indoleamine 2,3 dioxygenase (IDO) is the main enzyme controlling this pathway. Therefore, the effect of these two drugs on IDO gene expression was evaluated. The present study is a systematic review with meta-analysis. The search was conducted in the Cochrane, PubMed, Clinical K, and CRD databases for randomized clinical trial articles that compared two drugs, palonosetron, and ondansetron, regarding nausea and vomiting in patients undergoing surgery with general anesthesia. In the end, eight studies were included in the meta-analysis. STATA13 statistical software was used to estimate the overall risk, relative risk, and data analysis. The results showed that the number of samples in all articles was 739. The analysis of the results between 0 and 24 hours showed that palonosetron reduces the incidence of nausea by 50% and the incidence of vomiting by 79% compared to ondansetron (p=0.001). Also, there was no difference between the IDO gene expression in the two drug groups (p>0.05). In general, the analysis of the results related to the effectiveness of palonosetron and ondansetron 24 hours after surgery with a dose of 0.075 mg of palonosetron versus 4 mg of ondansetron showed that palonosetron is more effective in reducing the incidence of nausea and vomiting in patients than ondansetron.

Comparing the pRIFLE, AKIN, KDIGO, and modified KDIGO criteria in neonates after cardiac surgery.

BACKGROUND: While several standardized criteria for acute kidney injury (AKI) have been studied, there is no consensus on which criteria to use in neonates after cardiac surgery. The goal of this research was to compare the AKI incidence and outcomes according to the pediatric Risk, Injury, Failure and Loss, and End-Stage (pRIFLE), AKI Network (AKIN), Kidney Disease Improving Global Outcomes (KDIGO), and modified KDIGO (mKDIGO) criteria in neonates following congenital cardiac surgery. METHODS: A clinical database of all neonates undergoing congenital cardiac surgery admitted to the Cantonese cardiac center from 2014 to 2020 was retrospectively analyzed. AKI was based on the pRIFLE, AKIN, KDIGO, and mKDIGO classification. The predictive abilities for postoperative outcomes were compared by receiver operating curves, and multivariate logistic regression analysis was used to assess the association of AKI definitions with postoperative outcomes. RESULTS: In the study population of 522 patients, 177, 110, 131, and 114 neonates had AKI according to the pRIFLE, AKIN, KDIGO, and mKDIGO criteria, respectively. After multivariate analysis, all definitions were found to be significant predictors of increased mortality. The AUCs for mortality were substantially different with pRIFLE (AUC, 0.795), AKIN (AUC, 0.724), KDIGO (AUC, 0.819), and mKDIGO (AUC, 0.831) (P < 0.01) across the entire population, whereas the mKDIGO system was more accurate than the pRIFLE, AKIN, and KDIGO systems. CONCLUSIONS: The incidence of AKI varied across all definitions. However, the mKDIGO system was more accurate in predicting in-hospital mortality than the pRIFLE, AKIN, and KDIGO systems in neonates after heart surgery.

Effect of reactive oxygen species of the psoas major muscle in complete Freund's adjuvant-induced inflammatory pain in rats.

Lower limb pain is a common clinical disease that affects millions of people worldwide. It is found in previous studies that reactive oxygen species is closely related to neuropathic, cancer, chemotherapy, and inflammatory pain, which can be relieved by reactive oxygen species scavengers. Furthermore, acupuncture or electroacupuncture on the psoas major muscle has a great effect on adjuvant-induced arthritis and lower back pain. In our study, we investigated the function of reactive oxygen species scavengers locally injecting into the ipsilateral psoas major muscle on complete Freund's adjuvant-induced inflammatory pain. Our results demonstrated that in the development of complete Freund's adjuvant-induced inflammatory pain, early local continuous application of N-tert-Butyl-α-phenylnitrone (PBN, 1 and 5 mg/kg/0.2 ml) on the ipsilateral psoas major muscle effectively reduced mechanical and cold hyperalgesia. However, intraperitoneal injection of PBN (1 and 5 mg/kg) or local injection of PBN (1 and 5 mg/kg/0.2 ml) into contralateral psoas major muscle, ipsilateral quadratus lumborum, and ipsilateral erector spinae showed limited effect. In the developed inflammatory pain model, local injection of PBN into the ipsilateral psoas major muscle also alleviated pain and paw edema. In addition, reactive oxygen species level increased in ipsilateral psoas major muscle at seven days after complete Freund's adjuvant injection. In general, PBN reduces complete Freund's adjuvant-evoked inflammatory pain by inhibiting reactive oxygen species in the psoas major muscle.

Etiology and Risk Factors for Extubation Failure in Low Birth Weight Infants Undergoing Congenital Heart Surgery.

OBJECTIVE: The aim of the present study was to explore the etiology and risk factors of extubation failure (ExF) in low birth weight (LBW) infants undergoing congenital heart surgery. DESIGN: Retrospective, comparative study. SETTING: A Cantonese cardiac center in China. PARTICIPANTS: The cases of all LBW infants undergoing congenital heart surgery admitted to the authors' neonatal intensive care unit from January 2010 to September 2018 were reviewed retrospectively. ExF was defined as reintubation within 72 hours after extubation. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Demographic, preoperative, perioperative, and postoperative data were collected. The exclusion criteria were surgical ligation of patent ductus arteriosus and no extubation attempt. Risk factors for ExF were analyzed with univariate and multivariate logistic regression analysis. Ninety-nine infants met the inclusion criteria; the study comprised 66 males and 33 females, including 60 premature infants. ExF occurred in 16 of 99 infants for various kinds of reasons. Infants with ExF had longer postoperative intensive care unit length of stay (LOS) (p < 0.001) and total hospital LOS (p = 0.022). The multivariate logistic regression analysis identified preoperative mechanical ventilation (odds ratio 9.3; 95% confidence interval 1.11-79.52; p = 0.040) and prolonged mechanical ventilation before the first attempted extubation (odds ratio 6.48; 95% confidence interval 1.20-35.17; p = 0.030) as risk factors for ExF. CONCLUSIONS: The prevalence of ExF is very high in LBW infants undergoing congenital cardiac surgery. ExF in LBW infants is associated with an increase in hospital LOS. Presumed reasons for failed extubation are diverse. Preoperative mechanical ventilation and prolonged mechanical ventilation before the first attempted extubation were independent risk factors for ExF.

The effect of kinin B1 receptor on chronic itching sensitization.

BACKGROUND: Altered kallikrein-related peptidase activity and bradykinin are associated with skin disorders in humans and mice under chronic inflammation conditions. The bradykinin B1 receptor (B1R), also known as one of the G-protein-coupled receptor family and usually absent in intact tissues and upregulated during tissue injury, is responsible for vasodilation, capillary permeability, nociceptor sensitization, and pain; it is indispensable for physiopathological progress in chronic inflammation conditions, but its roles and effectors in the itching sensation of the allergic contact dermatitis model are poorly defined. RESULTS: We focused on incurable itching in a diphenylcyclopropenone (DCP) chronic inflammation experimental model. Preventive treatment with the B1R antagonist R892 significantly suppressed spontaneous scratching, while the B2R selective antagonist did not. B1R expression in the skin tissues of this model was detected using a quantitative, real-time polymerase chain reaction, Western blotting, and immunohistochemistry; B1R mRNA and protein levels were increased compared with a sham-treated control group. A higher B1R IHC staining signal was observed in the keratinocytes in DCP-treated mice compared with a vehicle-treated group, so we studied the B1R function when superimposed on a protease-activated receptor 2 (PAR2) background, establishing B1R as a pivotal mediator of PAR2 function in HaCaT cell lines. CONCLUSION: Our data provide evidence that B1R facilitates the chronic itching sensation related to keratinocytes in a DCP-treated chronic inflammation experimental model.

The effect and safety assessment of monitoring ethanol concentration in exhaled breath combined with intelligent control of renal pelvic pressure on the absorption of perfusion fluid during flexible ureteroscopic lithotripsy.

PURPOSE: Previously, we designed a ureteral access sheath with the capability of renal pelvic pressure (RPP) measurement and a medical perfusion and aspiration platform, allowing for the intelligent control of RPP. However, the effect of different RPP levels on perfusion fluid absorption remains unclear. This randomized controlled trial aimed to investigate the effects of exhaled ethanol concentration monitoring and intelligent pressure control on perfusion fluid absorption during flexible ureteroscopic lithotripsy. METHODS: Eighty patients scheduled for flexible ureteroscopic lithotripsy were randomly divided into four groups. In groups A, B, and C, the RPPs were set at 0, - 5, and - 10 mmHg, respectively. Group D was regarded as the controls with unfixed RPP. Isotonic saline containing 1% ethanol was used as the irrigation fluid, with an average irrigation flow rate of 100 mL/min. The primary outcome of this study was the absorption of perfusion fluid that was calculated based on the exhaled ethanol concentration. The secondary outcomes included duration of operation and amounts of perfusion fluid used. Postoperative complications, pre- and postoperative renal function, infection markers, and blood gas analysis were also recorded for safety assessment. RESULTS: In all, 76 patients were involved in this study, whose demographic characteristics and preoperative conditions were comparable among groups. Under the same perfusion flow rate, the groups with fixed RPP exhibited reduced absorption of perfusion fluid, duration of operation, and perfusion volume. In particular, the lowest values were observed in group C (RPP = - 10 mmHg). In contrast to the unfixed RPP group, no considerable difference were observed in levels of BUN, Scr, WBC, CRP, and blood gas values among the fixed RPP groups. Moreover, postoperative complications showed no significant difference among groups. CONCLUSION: In flexible ureteroscopic lithotripsy, the groups with fixed RPP had less absorption of perfusion fluid and perfusion volume, shorter duration of surgery, and higher safety than the unfixed group.

Capsaicin induces reflex scratching in inflamed skin.

We investigated whether capsaicin induces itching in skin with existing inflammation. We induced skin inflammation by intradermal injection of complete Freund's adjuvant (CFA) in the neck of mice. Four days later, we injected capsaicin in the same area and counted the number of scratching bouts for 30 min. We examined potential effects on pain in parallel experiments in which CFA and capsaicin were intradermally injected into hind paws. We used the time spent licking the hind paws during the 15 min after capsaicin injection as an estimate of pain. Capsaicin injection into the skin pretreated with CFA, but not into healthy skin, induced scratching. The scratching behavior was reduced by pretreatment with naloxone or capsazepine, selective antagonists for transient receptor potential vanilloid receptor-1 (TRPV1), but not morphine or mepyramine, selective antagonists for histamine 1 receptor. In animals injected with capsaicin into the hind paws, licking behavior was significantly inhibited via a µ-receptor-dependent mechanism. Our results show that TRPV1 activation, which normally induces pain, evokes an itch-related response in the presence of inflammation. This model may be interesting for future studies to explore the mechanism of a painful stimuli-induced itch observed under pathological conditions.

Revising ventricular septal defect residual shunts without aortic re-cross-clamping: a safe and effective surgical procedure.

BACKGROUND: The conventional approach to revising a residual shunt following ventricular septal defect (VSD) closure is to re-occlude the aorta and repair the residual shunt under cardioplegic arrest. The present study evaluated the safety and effectiveness of a new approach for revising residual shunts following VSD repair without re-occluding the aorta. This approach is known as on beating heart surgery. METHODS: This retrospective study included 80 pediatric patients who underwent surgical closure of a simple VSD. Residual shunts larger than 2 mm were intraoperatively detected by transesophageal echocardiography (TEE) and these patients received immediate reintervention. Of the patients, 37 received on beating heart surgery without aortic cross-clamping (Group A) and 43 patients were operated on with aortic cross-clamping and cardioplegia (Group B). RESULTS: Residual VSD closures were successfully performed in all patients. Group A had significantly shorter aortic cross-clamp times (P<0.0001), significantly shorter CPB times (P<0.01), a lower incidence of prolonged ventilation (>6 hours) (P=0.04), a lower incidence of prolonged intensive care unit (ICU) stay (ICU stay >1 day) (P=0.02), and reduced in-hospital expenses (P<0.0001) compared with Group B. There was no significant difference in the incidence of recurrent residual shunts (P=0.96), prolonged postoperative hospital stay (>5 days) (P=0.24), or the incidence of perioperative complications (P=0.81) between the groups. CONCLUSIONS: On beating heart surgery is a safe and effective approach for the closure of residual VSDs and is significantly associated with a lower incidence of prolonged ventilation, a lower incidence of prolonged ICU stay, and reduced in-hospital expenses.

The protective effects of hydrogen sulfide on the myocardial ischemia via regulating Bmal1.

BACKGROUND: To investigate the effect of hydrogen peroxide (H2S) on myocardial clock gene Bmal1 in ischemic cardiomyocytes. MATERIALS & METHODS: Quantitative PCR (qPCR) was used to detect the expression of Bmal1 at the mRNA level in H9C2 rat cardiomyocytes. The protein expressions of Bax and Bcl-2, PI3K/Akt, caspase-3 were measured by western blotting. The levels of reactive oxygen species (ROS) were determined by ELISA. RESULTS: The expression level of clock gene Bmal1 demonstrated a clock rhythm of periodic oscillation within 24 h. Compared with the control group, H2S treatment maintained the rhythm of the clock gene in ischemic cardiomyocytes and increased the transcription and expression levels of Bmal1. H2S increased cell survival by activating PI3K/Akt signaling pathway, inhibiting mitochondrial apoptosis signaling, and reducing intracellular oxidative stress. PI3K/Akt and Bmal1 were demonstrated to be involved in H2S protection of cardiomyocyte ischemia. Knockout of Bmal1 gene affects the degree of phosphorylation of Akt and Erk proteins, and the level of ROS production, resulting in a decrease in the protective effects of H2S. CONCLUSION: The expression level of Bmal1 has effects on the function of cardiomyocytes such as ROS production. The potential mechanism by which H2S regulates clock genes may be related to the effect of clock genes on protein phosphorylation levels in ischemic cardiomyocytes.

Pulmonary artery intimal sarcoma misdiagnosed as pulmonary embolism: A case report.

Intimal sarcoma of the pulmonary artery is rare, but false diagnosis of this sarcoma as pulmonary embolism is not infrequent. The present study reports a case of pulmonary artery intimal sarcoma misdiagnosed as pulmonary artery embolism in a 37-year-old female patient. The patient was admitted to the cardiac intensive care unit of Guangdong General Hospital (Guangzhou, China) with the complaint of progressive exertional dyspnea over the past two years. Multi-slice spiral computed tomography, transthoracic echocardiography, right-heart catheterization and cardiac magnetic resonance imaging revealed mimicking severe pulmonary embolism in the pulmonary trunk and right pulmonary artery, with symptoms including chest pain, cough and breathing difficulties. In addition, positron emission tomography-computed tomography results did not identify increased 18F-fluorodeoxyglucose uptake and failed to distinguish whether the mass was a thrombus or a malignancy. The patient was diagnosed with pulmonary embolism and a subcutaneous injection of 5,000 AxaIU enoxaparin sodium (100 AXAIU/kg) was administered every 12 h, but no improvement was achieved after 5 days of treatment. Finally, pulmonary endarterectomy was performed to relieve the worsening clinical symptoms. The clinicopathological diagnosis was pulmonary artery intimal sarcoma with poor clinical outcome. For this type of tumor with fatal prognosis, early and correct diagnosis may lead to appropriate intervention and prolong survival.

[Protective effect of dexmedetomidine against perioperative inflammation and on pulmonary function in patients undergoing radical resection of lung cancer].

OBJECTIVE: To study the protective effect of dexmedetomidine against perioperative inflammation and on pulmonary function in patients undergoing radical resection of lung cancer. METHODS: From May, 2014 to May, 2016, 124 patients with lung cancer receiving radical surgeries were randomized into experimental group (n=62) and control group (n=62). The patients in the control group received a single anesthetic agent for anesthesia, and additional dexmedetomidine was given in the experimental group. The levels of serum interleukin-1ß (IL-1ß), IL-10, and tumor necrosis factor-alpha (TNF-α) were measured before the operation (T0), at 30 min (T1) and 60 min (T2) during one lung ventilation (OLV) and at the end of operation (T3). Enzyme-linked immunosorbent assay (ELISA) was used to determine the levels of malondialdehyde (MDA), myeloperoxidase (MPO) and xanthine oxidase (XOD), and the arterial oxygen partial pressure (PaO2), oxygenation index (OI), airway plateau pressure (APP) and airway resistance (AR) were also recorded. RESULTS: At the time points of T1 and T2, IL-1ß, IL-10, MDA, MPO, TNF-α, and XOD levels were significantly increased in both of the groups, but the levels of IL-1, IL-10, TNF-α and MDA were significantly lower and MPO and XOD levels significantly higher in the experimental group than in the control group (P<0.05). In both groups, PaO2 and OI decreased and APP and AR increased significantly at T1 and T2, but APP and AR were significantly lower and PaO2 and OI significantly higher in the experimental group than in the control group (P<0.05). CONCLUSION: Anesthesia with dexmedetomidine in lung cancer patients undergoing radical surgery can effectively reduce the inflammatory response of the lungs and protect the lung function of the patients.

Role of ERK1/2 activation on itch sensation induced by bradykinin B1 activation in inflamed skin.

It has previously been demonstrated that bradykinin receptor B1 (B1R) agonists evoke an itch-related scratching response in inflamed skin via the B1 receptor; however, the mechanisms responsible for this abnormal itch sensation remain unclear. Therefore, the present study utilized a complete Freund's adjuvant (CFA)-induced mouse model of inflammation to elucidate the mechanisms responsible. Over a period of 30 min, scratching behavior was quantified by the number of hind limb scratches of the area surrounding the drug injection site on the neck. Furthermore, western blot analysis was used to investigate the potential role of extracellular signal-regulated kinase (ERK) 1/2 signaling as a mediator of itch in CFA-treated mice. The results demonstrated that CFA-induced inflammation at the back of the neck is associated with sustained enhancement of ERK1/2 activation in the spinal cord. Moreover, B1R agonist treatment resulted in increased expression of phosphorylated ERK1/2 in the spinal cord, which peaked at 45 min. Consistent with these findings, inhibition of either mitogen-activated protein/ERK kinase or ERK1/2, as well as inhibition of ERK1/2 activation following inflammation, attenuated B1 receptor-mediated scratching responses to a greater extent, as compared with control mice. Collectively, the results of the present study indicated that enhanced and persistent ERK1/2 activation in the spinal cord may be required to induce a scratching response to B1R agonists following CFA-induced inflammation.

The kinin B1 receptor mediates alloknesis in a murine model of inflammation.

Noxious stimuli and non-noxious mechanical stimuli elicit itch (alloknesis) instead of pain on skin lesions of patients with atopic dermatitis. We previously found that bradykinin evokes an itch-related scratching response through activation of kinin B1 receptor in skin inflamed using complete Freund's adjuvant. In this study we investigated whether alloknesis is evoked in CFA-inflamed skin and the involvement of kinin receptors. In our results, alloknesis was elicited four days after CFA-inflammation. Furthermore, pretreatment with a B1 receptor antagonist or µ-opioid receptor antagonist significantly reduced alloknesis. In contrast, treatment with a B2 receptor antagonist significantly increased alloknesis. These results suggest that the alloknesis response is mediated by the activation of kinin B1 receptor but antagonized by the B2 receptor in CFA-inflamed mice.

Paradoxic effects of propofol on visceral pain induced by various TRPV1 agonists.

Intraperitoneal injection of propofol inhibits subsequent acetic acid-induced writhing response in mice. Propofol increases the sensitivity of dorsal root ganglion neurons to capsaicin through transient receptor potential ankyrin subtype-1 (TRPA1) and protein kinase Cε (PKCε)-mediated phosphorylation of transient receptor potential vanilloid subtype-1 (TRPV1). Intraperitoneal co-injection of propofol may increase visceral nociception induced by TRPV1 agonists via sensitization of TRPV1. Therefore, we investigated the effects of intraperitoneal co-injection of propofol on nociception induced by acetic acid and capsaicin. The number of writhing movements induced by acetic acid or nociception time by capsaicin with or without propofol were counted. Neonatal capsaicin-treated mice were also used to demonstrate the role of TRPV1 in the effects of propofol on nociception, induced by TRPV1 agonists. Co-injection of propofol resulted in a pronociceptive effect on the writhing response induced by acetic acid, while the same dose of propofol ameliorated the response to capsaicin. The writhing response to intraperitoneal acetic acid was sharply inhibited following neonatal treatment with capsaicin. Co-injection with propofol reduced the number of writhing movements induced by acetic acid in neonatal capsaicin-treated mice. These results suggest that propofol binds to TRPV1 at the capsaicin-binding pocket.

[Anesthetic management of low birth weight infants undergoing surgery for congenital heart disease without cardiopulmonary bypass].

OBJECTIVE: To summarize anesthetic management of low birth weight infants undergoing surgical intervention of congenital heart disease without cardiopulmonary bypass. METHODS: Fifty-three low birth weight infants (including 49 premature infants) with congenital heart disease underwent surgical treatment without cardiopulmonary bypass during the period from June, 2003 to July, 2013. The mean gestational age of the infants was 30.96∓3.09 weeks (26-40 weeks) with a mean age on the operation day of 32.81∓20.76 days (4-87 days), birth weight of 1429.90∓455.08 g (640-2460 g), and weight on the operation day of 1750.20∓481.59 g (650-2460 g). All the infants underwent cardiac operations without cardiopulmonary bypass under general anesthesia. The respiratory parameters and acid-base and electrolyte balance were adjusted according to blood gas analysis. The inotropic drug was used to maintain the hemodynamic stability. RESULTS: Forty-seven of the infants received patent ductus arteriosus (PDA) ligation. Of these infants, 1 had cardiac arrest before the operation with failed cardiopulmonary resuscitation, and in another case, PDA ligation was aborted due to severe hypoplasia of the aortic valve and ascending aorta found intraoperatively by transesophageal echocardiography. Two infants underwent coarctation of the aorta (CoA), and 1 of them died during the operation due to cardiac arrest. The total mortality of these infants was 3.77% and the early postoperative mortality (<72 h) was 5.66%. CONCLUSIONS: Non-cardiopulmonary bypass surgery can be performed in low birth weight infants in early stage, and effective anesthetic management can reduce the perioperative mortality and improve the postoperative survival rate.

Bradykinin-evoked scratching responses in complete Freund's adjuvant-inflamed skin through activation of B1 receptor.

Capsaicin, a potent algogen, induces an itch-related behavior in the presence of inflammation. In this study, we tested whether bradykinin (BK) can evoke a similar response and investigated the potential mechanisms involved in this process. Local inflammation was induced by intradermal injection of complete Freund's adjuvant (CFA) into the back of the neck, left hind foot or left cheek of male C57BL/6J mice. BK was then injected intradermally into the same area on indicated days. Four days after CFA inflammation, BK treatment evoked scratching responses in a time- and dose-dependent manner. For BK receptor antagonist treatment, inflamed-mice were either given an intraperitoneal injection of B(1) receptor (B(1)R) or B(2) receptor (B(2)R) antagonist 30 min prior to BK administration, or an intradermal co-injection of antagonist and BK into the inflamed area. Our results indicate that B(1)R and B(2)R act in an opposite fashion during this process, as pretreatment with B(1)R antagonist by intraperitoneal injection significantly reduced BK-induced scratching behavior, whereas B(2)R antagonist treatment dramatically increased scratching behavior. Moreover, combined injection of BK and B(2)R antagonist enhanced BK-induced scratching activity in CFA-inflamed mice. In addition, pretreatment or co-injection with B(2)R antagonist dramatically reduced the pain-related licking behavior induced by BK injection. The data suggest that BK-induced scratching responses in CFA-inflamed mouse skin occur via activation of B(1)R. Furthermore, B(1) and B(2) receptors play different roles in modulating BK-induced itch-related behavior in CFA-inflamed mice.

Endothelin B receptors exert antipruritic effects via peripheral κ-opioid receptors.

Endothelin B receptor agonists exert antipruritic effects on itching induced via endothelin-1 (ET-1) and compound 48/80. Peripheral µ- and κ-opioid receptors (MORs and KORs, respectively) are reported to be involved in the anti-nociceptive properties triggered by ET(B) agonists. Therefore, we investigated the role of peripheral opioid receptors in the scratching response induced by ET-1. ET(A) and ET(B) antagonists and non-selective and selective opioid receptor antagonists were co-injected with ET-1 in the neck of mice and the number of scratching bouts was counted. Pretreatment with systemically administered naloxone significantly reduced the number of scratches, while co-injection of naloxone substantially augmented the effect of ET-1. Co-injection of nor-Binaltorphimine (nor-BNI), a KOR antagonist, significantly increased the number of scratches induced by ET-1. However, CTOP (a MOR antagonist) and naltrindole [a δ-opioid receptor (DOR) antagonist] did not alter the scratching response elicited by ET-1. These results indicate that peripheral KORs mediate the antipruritic effect of endothelin B receptor activation.

Role of transient receptor potential ankyrin subfamily member 1 in pruritus induced by endothelin-1.

Noxious cold reduces pruritus and transient receptor potential ankyrin subfamily member 1 (TRPA1), a non-selective cation channel, is known as a noxious cold-activated ion channel. Recent findings implicated the involvement of TRPA1 in pain induced by endothelin-1 (ET-1). Therefore, we evaluated its potential role in pruritus induced by ET-1. We found that ruthenium red (RR; a nonselective TRP inhibitor) and AP18 (a TRPA1 antagonist) significantly increased scratching bouts caused by ET-1, while capsazepine (a TRPV1 antagonist) and morphine showed no effects in the ET-1-induced scratching response. However, RR and capsazepine significantly reduced scratching bouts caused by histamine. Our results suggested that activation of TRPA1 could suppress itch induced by ET-1 and this is not related to pain induced by ET-1.

Molecular signaling of pruritus induced by endothelin-1 in mice.

Endothelin-1 (ET-1) has recently been identified to evoke pruritus/itching sensation in both humans and animals. It is most likely that the signaling is through the specific G-protein-coupled ET(A) and ET(B) receptors, but the downstream signaling mediators for ET-1 remain elusive. In the present study, we examined the potential involvement of several distinct signaling molecules in ET-1-induced pruritus in a murine model. We applied an in vivo pruritus model in C57BL/6J mice by injecting ET-1 intradermally into the scruff, and recording the number of scratching bouts within 30 min after injection. Then specific antagonists/inhibitors for distinct signaling molecules, including cell-surface ET(A) and ET(B) receptors, histamine receptor type 1 (H1 receptor), protein kinases A (PKA) and C (PKC), phospholipase C (PLC) or adenylyl cyclase (AC), were co-injected with ET-1. The results showed that ET-1 induced a vigorous scratching response in mice in a dose-dependent manner. This response was further enhanced by a specific antagonist for ET(B) receptor, BQ-788, reduced by a specific antagonist for ET(A) receptor, BQ-123, and not affected by mepyramine, the specific inhibitor for H1 receptor. In addition, the scratching response was significantly reduced by inhibitors for PKC and AC, but was significantly enhanced by PLC inhibitor, while PKA inhibitors showed no effects in the ET-1-induced scratching response. Our data suggested that ET-1 may signal through the ET(A) receptor, AC and PKC pathway to induce pruritus sensation, while ET(B) receptor and PLC may antagonize the pruritus evoked by ET-1. These results may provide a basis for the future development of antipruritic therapy.