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A 22.5‐kg, 8.4‐year‐old female mixed breed dog was presented for an emergency ovariohysterectomy for pyometra. No neurological abnormalities were observed on preoperative physical examination. Surgery was completed uneventfully under fentanyl‐ and sevoflurane‐based anaesthesia. Cardiorespiratory indices remained stable under mechanical ventilation throughout the procedure. Approximately 23 min after the discontinuation of fentanyl infusion, the investigator noticed jaw closure and stiffness and thoraco‐abdominal muscle rigidity. To rule out fentanyl‐induced muscle rigidity, naloxone was administered. Following administration of naloxone, there was a return of spontaneous respiratory effort, indicated by capnogram and visible chest wall excursion. Based on the clinical signs and response to naloxone administration, the dog was diagnosed with suspected fentanyl‐induced muscle rigidity. Six minutes after the return of spontaneous respiration, the dog was extubated uneventfully without additional naloxone administration. During 4 days of postoperative hospitalization, no recurrent muscle rigidity was observed, and the patient was discharged safely. The total dose of fentanyl administered was 0.61 mg (27 μg kg−1). [ABSTRACT FROM AUTHOR]

Butorphanol and buprenorphine are mixed opioid receptor agonist‐antagonist drugs widely used as analgesics in people and animals. There are few reports concerning the interaction of multiple opioids, and their antinociceptive effects, when combined with other opioids, remain unclear. Therefore, we report the preliminary findings of the antinociceptive effects of the combined use of butorphanol and buprenorphine in C57BL/6JJcl mice. Both drugs were administered either simultaneously or in different orders. Compared with the baseline values, the tail‐flick and hot‐plate test latencies increased regardless of the order of administration. Furthermore, enhanced latencies were observed on administration of butorphanol followed by buprenorphine. Combined use of these drugs may not attenuate analgesic efficacy. Besides, enhancement of these effects can be obtained by changing the order of the administration of these drugs. It is necessary to further investigate the molecular basis of the underlying mechanism in future definitive studies. [ABSTRACT FROM AUTHOR]

Objective: Optimizing cardiac stroke volume during high-risk surgical anesthesia is of particular interest with regard to a therapeutic target to reduce the incidence of postoperative complications. However, intensive fluid management in critically ill small animals with pulmonary hypertension (PH) has been empirically performed, and thus it can be challenging. Stroke volume variation (SVV) has been used as a dynamic preload predictor of fluid responsiveness. We hypothesized that if SVV exhibited robust reliability in the setting of hemodynamically unstable condition, it would provide more precise information on fluid resuscitation to translate it into veterinary anesthesia. Thus the aim of this study was to investigate the utility of SVV measured by the electrical velocimetry (EV) method for predicting fluid responsiveness in dogs with PH. Methods: Sixteen dogs undergoing emergency abdominal surgery and diagnosed with PH secondary to myxomatous mitral valve disease (MMVD) on preoperative transthoracic echocardiogram were included. Dogs were randomly assigned to 2 groups with and without inotropic cardiac support with dobutamine. Hemodynamic measurements including stroke volume and SVV derived from the EV device were performed under general anesthesia before (baseline) and after surgery (fluid challenge with a colloid solution defined by a SV increase of ≥ 10%). Results: In both groups, SVV elevated significantly after abdominal surgery compared with baseline. In dobutamine infused group, the SVV values decreased significantly after fluid challenge (P < 0.05) with a greater number of responders than saline infused control group (P < 0.01). Receiver operating curve analysis of SVV confirmed high positive predictive value for dogs during dobutamine infusion (P < 0.05; cut-off value of 15%; specificity 90%, sensitivity 82%). Conclusions: Noninvasive EV monitoring may be useful for the prediction of fluid responsiveness in critically ill dogs with left-sided heart failure-related PH. This normalization of dynamic preload indices, which could be achieved more precisely under inotropic support, may prevent further detrimental consequence of fluid loading. [ABSTRACT FROM AUTHOR]

Summary: We evaluated the utility of noninvasive stroke volume variation (SVV) as a functional haemodynamic predictor for fluid responsiveness under different ventilation modes (assist control [A/C], synchronized intermittent mandatory ventilation [SIMV], and continuous positive airway pressure [CPAP]) in 45 anaesthetized dogs, using an electrical velocimetry device. Receiver operating curve analysis confirmed the best predictive value during SVVA/C (12.5% of cut‐off value; 75% sensitivity and 86% specificity) followed by SVVSIMV (13.5% of cut‐off value; 75% sensitivity and 75% specificity), while no statistical significance was detected during SVVCPAP (P > .05). These data suggest that SVV is useful for the prediction of fluid responsiveness in laboratory dogs during A/C and SIMV, while its reliability during CPAP is poor. [ABSTRACT FROM AUTHOR]

Summary: We evaluated the neuroprotective role of rapamycin, a mammalian target of rapamycin (mTOR) kinase inhibitor, in cerebral ischaemia and locomotor function in a mouse model of subarachnoid haemorrhage (SAH). Pretreatment with rapamycin, an mTOR kinase inhibitor, resulted in better recovery from cerebral hypoxia early after SAH than control (P < .05), while the values of peak flow velocity in the middle cerebral artery did not change significantly (P > .05). Average distance travelled and the ratio of central‐area distance/total travelled distance determined by open‐field test after day 14 was significantly higher in mice pretreated with rapamycin than in control mice (P < .05). Inhibition of the mTOR pathway could be protective against post‐SAH early brain injury, ameliorating brain tissue hypoxia and locomotor hypoactivity. [ABSTRACT FROM AUTHOR]

Summary: Tooth loss and related changes in the functionality may lead to worse outcome of stroke patients, but the effect on hemorrhagic stroke remains unclear. This study aimed to determine the impact of impaired masticatory function on acute cerebral oxygenation and locomotor activity after experimental subarachnoid haemorrhage (SAH). Twenty C57BL/6 mice with (MC‐treated group) or without (control group) prior treatment of cutting off the upper molars were subjected to SAH by endovascular perforation. Grading of SAH and acute cerebral infarction were assessed by MR images. Brain tissue oxygen saturation (SbtO2) by photoacoustic imaging and parameters related to locomotor activity by open‐field test were analyzed serially after SAH. In all mice, global SbtO2 depression was notable immediately after SAH induction (P <.001), which recovered close to the baseline levels until day 3. However, MC‐treated mice demonstrated a prolonged relative cerebral hypoxia (<40% of the baseline SbtO2) as compared to the control (3 ± 1 vs 1 ± 1 days; P <.05). The average distance travelled on day 7 and the ratio of central‐area distance/total travelled distance by open‐field test between days 7 and 14 were significantly lower in MC‐treated mice than in the control mice (P <.05), although the occurrences of new infarction were not statistically different (P >.05). These data suggest a possible link between preceding masticatory impairment and early brain injury to deteriorate neurobehavioural function in patients after SAH. [ABSTRACT FROM AUTHOR]

Background and purpose Experimental subarachnoid hemorrhage (SAH) by endovascular filament perforation method is used widely in mice, but it sometimes present acute cerebral infarctions with varied magnitude and anatomical location. This study aimed to determine the prevalence and location of the acute ischemic injury in this experimental model. Methods Male C57BL/6 mice were subjected to SAH by endovascular perforation. Distribution of SAH was defined by T2*-weighted images within 1 h after SAH. Prevalence and location of acute infarction were assessed by diffusion-weighted MR images on day 1 after the induction. Results Among 72 mice successfully acquired post-SAH MR images, 29 (40%) developed acute infarction. Location of the infarcts was classified into either single infarct (ipsilateral cortex, n = 12; caudate putamen, n = 3; hippocampus, n = 1) or multiple lesions (cortex and caudate putamen, n = 6; cortex and hippocampus, n = 2; cortex, hippocampus and thalamus/hypothalamus, n = 3; bilateral cortex, n = 2). The mortality rate within 24 h was significantly higher in mice with multiple infarcts than those with single lesion (30% versus 0%; P = 0.03). Distribution of the ischemic lesion positively correlated with MRI-evidenced SAH grading ( r 2 = 0.31, P = 0.0002). Conclusion Experimental SAH immediately after the vessel perforation can induce acute cerebral infarction in varying vascular territories, resulting in increased mortality. The present model may in part, help researchers to interpret the mechanism of clinically-evidenced early multiple combined infarction. [ABSTRACT FROM AUTHOR]

Background and Purpose: μ Opioid receptor knockout (MOP-KO) mice display several behavioural differences from wild-type (WT) littermates including differential responses to nociceptive stimuli. Brain structural changes have been tied to behavioural alterations noted in transgenic mice with targeting of different genes. Hence, we assess the brain structure of MOP-KO mice.Experimental Approach: Magnetic resonance imaging (MRI) voxel-based morphometry (VBM) and histological methods were used to identify structural differences between extensively backcrossed MOP-KO mice and WT mice.Key Results: MOP-KO mice displayed robust increases in regional grey matter volume in olfactory bulb, several hypothalamic nuclei, periaqueductal grey (PAG) and several cerebellar areas, most confirmed by VBM analysis. The largest increases in grey matter volume were detected in the glomerular layer of the olfactory bulb, arcuate nucleus of hypothalamus, ventrolateral PAG (VLPAG) and cerebellar regions including paramedian and cerebellar lobules. Histological analyses confirm several of these results, with increased VLPAG cell numbers and increased thickness of the olfactory bulb granule cell layer and cerebellar molecular and granular cell layers.Conclusions and Implications: MOP deletion causes previously undescribed structural changes in specific brain regions, but not in all regions with high MOP receptor densities (e.g. thalamus, nucleus accumbens) or that exhibit adult neurogenesis (e.g. hippocampus). Volume differences in hypothalamus and PAG may reflect behavioural changes including hyperalgesia. Although the precise relationship between volume change and MOP receptor deletion was not determined from this study alone, these findings suggest that levels of MOP receptor expression may influence a broader range of neural structure and function in humans than previously supposed.Linked Articles: This article is part of a themed section on Opioids: New Pathways to Functional Selectivity. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-2. [ABSTRACT FROM AUTHOR]

Background and Purpose μ Opioid receptor knockout ( MOP-KO) mice display several behavioural differences from wild-type ( WT) littermates including differential responses to nociceptive stimuli. Brain structural changes have been tied to behavioural alterations noted in transgenic mice with targeting of different genes. Hence, we assess the brain structure of MOP-KO mice. Experimental Approach Magnetic resonance imaging ( MRI) voxel-based morphometry ( VBM) and histological methods were used to identify structural differences between extensively backcrossed MOP-KO mice and WT mice. Key Results MOP-KO mice displayed robust increases in regional grey matter volume in olfactory bulb, several hypothalamic nuclei, periaqueductal grey ( PAG) and several cerebellar areas, most confirmed by VBM analysis. The largest increases in grey matter volume were detected in the glomerular layer of the olfactory bulb, arcuate nucleus of hypothalamus, ventrolateral PAG ( VLPAG) and cerebellar regions including paramedian and cerebellar lobules. Histological analyses confirm several of these results, with increased VLPAG cell numbers and increased thickness of the olfactory bulb granule cell layer and cerebellar molecular and granular cell layers. Conclusions and Implications MOP deletion causes previously undescribed structural changes in specific brain regions, but not in all regions with high MOP receptor densities (e.g. thalamus, nucleus accumbens) or that exhibit adult neurogenesis (e.g. hippocampus). Volume differences in hypothalamus and PAG may reflect behavioural changes including hyperalgesia. Although the precise relationship between volume change and MOP receptor deletion was not determined from this study alone, these findings suggest that levels of MOP receptor expression may influence a broader range of neural structure and function in humans than previously supposed. Linked Articles This article is part of a themed section on Opioids: New Pathways to Functional Selectivity. To view the other articles in this section visit [ABSTRACT FROM AUTHOR]

B Learning Objectives: b Intensive hemodynamic therapy is a valuable option for treating neurological symptoms attributable to delayed cerebral ischemia (DCI) in patients after subarachnoid hemorrhage (SAH). In the other group (n=24), each drug was started at low dose infusion and raised at each dose increment (3 or 0.125 g/kg/min; step-wise [SW] group) until neurological deficits resolved, through which effective lowest dose was infused until day 14. The maximum infusion dose of dobutamine was greater in CI than in SW (P < 0.01), while the CO values at each final dose did not statistically different between the regimens (P = 0.13). [Extracted from the article]

B Learning Objectives: b Microcirculatory dysfunction is a critical element of early brain injury after subarachnoid hemorrhage (SAH). Relationships between %vascularity and CBF determined either by laser Doppler flowmetry-blood flow index (BFI) or MRI-arterial spin labeling (ASL) before and after creating SAH were analyzed. B Conclusions: b The data suggest that noninvasive micro-ultrasound derived %vascularity successfully reflected CBF during acute phase of experimental SAH, which may be applicable to preclinical hemodynamic studies on early brain injury. [Extracted from the article]

Introduction: Subarachnoid hemorrhage (SAH) can cause various neurogenic cardiovascular complications such as Takotsubo cardiomyopathy. Mammalian target of rapamycin (mTOR) signalling may play an important protective role against myocardial and cerebral injuries in patients after SAH. Hypothesis: To visualize hemodynamic interaction between heart and brain using an advanced in vivo experimental technology and to determine the role of mTOR pathway early after SAH. Methods: Male C57BL/6 mice were subjected to SAH by endovascular perforation and a mTOR inhibitor rapamycin (2 mg/kg for 3 consecutive days) or its vehicle (control) was started. Serial analyses of the hemodyamic parameters including stroke volume, cardiac output (CO) and 3D-reconstructed % vascularity of the middle cerebral artery territory (an index of the cerebral blood volume) were performed under light anesthesia using the VEVO 3100 micro-ultrasound system (FUJIFILM VisualSonics). Newly developed cerebral infarcts (CI) were assessed by a 1.05T MRI scanner (ASPECT Imaging). Results: In both groups, all cerebral indices depressed immediately after SAH induction (P <0.001), recovering close to the baseline levels within 48 h. Although the peak depression were not changed significantly between the groups, rapamycin showed a better recovery from cardiac depression and % vascularity of the brain than control (P <0.05). The number of CI were greater in mice with persisted CO depression (24-48 h), the number which were smaller in rapamycin treated group (P <0.05). Conclusions: Inhibition of the mTOR signal pathway may act as functionally protective for both heart and brain injuries in a mouse model of SAH. The present multi-modality in vivo imaging would shed lights on pathophysiology in heart-brain interaction during super-acute phase after SAH. [ABSTRACT FROM AUTHOR]

Summary: We aimed to evaluate the feasibility of a non‐invasive method of cerebral blood flow (CBF) measurement using high‐frequency power Doppler ultrasound imaging in a mouse model of subarachnoid haemorrhage (SAH). The 3‐dimensionally (3D) reconstructed blood flow signals (%vascularity) within the brain volume of the middle cerebral artery territory correlated well with reference parameters, baseline carotid artery blood flow (r2 = 0.52, P < 0.0001) and normalized CBF changes (r2 = 0.74 P < 0.0001). These data suggest that the 3D power Doppler analysis may have the potential for reflecting real‐time CBF changes during the acute phase of experimental SAH, which may be applicable to preclinical studies on early brain injury. [ABSTRACT FROM AUTHOR]

Highlights • Rapamycin exerts neuroprotectiosn against EBI early after murine SAH. • Central rapamycin microinjection improved post-SAH CBF, SbtO 2 , and CO depression. • Stattic or PD98059 attenuated the neurocardiac support benefit from rapamycin. • ERK and JAK/STAT3 pathways play an important role in the central rapamycin effects. Abstract Early brain injury and related cardiac consequences play a key role in the devastating outcomes after subarachnoid hemorrhage (SAH). We reported that rapamycin exerts neuroprotection against cortical hypoxia early after SAH, but its mechanism is poorly understood. This in vivo study aimed to determine the potential role of the transcription factor STAT3 in the rapamycin-mediated neuroprotection in a mouse model of SAH. Forty C57BL/6 N mice were treated with an intracerebroventricular injection of rapamycin or vehicle (control) given after SAH induction by a filament perforation method, with or without STAT3 (Stattic) or ERK (PD98059) inhibitor pretreatment. Cerebral blood flow signals (%vascularity), brain tissue oxygen saturation (SbtO 2), and cardiac output (CO) were analyzed using an ultrasound/photoacoustic imaging system. Clinically relevant neurocardiac depression was notable in severe SAH mice. Rapamycin improved %vascularity, SbtO 2 , and CO on day 1 after SAH onset. The beneficial effects of rapamycin on cerebral blood flow and oxygenation persisted until day 3, resulting in a significant reduction in post-SAH new cerebral infarctions and survival, as well as improved neurological functions, compared to the control group. All of the effects were attenuated by pretreatment with Stattic or PD98059. These data suggest that ERK and JAK/STAT3 pathways play an important role in the neurocardiac protection by rapamycin after SAH. We propose that rapamycin is a novel pharmacological strategy to target STAT3 activation, with a possible crosstalk through the ERK pathway, for the treatment of post-SAH early brain injury. [ABSTRACT FROM AUTHOR]

Background and purpose Acute cerebral hypoperfusion following subarachnoid hemorrhage (SAH) is highly related to the pathogenesis of delayed cerebral ischemia (DCI), but the therapeutic option is poorly available. This study aimed to clarify the effect of milrinone (MIL) on cerebral blood flow (CBF) and related outcomes after experimental SAH. Methods Twenty-seven male C57BL/6 mice were assigned to either sham surgery (SAH-sham; n = 6), SAH induced by endovascular perforation (control; n = 10), or SAH followed by cardiac support with intravenous MIL (n = 11) performed 1.5-h after SAH induction. CBF, neurobehavioral function, occurrence of DCI were assessed by MR-continuous arterial spin labeling, daily neurological score testing, and diffusion- and T2-weighted MR images on days 1 and 3, respectively. Results Initial global CBF depression was notable in mice of control and MIL groups as compared to the SAH-sham group ( P < 0.05). MIL raised CBF in a dose-dependent manner ( P < 0.001), resulted in lower incidence of DCI ( P = 0.008) and better recovery from neurobehavioral decline than control ( P < 0.001). The CBF values on day 1 predicted DCI with a cut-off of 42.5 ml/100 g/min (82% specificity and 83% sensitivity), which was greater in mice treated with MIL than those of control (51.7 versus 37.6 ml/100 g/min; P < 0.001). Conclusion MIL improves post-SAH acute hypoperfusion that can lead to the prevention of DCI and functional worsening, acting as a neurocardiac protective agent against EBI. [ABSTRACT FROM AUTHOR]

Aims Neurocardiac dysfunction is a life-threatening systemic consequence of subarachnoid hemorrhage (SAH) that contributes to triggering delayed cerebral ischemia (DCI). This study aimed to determine the impact of dobutamine cardiac support during isoflurane postconditioning on pos t -SAH DCI. Main methods Male C57BL/6 mice were subjected to SAH, SAH plus isoflurane postconditioning, or SAH plus isoflurane postconditioning with dobutamine. Severity of SAH was graded from 1 to 4 (mild, 1–2; severe, 3–4) based on T2*-weighted magnetic resonance imaging (MRI). Cardiac output (CO) measured by transthoracic pulsed wave Doppler-echocardiography was titrated at a supra-normal level with intravenous dobutamine infusion. Neurological function was examined daily by neurological score and Rotarod tests. DCI was analyzed 3 days later by determining new infarction on diffusion-weighted MRI. In a separate experiment, mice were pretreated with hypoxia-inducible factor (HIF) inhibitor 2-methoxyestradiol (2ME2). Key findings Clinically relevant CO depression was notable in severe SAH grade mice, in which dobutamine CO management combined with isoflurane postconditioning showed earlier and improved functional recovery than postconditioning with single isoflurane inhalation. Incidence of infarction and volumes on day 3 reduced significantly in this subgroup. All of the effects during preconditioning were attenuated by 2ME2 pretreatment. Significance Isoflurane postconditioning under dobutamine cardiac support improves recovery from SAH-induced early brain injury, leading to reduced DCI resultant from severe experimental SAH. These results indicate the importance of neuro-cardiac protection, in which HIF may be acting as a critical mediator, as a promising therapeutic approach to SAH. [ABSTRACT FROM AUTHOR]

Abstract: Substantial evidence exists that opioid systems are involved in stress response and that changes in opioid systems in response to stressors affect both reward and analgesia. Reportedly, mice suffering chronic social defeat stress subsequently show aversion to social contact with unfamiliar mice. To further examine the role of opioid systems in stress response, the behavioral and neurochemical effects of chronic social defeat stress (psychosocial stress) were evaluated in μ-opioid-receptor knockout (MOR-KO) mice. Aversion to social contact was induced by chronic social defeat stress in wild-type mice but was reduced in MOR-KO mice. Moreover, basal expression of brain-derived neurotrophic factor (BDNF) mRNA in MOR-KO mice hippocampi was significantly lower than in wild-type mice. Psychosocial stress significantly decreased BDNF mRNA expression in wild-type mice but did not affect BDNF expression in MOR-KO mice; no difference in basal levels of plasma corticosterone was observed. These results suggest that the μ-opioid receptor is involved in the behavioral sequelae of psychosocial stress and consequent regulation of BDNF expression in the hippocampus, and may play an important role in psychiatric disorders for which stress is an important predisposing or precipitating factor, such as depression, posttraumatic stress disorder, and social anxiety disorder. [Copyright &y& Elsevier]

Early brain injury/ischemia is a recent therapeutic target that contributes to triggering delayed cerebral ischemia (DCI) in the setting of subarachnoid hemorrhage (SAH). This study aimed to determine the role of dobutamine for inotropic cardiac support in improving cerebral blood flow (CBF) and outcomes after experimental SAH, mediated by hypoxia-inducible factor (HIF). Thirty-one mice were subjected to SAH by endovascular perforation, and assigned to either 2% isoflurane postconditioning performed between 1 and 2.5 h after SAH induction or concomitant intravenous dobutamine infusion (15 μg/kg/min) with or without HIF inhibitor 2-methoxyestradiol (2ME2) (10 mg/kg) administered intraperitoneally. Neurobehavioral function was assessed daily by neurological scores and open field testing. DCI was defined 3 days later by detecting a new infarction on MRI. Global CBF depression was notable early after SAH, but dobutamine showed significant improvement in CBF, lower incidence of DCI, and better recovery of neuroscores and open field test variables compared with isoflurane postconditioning ( P < 0.05). CBF over the entire brain on day 1 predicted DCI with a cut-off of 36.5 ml/100 g/min (80% specificity and 67% sensitivity), with a better area under the curve (0.83 versus 0.75) than the hemispheric CBF measured on the perforated side. The dobutamine-mediated outcomes were attenuated ( P < 0.05) by 2ME2 pretreatment. The data suggest that cardiac support with dobutamine improves global CBF depression induced by early brain injury, leading to reduced prevalence of DCI and better functional outcomes after experimental SAH, in which HIF may be acting as a critical mediator. [ABSTRACT FROM AUTHOR]

Background: Psychological stress has a recognized association with asthma symptoms. Using a murine model of allergic asthma, we recently demonstrated the involvement of μ-opioid receptors (MORs) in the central nervous system in the stress-induced exacerbation of airway inflammation. However, the involvement of MORs on neurons and immunological alterations in the stress asthma model remain unclear. Methods: MOR-knockout (MORKO) mice that express MORs only on noradrenergic and adrenergic neurons (MORKO/Tg mice) were produced and characterized for stress responses. Sensitized mice inhaled antigen and were then subjected to restraint stress. After a second antigen inhalation, bronchoalveolar lavage cells were counted. Before the second inhalation, bronchial lymph node (BLN) cells and splenocytes from stressed and non-stressed mice were cultured with antigen, and cytokine levels and the proportions of T cell subsets were measured. Results: Stress-induced worsening of allergic airway inflammation was observed in wild-type and MORKO/Tg mice but not MORKO mice. In wild-type stressed mice, IFN-&gamma/IL-4 ratios in cell culture supernatants and the proportion of regulatory T cells in BLN cell populations were significantly lower than those in non-stressed mice. These differences in BLN cells were not observed between the stressed and non-stressed MORKO mice. Restraint stress had no effect on cytokine production or T cell subsets in splenocytes. Conclusions: Restraint stress aggravated allergic airway inflammation in association with alterations in local immunity characterized by greater Th2-associated cytokine production and a reduced development of regulatory T cells, mediated by MORs. [ABSTRACT FROM AUTHOR]