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The increasing incidence of anthracnose disease in tea plant caused by Colletotrichum has become an important global concern. It is the cause of withered leaves of the tea plant, leading to a considerable decrease in the economic yield of tea, and thereby threatening the sustainable development of tea industries. In this study, Colletotrichum infected tea leaves were collected from three separate regions: Zhouning, Longyan, and Ningde in Fujian province, China. The pathogen was isolated from the leaves and identified based on morphology following Koch’s postulates and DNA sequencing of the nuclear rDNA internal transcribed spacer (ITS) region, beta-tubulin 2 (β-Tub2), the large subunit of the nuclear ribosomal RNA gene (LSU), Glutamine synthetase (GS), and an oligonucleotide primer (CgInt). A total of six strains were identified with different cultural, morphological, and molecular characteristics. Furthermore, multi-locus phylogenetic analysis showed the six strains that belong to C.fructicola. Finally, a preliminary screening of nine chemical fungicides to inhibit the strain N by toxicity test identified 40% prochloraz at 0.1 μg mL–1 as the most effective method. The phylogenetic tree analysis revealed a close relationship between the identified strains, and the strains were classified based on cultural, morphological, and molecular characteristics. The findings of this study add to our understanding of C.fructicola, which will aid in the development of preventive measures, the improvement of tea quality, and the assurance of safe production.

Background: Pancreatic cancer was prone to metastasis, which leaded to the poor survival and low quality of life. Here, we found that FAM83H-AS1 was highly correlated with metastasis of pancreatic cancer and further explored the functions and mechanisms involving in the malignant progression of pancreatic cancer. Method: We profiled and analyzed the aberrant expression of lncRNA (long non-coding RNA) in TCGA database and screened FAM83H-AS1 most effective in promoting the migration of pancreatic cancer cells. Firstly, the expression level of FAM83H-AS1 in serum, tissues and cells were detected by RT-qPCR, and the distribution of it in pancreatic cancer cells was tested by FISH and nuclear/cytosol fractionation RT-qPCR. Next, a series of functional assays were conducted to elucidate the relationship between FAM83H-AS1 and pancreatic cancer in vivo and vitro. The regulation relationship between FAM83H-AS1 and FAM83H was verified by protein and RNA degradation assays respectively. A series of Co-immunoprecipitation assays was utilized to explore the potential mechanism of FAM83H and β-catenin. Rescue assays were used to illustrate the regulation axis of FAM83H-AS1/FAM83H/ Wnt/β-catenin in pancreatic cancer.Results: FAM83H-AS1 was highly expressed in cancer tissues and serum of PDAC patients, and was correlated with poorer survival. FAM83H-AS1, as an oncogene, promoted the proliferation, invasion and metastasis of PDAC cells by functional assays and bioinformatics analysis. FAM83H, the homologous gene of FAM83H-AS1, also manifested the same biological behaviour as FAM83H-AS1 in PDAC. Also, FAM83H-AS1 protected FAM83H mRNA from degradation and FAM83H directly bound β-catenin. Mechanically, FAM83H-AS1 facilitated the expression of FAM83H by stabilizing its mRNA and promoted FAM83H to decrease the ubiquitylation of β-catenin, which activated the effect genes of Wnt/β-catenin signalling.Conclusions: This study revealed the function of FAM83H-AS1 involving in the progression of PDAC, and might provide a new prognostic indicator and therapy target for PDAC.

With a 5-year survival rate of approximately 10%, pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal solid malignancies in humans. A poor understanding of the underlying biology has resulted in a lack of effective targeted therapeutic strategies. Tissue microarray and bioinformatics analyses have revealed that the downstream transcriptional coactivator of the Hippo pathway, transcriptional coactivator with PDZ-binding motif (TAZ), might be a therapeutic target in PDAC. Since pharmacological inhibition of TAZ is challenging, we performed unbiased deubiquitinase (DUB) library screening to explore the pivotal regulators of TAZ ubiquitination as potential targets in PDAC models. We found that USP14 contributed to Yes-associated protein (YAP)/TAZ transcriptional activity and stabilized TAZ but not YAP. Mechanistically, USP14 catalyzed the K48-linked deubiquitination of TAZ to promote TAZ stabilization. Moreover, TAZ facilitated the transcription of USP14 by binding to the TEA domain transcription factor (TEAD) 1/4 response element in the promoter of USP14. USP14 was found to modulate the expression of TAZ downstream target genes through a feedback mechanism and ultimately promoted cancer progression and liver metastasis in PDAC models in vitro and in vivo. In addition, depletion of USP14 led to proteasome-dependent degradation of TAZ and ultimately arrested PDAC tumour growth and liver metastasis. A strong positive correlation between USP14 and TAZ expression was also detected in PDAC patients. The small molecule inhibitor of USP14 catalytic activity, IU1, inhibited the development of PDAC in subcutaneous xenograft and liver metastasis models. Overall, our data strongly suggested that the self-amplifying USP14-TAZ loop was a previously unrecognized mechanism causing upregulated TAZ expression, and identified USP14 as a viable therapeutic target in PDAC.

Validity of the laparoscopic approach in pancreatic head lesion remains debatable. This study aims to compare the safety and effectiveness of laparoscopic pancreatoduodenectomy (LPD) and open pancreatoduodenectomy (OPD) and investigate the source of heterogeneity from surgeons' and patients' perspectives.We searched PubMed, Cochrane, Embase, and Web of Science for studies published before February 1, 2021. Of 6578 articles, 81 were full-text reviewed. The primary outcome was mortality. Three independent reviewers screened and extracted the data and resolved disagreements by consensus. Studies were evaluated for quality using ROB2.0 and ROBINS-I. According to different study designs, sensitivity and meta-regression analyses were conducted to explore the heterogeneity source. This meta-analyses was also conducted to explore the learning curve's heterogeneity. This study was registered with PROSPERO, CRD42021234579.We analyzed 34 studies involving 46,729 patients (4705 LPD and 42,024 OPD). LPD was associated with lower (P = 0.025) in unmatched studies (P = 0.017). No differences in mortality existed in randomized controlled trials (P = 0.854) and matched studies (P = 0.726). Sensitivity analysis found no significant difference in mortality in elderly patients, patients with pancreatic cancer, and in high- and low-volume hospitals (all P 0.05). In studies at the early period of LPD (40 cases), higher mortality (P 0.001) was found (all P 0.05).LPD showed non-inferiority in length of stay, complications, and survival outcomes in all analyses.In high-volume centers with adequate surgical experience, LPD in selected patients appears to be a valid alternative to LPD with comparable mortality, LOS, complications, and survival outcomes.

Human monocyte differentiation antigen CD14 is a pattern recognition receptor (PRR) that enhances innate immune responses. CD14 was first identified as a marker of monocytes to signal intracellular responses upon bacterial encounters. Given the absence of an intracellular tail, CD14 was doubted to have the signaling capacities. Later CD14 was confirmed as the TLR co-receptor for the detection of pathogen-associated molecular patterns. However, CD14 has been revealed as a multi-talented receptor. In last decade, CD14 was identified to activate NFAT to regulate the life cycle of myeloid cells in a TLR4-independent manner and to transport inflammatory lipids to induce phagocyte hyperactivation. And its influences on multiple related diseases have been further considered. In this review, we summarize advancements in the basic biology of the CD14 including its structure, binding ligands, signaling pathways, and its roles in the pathogenesis of inflammation, atherosclerosis, tumor and metabolic diseases. We also discuss the therapeutic potential of targeting the CD14 in related diseases.

Background: Due to the significant heterogeneity in previous studies, concerns persist regarding the safety and effectiveness of laparoscopic pancreatoduodenectomy (LPD). Therefore, with the publication of new researches, a comprehensive systematic review is needed to evaluate the potential benefits of laparoscopic pancreatoduodenectomy. We aimed to compare safety and effectiveness of laparoscopic and open pancreatoduodenectomy (OPD) from the published studies, and investigate the source of heterogeneity from the surgeons’ and patients’ perspectives. Methods: We searched PubMed, Cochrane, Embase, and Web of Science databases for relevant studies published before February 1, 2021 comparing laparoscopic and open pancreatoduodenectomy. The database search yielded a total of 6,578 articles, and 81 articles were full-text reviewed. Studies of laparoscopic-assisted surgery were not included. The primary outcome was mortality. Three independent reviewers screened and extracted the data, and resolved disagreements by consensus. Studies were evaluated for quality using ROB2·0 and ROBINS-I. Meta-analyses were conducted in random-effect and fixed-effect models. Different meta-analyses were conducted according to the different designs of the studies. The sensitivity analyses and meta-regression were conducted to explore the source of heterogeneity. This study was registered with PROSPERO, ID CRD42021234579. Findings: We analyzed 34 studies involving 46,729 patients (4,705 LPD and 42,024 OPD). LPD was associated with lower mortality in overall studies (odds ratio [OR] 0·800, 95% confidence interval [CI] 0·659–0·973, P=0·025, I2=0·0%) and unmatched studies (OR 0·774, 95%CI 0·628–0·954, P=0·017, I2=0·0%). However, no differences in mortality were seen in RCTs (randomized controlled trial) (risk ratio 1·080, 95%CI 0·473–2·466, P=0·854, I2=13·4%) and matched studies (OR 0·904, 95%CI 0·515–1·587, P=0·726, I2=0·0%). Sensitivity analysis found that mortality was also similar between the two groups in elderly patients, patients with pancreatic ductal adenocarcinoma (PDAC), high-volume hospitals, and low-volume hospitals (all P >0·05). However, LPD showed non-inferiority in length of stay (LOS), severe complications, clinical relevant-postoperative pancreatic fistula, clinical relevant-biliary leak, intra-abdominal infection, readmission, overall survival, and 2-year relapse. Elderly patients benefited marginally from LPD, while patients with PDAC and patients in high-volume hospitals benefit significantly. Meta-regression confirmed that baseline differences including the proportion of males, age, proportion of biliary drainage, diagnosis of PDAC, and lesion size between LPD and OPD groups had a significant impact on LOS, severe complications, ICU stay, estimated intraoperative blood loss, and lymph node harvest (all P

Semi-airborne transient electromagnetic method (SATEM) is a new type of transient electromagnetic measurement method. Compared with the ground transient electromagnetic system, the system has the characteristics of convenience, high efficiency, large detection range, repeatable observation, high lateral resolution, etc. At the same time, this ground-space model shows that this method is suitable for detecting missions in mountainous and undulating terrain, and has obvious advantages in dividing underground space structure. In this paper, the theory of semi-airborne transient electromagnetic method is systematically studied and forward modeling is used to simulate the diffusion law of the end value under different resistivity and the characteristics of the response curve under different influencing factors of G model. The identification capability of SATEM for multi-layer model is verified by theoretical inversion, which lays a foundation for the practical application of SATEM in an ancient river channel. Finally, the application of SATEM to an example of an ancient river channel verifies the practicability and efficiency of the method, and the detection results are in good agreement with the local geological data.

Our previous study has shown that activating peripheral μ-receptors is necessary for switching the bronchopulmonary C-fibers (PCFs)-mediated rapid shallow breathing (RSB) into an apnea by systemic administration of fentanyl. The brainstem nuclei, such as the medial nucleus tractus solitarius (mNTS) and the pre-Botzinger complex (PBC), are required for completing the PCF-mediated respiratory reflexes. Moreover, these areas contain abundant μ-receptors and their activation prolongs expiratory duration (TE). Thus, we asked if central μ-receptors, especially those in the mNTS and PBC, are involved in fully expressing this RSB-apnea switch by fentanyl. In anesthetized rats, the cardiorespiratory responses to right atrial injection of phenylbiguanide (PBG, 3–6 μg/kg) were repeated after: (1) fentanyl (iv), a μ-receptor agonist, alone (8 μg/kg, iv); (2) fentanyl following microinjection of naloxone methiodide (NXM, an opioid receptor antagonist) into the cisterna magna (10 μg/4 μl); (3) the bilateral mNTS (10 mM, 20 nl); or (4) PBC (10 mM, 20 nl). Our results showed that PBG shortened TE by 37 ± 6% (RSB, from 0.41 ± 0.05 to 0.26 ± 0.03 s, P < 0.01), but it markedly prolonged TE by 5.8-fold (an apnea, from 0.50 ± 0.04 s to 2.9 ± 0.57 s, P < 0.01) after fentanyl (iv). Pretreatment with NXM injected into the cisterna magna or the PBC, but not the mNTS, prevented the fentanyl-induced switch. This study, along with our previous results mentioned above, suggests that although peripheral μ-receptors are essential for triggering the fentanyl-induced switch, central μ-receptors, especially those in the PBC, are required to fully exhibit such switch. Summary statement: Our results suggest that the activation of central μ-receptors, especially those in the pre-Botzinger complex, is required for switching the pulmonary C-fiber-mediated rapid shallow breathing into an apnea by systemic administration of fentanyl.

General anesthetics variably enhance inhibitory synaptic transmission that relies on (-aminobutyric acid (GABA) and GABAA receptor function with distinct differences across brain regions. Activation of "extra-synaptic" GABAA receptors produces a tonic current considered the most sensitive target for general anesthetics, particularly in forebrain neurons. To evaluate the contribution of poor drug access to neurons in slices, we tested the intravenous anesthetic propofol in mechanically isolated neurons from the solitary tract nucleus (NTS). Setting chloride concentrations to ECl=-29 mV made GABA currents inward at holding potentials of -60 mV. Propofol triggered pronounced but slowly-developing tonic currents that reversed with 5 min washing. Effective concentrations in isolated cells were lower than in slices and propofol enhanced phasic IPSCs more potently than tonic currents (1 microM increased phasic decay-time constant vs. >3 microM tonic currents). Propofol increased IPSC frequency (>3 microM), a presynaptic action. Bicuculline blocked all propofol actions. Gabazine blocked only phasic IPSCs. IPSCs persisted in TTX and/or cadmium but these agents prevented propofol-induced increases in IPSC frequency. Furosemide (>1 mM) reversibly blocked propofol-evoked IPSC frequency changes without altering waveforms. We conclude that presynaptic actions of propofol depend on a depolarizing chloride gradient across presynaptic inhibitory terminals. Our results in isolated neurons indicate that propofol pharmacokinetics intrinsically trigger the tonic currents slowly and the time course is not related to slow permeation or delivery. Unlike forebrain, phasic NTS GABAA receptors are more sensitive to propofol than tonic receptors but that presynaptic GABAA receptor mechanisms regulate GABA release.

Sighs, a well-known phenomenon in mammals, are substantially augmented by hypoxia and hypercapnia. Because (d-Ala2,N-Me-Phe4,Gly-ol)-enkephalin (DAMGO), a μ-receptor agonist, injected intravenously and locally in the caudal medullary raphe region (cMRR) decreased the ventilatory response to hypoxia and hypercapnia, we hypothesized that these treatments could inhibit sigh responses to these chemical stimuli. The number and amplitude of sighs were recorded during three levels of isocapnic hypoxia (15%, 10%, and 5% O2for 1.5 min) or hypercapnia (3%, 7%, and 10% CO2for 4 min) to test the dependence of sigh responses on the intensity of chemical drive in anesthetized and spontaneously breathing rats. The role of μ-receptors in modulating sigh responses to 10% O2or 7% CO2was subsequently evaluated by comparing the sighs before and after 1) intravenous administration of DAMGO (100 μg/kg), 2) microinjection of DAMGO (35 ng/100 nl) into the cMRR, and 3) intravenous administration of DAMGO after microinjection of d-Phe-Cys-Tyr-d-Trp-Arg-Thr-Pen-Thr-NH2(CTAP, 100 ng/100 nl), a μ-receptor antagonist, into the cMRR. Hypoxia and hypercapnia increased the number, but not amplitude, of sighs in a concentration-dependent manner, and the responses to hypoxia were significantly greater than those to hypercapnia. Systemic and local injection of DAMGO into the cMRR predominantly decreased the number of sighs, while microinjection into the rostral and middle MRR had no or limited effects. Microinjecting CTAP into the cMRR significantly diminished the systemic DAMGO-induced reduction of the number of sighs in response to hypoxia, but not to hypercapnia. Thus we conclude that hypoxia and hypercapnia elevate the number of sighs in a concentration-dependent manner in anesthetized rats, and this response is significantly depressed by activating systemic μ-receptors, especially those within the cMRR.

Background : Opioids, extensively used as analgesics, markedly depress ventilation, particularly the ventilatory responsiveness to hypercapnia in humans and animals predominantly via acting on mu receptors. The medullary raphe region (MRR) contains abundant mu receptors responsible for analgesia and is also an important central area involving carbon dioxide chemoreception and contributing to the ventilatory responsiveness to hypercapnia. Therefore, the authors asked whether activation of mu receptors in the caudal, medial, or rostral MRR depressed ventilation and the response to hypercapnia, respectively. Methods : Experiments were conducted in 32 anesthetized and spontaneously breathing rats. Ventilation and it response to progressive hypercapnia were recorded. The slopes obtained from plotting minute ventilation, respiratory frequency, and tidal volume against the corresponding levels of end-tidal pressure of carbon dioxide were used as the indices of the respiratory responsiveness to carbon dioxide. DAMGO ([d-Ala2, N-Me-Phe4, Gly-ol]-enkephalin), a mu-receptor agonist, was systemically administered (100 mug/kg) before and/or after local injection of CTAP (D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2) (100 ng/100 nl), a mu-receptor antagonist, into the caudal MRR, or locally administered (35 ng/100 nl) into the MRR subnuclei. Results : The authors found that systemic DAMGO significantly inhibited ventilation and the response to carbon dioxide by 20% and 31%, respectively, and these responses were significantly diminished to 11% and 14% after pretreatment of the caudal MRR with CTAP. Local administration of DAMGO into the caudal MRR also reduced ventilation and the response to carbon dioxide by 22% and 28%, respectively. In sharp contrast, these responses were not observed when the DAMGO microinjection was made in the middle MRR or rostral MRR. Conclusions : These results lead to the conclusion that mu receptors in the caudal MRR rather than the middle MRR or rostral MRR are important but not exclusive for attenuating the hypercapnic ventilatory response.

A previous study by the authors has shown that isoflurane (ISO), a commonly used volatile anesthetic, has an excitatory effect on bronchopulmonary C-fibers (PCFs). Since selective stimulation of PCFs by action on local 5-HT 3 receptors could evoke an apnea, this current study addresses whether inhalation of ISO would facilitate the PCF 5-HT 3 receptor-mediated apneic response and, if so, how. In anesthetized and spontaneously breathing rats, inhalation of 5% ISO markedly inhibited the apneic response to intra-atrium injection of phenylbiguanide (PBG, 25 μg/kg), a 5-HT 3 receptor agonist, which was contrary to the hypothesis. Extracellular recording of the nodose ganglion neurons in anesthetized, paralyzed and ventilated rats revealed that ISO attenuated the PBG-elicited excitation of pulmonary C neurons. Furthermore, using the patch clamp technique, it was found that ISO depressed the PBG-induced inward current of the pulmonary C neurons labeled with 1,1′-dioctadecyl-3,3,3′,3′-tetramethylindocarbocyanine perchlorate (DiI) instilled previously into the lungs. These results suggest that ISO inhibits PCF 5-HT 3 channel functions, and thereby attenuates PCF excitatory response to PBG, likely contributing to the diminution of the PBG-induced apnea by ISO in rats.

Inhalation of isoflurane (ISO), a widely used volatile anesthetic, can produce clinical tachypnea. In dogs, this response is reportedly mediated by bronchopulmonary C-fibers (PCFs), but the relevant mechanisms remain unclear. Activation of transient A-type potassium current ( I A ) channels and delayed rectifier potassium current ( I K ) channels hyperpolarizes neurons, and inhibition of both channels by ISO increases neural firing. Due to the presence of these channels in the cell bodies of rat PCFs, we determined whether ISO could stimulate PCFs to produce tachypnea in anesthetized rats, and, if so, whether this response resulted from ISO-induced depolarization of the pulmonary C neurons via the inhibition of I A and I K . We recorded ventilatory responses to 5% ISO exposure in anesthetized rats before and after blocking PCF conduction and the responses of pulmonary C neurons (extracellularly recorded) to ISO exposure. ISO-induced (1 mM) changes in pulmonary C neuron membrane potential and I A / I K were tested using the perforated patch clamp technique. We found that: (1) ISO inhalation evoked a brief tachypnea (∼7 s) and that this response disappeared after blocking PCF conduction; (2) the ISO significantly elevated (by 138%) the firing rate of most pulmonary C neurons (17 out of 21) in the nodose ganglion; and (3) ISO perfusion depolarized the pulmonary C neurons in the vitro and inhibited both I A and I K , and this evoked-depolarization was largely diminished after blocking both I A and I K . Our results suggest that ISO is able to stimulate PCFs to elicit tachypnea in rats, at least partly, via inhibiting I A and I K , thereby depolarizing the pulmonary C neurons.

Rapid shallow breathing (RSB) is mainly mediated by bronchopulmonary C-fibers (PCFs). We asked whether this RSB could be modulated by opioids. In anesthetized rats right atrial bolus injection of phenylbiguanide (PBG) to evoke RSB was repeated after: (1) intravenously giving fentanyl (μ-receptor agonist), DPDPE (δ-receptor agonist), or U-50488H (κ-receptor agonist); (2) fentanyl (iv) following naloxone methiodide, a peripheral opioid receptor antagonist; (3) bilateral microinjection of fentanyl into the nodose ganglia; (4) fentanyl (iv) with pre-blocking histamine H 1 and H 2 receptors by diphenhydramine and ranitidine. Systemic fentanyl challenge, but not DPDPE or U-50488H, switched the PBG-induced RSB to a long lasting apnea. This switch was blocked by naloxone methiodide rather than diphenhydramine and ranitidine. After microinjecting fentanyl into the nodose ganglia, PBG also produced an apnea. Our results suggest that activating μ-receptors is capable of turning the PCF-mediated RSB into an apnea, at least partly, via facilitating PCFs’ activity and this switching effect appears independent of the released histamine.

Intravenous bolus injection of morphine causes a vagal-mediated brief apnea (∼3 s), while continuous injection, via action upon central μ-opioid receptor (MOR), arrests ventilation (>20 s) that is eliminated by stimulating central 5-hydroxytryptamine 1A receptors (5HT1ARs). Bronchopulmonary C-fibers (PCFs) are essential for triggering a brief apnea, and their afferents terminate at the caudomedial region of the nucleus tractus solitarius (mNTS) that densely expresses 5HT1ARs. Thus we asked whether the vagal-mediated apneic response to MOR agonists was PCF dependent, and if so, whether this apnea was abolished by systemic administration of 8-hydroxy-2-(di- n-propylamino)tetral (8-OH-DPAT) largely through action upon mNTS 5HT1ARs. Right atrial bolus injection of fentanyl (5.0 μg/kg, a MOR agonist) was performed in the anesthetized and spontaneously breathing rats before and after: 1) selective blockade of PCFs' conduction and subsequent bivagotomy; 2) intravenous administration of 5HT1AR agonist 8-OH-DPAT; 3) intra-mNTS injection of 8-OH-DPAT; and 4) intra-mNTS injection of 5HT1AR antagonist WAY-100635 followed by 8-OH-DPAT (iv). We found the following: First, fentanyl evoked an immediate apnea (2.5 ± 0.4 s, ∼6-fold longer than the baseline expiratory duration, TE), which was abolished by either blocking PCFs' conduction or bivagotomy. Second, this apnea was prevented by systemic 8-OH-DPAT challenge. Third, intra-mNTS injection of 8-OH-DPAT greatly attenuated the apnea by 64%. Finally, intra-mNTS microinjection of WAY-100635 significantly attenuated (58%) the apneic blockade by 8-OH-DPAT (iv). We conclude that the vagal-mediated apneic response to MOR activation depends on PCFs, which is fully antagonized by systemic 8-OH-DPAT challenge largely via acting on mNTS 5HT1ARs.

Background : The commissural subnucleus of the nucleus tractus solitarius (comNTS) is a key region in the brainstem responsible for the hypoxic ventilatory response (HVR) because it contains the input terminals of the carotid chemoreceptor. Because opioids inhibit the HVR via activating central μ-receptors that are expressed abundantly in the comNTS, the authors of the current study asked whether activating local μ-receptors attenuated the carotid body-mediated HVR. Methods : To primarily stimulate the carotid body, brief hypoxia (100% N2) and hypercapnia (15% CO2) for 10 s and/or intracarotid injection of NaCN (10 μg/100 μl) were performed in anesthetized and spontaneously breathing rats. These stimulations were repeated after: (1) microinjecting three doses of μ-receptor agonist [d-Ala2, N-Me-Phe4, Gly-ol]-Enkephalin (DAMGO) (approximately 3.5 nl) into the comNTS; (2) carotid body denervation; and (3) systemic administration of DAMGO (300 μg/kg) without and with previous intracomNTS injection of d-Phe-Cys-Tyr-d-Trp-Arg-Thr-Pen-Thr-NH2, a μ-receptor antagonist. Results : Study results showed that DAMGO at 0.25 and 2.5, but not 0.025 mM, caused a similar decrease in baseline ventilation (approximately 12%). DAMGO at 0.25 mM largely reduced (64%) the HVR, whereas DAMGO at 2.5 mM abolished the HVR (and the VE response to NaCN) and moderately attenuated (31%) the hypercapnic ventilatory response. Interestingly, similar HVR abolition and depression of the hypercapnic ventilatory response were observed after carotid body denervation. Blocking comNTS μ-receptors by d-Phe-Cys-Tyr-d-Trp-Arg-Thr-Pen-Thr-NH2 significantly attenuated the HVR depression by systemic DAMGO with little change in the DAMGO modulatory effects on baseline ventilation and the hypercapnic ventilatory response. Conclusion : The data suggest that opioids within the comNTS, via acting on μ-receptors, are able to abolish the HVR by affecting the afferent pathway of the carotid chemoreceptor.

Opioids can attenuate the peripheral chemoreceptor-mediated hypoxic ventilatory response (HVR) by acting on central mu-type opioid receptors. Since the medullary raphe region (MRR) expresses abundant mu-receptors and participates in modulating HVR, we tested the role of mu-receptors within the caudal, medial, and rostral MRR (cMRR, mMRR, and rMRR) in modulating the HVR. We recorded cardiorespiratory activities and their responses to isocapnic hypoxia in anesthetized rats before and after local microinjection of DAMGO into the MRR, and intravenous administration of DAMGO (100 microg/kg) alone or coupled with a previous local injection of CTAP. Microinjecting DAMGO into the cMRR or mMRR but not the rMRR significantly attenuated the HVR. However, systemic DAMGO-induced HVR attenuation was not significantly affected by pretreating the cMRR and mMRR with CTAP. Our data suggest that cMRR and mMRR mu-receptors are capable of depressing the HVR, while their contribution to the attenuated HVR by systemic DAMGO is limited.