Toxicologic and Inhibitory Receptor Actions of the Etomidate Analog ABP-700 and Its Metabolite CPM-Acid.

BACKGROUND: The etomidate analog ABP-700 produces involuntary muscle movements that could be manifestations of seizures. To define the relationship (if any) between involuntary muscle movements and seizures, electroencephalographic studies were performed in Beagle dogs receiving supra-therapeutic (~10× clinical) ABP-700 doses. γ-aminobutyric acid type A (GABAA) and glycine receptor studies were undertaken to test receptor inhibition as the potential mechanism for ABP-700 seizures. METHODS: ABP-700 was administered to 14 dogs (6 mg/kg bolus followed by a 2-h infusion at 1 mg · kg(-1) · min(-1), 1.5 mg · kg(-1) · min(-1), or 2.3 mg · kg(-1) · min(-1)). Involuntary muscle movements were documented, electroencephalograph was recorded, and plasma ABP-700 and CPM-acid concentrations were measured during and after ABP-700 administration. The concentration-dependent modulatory actions of ABP-700 and CPM-acid were defined in oocyte-expressed α1ß3γ2L GABAA and α1ß glycine receptors (n = 5 oocytes/concentration) using electrophysiologic techniques. RESULTS: ABP-700 produced both involuntary muscle movements (14 of 14 dogs) and seizures (5 of 14 dogs). However, these phenomena were temporally and electroencephalographically distinct. Mean peak plasma concentrations were (from lowest to highest dosed groups) 35 µM, 45 µM, and 102 µM (ABP-700) and 282 µM, 478 µM, and 1,110 µM (CPM-acid). ABP-700 and CPM-acid concentration-GABAA receptor response curves defined using 6 µM γ-aminobutyric acid exhibited potentiation at low and/or intermediate concentrations and inhibition at high ones. The half-maximal inhibitory concentrations of ABP-700 and CPM-acid defined using 1 mM γ-aminobutyric acid were 770 µM (95% CI, 590 to 1,010 µM) and 1,450 µM (95% CI, 1,340 to 1,560 µM), respectively. CPM-acid similarly inhibited glycine receptors activated by 1 mM glycine with a half-maximal inhibitory concentration of 1,290 µM (95% CI, 1,240 to 1,330 µM). CONCLUSIONS: High dose ABP-700 infusions produce involuntary muscle movements and seizures in Beagle dogs via distinct mechanisms. CPM-acid inhibits both GABAA and glycine receptors at the high (~100× clinical) plasma concentrations achieved during the dog studies, providing a plausible mechanism for the seizures.

A leptin-mediated central mechanism in analgesia-enhanced opioid reward in rats.

Opioid analgesics are commonly used in chronic pain management despite a potential risk of rewarding. However, it remains unclear whether opioid analgesia would enhance the opioid rewarding effect thereby contributing to opioid rewarding. Utilizing a rat paradigm of conditioned place preference (CPP) combined with ankle monoarthritis as a condition of persistent nociception, we showed that analgesia induced by either morphine or the nonsteroid anti-inflammatory drug ibuprofen increased CPP scores in arthritic rats, suggesting that analgesia itself had a rewarding effect. However, arthritic rats exhibited a significantly higher CPP score in response to morphine than ibuprofen. Thus, the rewarding effect of morphine was enhanced in the presence of persistent nociception, producing a phenomenon of analgesia-enhanced opioid reward. At the cellular level, administration of morphine activated a cascade of leptin expression, glial activation, and dopamine receptor upregulation in the nucleus accumbens (NAc), while administration of ibuprofen decreased glial activation with no effect on leptin expression in the NAc. Furthermore, the morphine rewarding effect was blocked in leptin deficient ob/ob mice or by neutralizing leptin or interleukin-1ß in the NAc without diminishing morphine analgesia. The data indicate that systemic opioid can activate a leptin-mediated central mechanism in the NAc that led to the enhanced opioid rewarding effect. These findings provide evidence for an interaction between opioid analgesia and opioid rewarding, which may have implications in clinical opioid dose escalation in chronic pain management.

Data collection and analysis strategies for phMRI.

Although functional MRI traditionally has been applied mainly to study changes in task-induced brain function, evolving acquisition methodologies and improved knowledge of signal mechanisms have increased the utility of this method for studying responses to pharmacological stimuli, a technique often dubbed "phMRI". The proliferation of higher magnetic field strengths and the use of exogenous contrast agent have boosted detection power, a critical factor for successful phMRI due to the restricted ability to average multiple stimuli within subjects. Receptor-based models of neurovascular coupling, including explicit pharmacological models incorporating receptor densities and affinities and data-driven models that incorporate weak biophysical constraints, have demonstrated compelling descriptions of phMRI signal induced by dopaminergic stimuli. This report describes phMRI acquisition and analysis methodologies, with an emphasis on data-driven analyses. As an example application, statistically efficient data-driven regressors were used to describe the biphasic response to the mu-opioid agonist remifentanil, and antagonism using dopaminergic and GABAergic ligands revealed modulation of the mesolimbic pathway. Results illustrate the power of phMRI as well as our incomplete understanding of mechanisms underlying the signal. Future directions are discussed for phMRI acquisitions in human studies, for evolving analysis methodologies, and for interpretative studies using the new generation of simultaneous PET/MRI scanners. This article is part of the Special Issue Section entitled 'Neuroimaging in Neuropharmacology'.

Dynamic functional cerebral blood volume responses to normobaric hyperoxia in acute ischemic stroke.

Studies suggest that neuroprotective effects of normobaric oxygen (NBO) therapy in acute stroke are partly mediated by hemodynamic alterations. We investigated cerebral hemodynamic effects of repeated NBO exposures. Serial magnetic resonance imaging (MRI) was performed in Wistar rats subjected to focal ischemic stroke. Normobaric oxygen-induced functional cerebral blood volume (fCBV) responses were analyzed. All rats had diffusion-weighted MRI (DWI) lesions within larger perfusion deficits, with DWI lesion expansion after 3 hours. Functional cerebral blood volume responses to NBO were spatially and temporally heterogeneous. Contralateral healthy tissue responded consistently with vasoconstriction that increased with time. No significant responses were evident in the acute DWI lesion. In hypoperfused regions surrounding the acute DWI lesion, tissue that remained viable until the end of the experiment showed relative preservation of mean fCBV at early time points, with some rats showing increased fCBV (vasodilation); however, these regions later exhibited significantly decreased fCBV (vasoconstriction). Tissue that became DWI abnormal by study-end initially showed marginal fCBV changes that later became moderate fCBV reductions. Our results suggest that a reverse-steal hemodynamic effect may occur in peripheral ischemic zones during NBO treatment of focal stroke. In addition, CBV responses to NBO challenge may have potential as an imaging marker to distinguish ischemic core from salvageable tissues.

Neural correlates of the formation and retention of cocaine-induced stimulus-reward associations.

BACKGROUND: Cocaine can elicit drug-seeking behavior for drug-predicting stimuli, even after a single stimulus-cocaine pairing. Although orbitofrontal cortex is thought to be important during encoding and maintenance of stimulus-reward value, we still lack a comprehensive model of the neural circuitry underlying this cognitive process. METHODS: We studied the conditioned effects of cocaine with monkey functional magnetic resonance imaging and classical conditioning by pairing a visual shape (conditioning stimulus [CS+]) with a noncontingent cocaine infusion; a control stimulus was never paired. We correlated the behavioral preference of the monkey for the CS+, as measured offline, with the activity induced by the CS+ relative to the control stimulus as function of time. RESULTS: We observed that during formation of stimulus-cocaine associations strong CS+-induced functional magnetic resonance imaging activations emerged in frontal cortex that correlated significantly with behavioral CS+ preference. Afterward, CS+ preference correlated only with activity in early visual cortex. Control experiments suggest that these findings cannot be explained by increased familiarity for the CS+. CONCLUSIONS: Our findings suggest a complex interaction between frontal and occipital cortex during cocaine conditioning. Frontal cortex is important for establishing novel representations of stimulus valence when cocaine is used as reinforcer, whereas early visual cortex is involved in retaining these cocaine-stimulus associations.

Cortical depth-specific microvascular dilation underlies laminar differences in blood oxygenation level-dependent functional MRI signal.

Changes in neuronal activity are accompanied by the release of vasoactive mediators that cause microscopic dilation and constriction of the cerebral microvasculature and are manifested in macroscopic blood oxygenation level-dependent (BOLD) functional MRI (fMRI) signals. We used two-photon microscopy to measure the diameters of single arterioles and capillaries at different depths within the rat primary somatosensory cortex. These measurements were compared with cortical depth-resolved fMRI signal changes. Our microscopic results demonstrate a spatial gradient of dilation onset and peak times consistent with "upstream" propagation of vasodilation toward the cortical surface along the diving arterioles and "downstream" propagation into local capillary beds. The observed BOLD response exhibited the fastest onset in deep layers, and the "initial dip" was most pronounced in layer I. The present results indicate that both the onset of the BOLD response and the initial dip depend on cortical depth and can be explained, at least in part, by the spatial gradient of delays in microvascular dilation, the fastest response being in the deep layers and the most delayed response in the capillary bed of layer I.

Hemodynamic management and outcome of patients treated for cerebral vasospasm with intraarterial nicardipine and/or milrinone.

BACKGROUND: Vasospasm is a potentially devastating complication after aneurysmal subarachnoid hemorrhage. Although endovascular treatment with intraarterial nicardipine and milrinone is an accepted clinical treatment strategy, there is little information either on hemodynamic management during treatment or on outcome and consequences of the hemodynamic management. We tested 2 hypotheses: (1) intraarterial administration of nicardipine and milrinone to treat cerebral vasospasm would require increased administration of vasoconstrictor to support arterial blood pressure at target levels; and (2) high-dose vasopressors administered to increase blood pressure in these patients would lead to systemic acidosis and end-organ ischemic damage. METHODS: We conducted a single-center, retrospective review of consecutive patients with clinically symptomatic vasospasm after aneurysmal subarachnoid hemorrhage that failed medical management with "triple H therapy" and subsequently received intraarterial nicardipine and/or milrinone between March 2005 and July 2007. RESULTS: Of 160 endovascular interventions in 73 patients (aged 52 +/- 10 years; 50 women), 96 received only nicardipine, 5 only milrinone, and 59 both drugs. General anesthesia with muscle relaxation was performed for 93% of procedures. During treatment, both the number and dose of vasopressors required to maintain arterial blood pressure at target levels increased; the median dose of phenylephrine increased from 200 (n = 121) to 325 microg/min (n = 122), norepinephrine increased from 12 (n = 60) to 24.5 microg/min (n = 87), and vasopressin infusions increased from 7 to 24. Nonetheless, arterial blood pressure decreased 13% during treatment. In >90% of procedures, the postprocedure angiogram showed improved vessel caliber. A single patient demonstrated troponin T increase; no patients had a decrease in renal function, bowel or peripheral ischemia, systemic acidosis, or acute stroke. Overall mortality was 11%. CONCLUSIONS: Intraarterial administration of nicardipine and/or milrinone requires use of vasopressors to maintain arterial blood pressure. Despite high doses of vasoconstrictors, treatment has low mortality, minimal end-organ ischemic damage or systemic acidosis, and results in improved caliber of cerebral vessels affected by vasospasm.

Spin-echo MRI underestimates functional changes in microvascular cerebral blood plasma volume using exogenous contrast agent.

While most functional MRI studies using exogenous contrast agent employ gradient-echo (GE) signal, spin echo (SE) imaging would represent an attractive alternative if its detection power were more comparable with GE imaging. This study demonstrates that SE methods systematically underestimate functional changes in microvascular cerebral blood plasma volume (CBV), so that SE detection power in brain tissue cannot match that provided by GE signal. Empirically, the in vivo response of SE-CBV was about 40% smaller than that of GE-CBV in rat brain at low basal values of CBV, a result that is consistent with physics predictions under the simplifying assumption of uniform vessel dilation. However, increasing values of basal CBV were associated with monotonically increasing mean vessel sizes and monotonically decreasing GE to SE ratios of functional changes in CBV (fCBV). This result suggests the presence of large but weakly reactive conduit vessels at high basal values of CBV. Hence, we conclude that GE imaging is the method of choice for functional MRI (fMRI) using exogenous contrast agent in most cases, although SE methods may represent a more spatially linear representation of underlying neural activity that becomes most apparent in regions with high basal CBV, such as the cortical surface.

Remifentanil administration reveals biphasic phMRI temporal responses in rat consistent with dynamic receptor regulation.

Many pharmacological stimuli influence multiple neurotransmitter systems in the brain, and the dynamics of the functional brain response can vary regionally. In this study, the temporal response of cerebral blood volume (CBV) was employed to spatially segment cerebral effects due to infusion of a potent mu-opioid receptor agonist. Repeated intravenous injection of 10 mug/kg remifentanil in rats caused reproducible regional positive, negative, and biphasic changes in CBV. Three temporal processes were identified in the cerebral response and analyzed within the framework of the general linear model. Firstly, a slow component identified CBV changes that were almost exclusively negative, and the spatial distribution was similar to the inhibition produced by morphine (200 microg/kg). The largest CBV reductions occurred in caudate, accumbens, ventral hippocampus, cingulate, and piriform cortex. Secondly, a more rapid temporal component corresponded primarily with a regional distribution of positive changes in CBV consistent with GABAergic inhibition of hippocampal interneurons and associated projections. Thirdly, a response with the dynamics of mean arterial blood pressure correlated positively with CBV changes in hypothalamus, consistent with a central mechanism for control of blood pressure. We propose that the dominant source of the temporal variance in signal is dynamic modulation of drug targets by receptor endocytosis, an established effect in vitro. These results suggest that the temporal response of fMRI signal reflects underlying neurobiological processes, so that temporal decomposition strategies may aid interpretation of pharmacological mechanisms by identifying interconnected regions or those associated with common neural targets and processes.

Vertebral augmentation complicated by perioperative addisonian crisis.

BACKGROUND: We describe a case of perioperative Addisonian crisis induced by vertebral augmentation. While several complications of vertebral augmentation have been reported previously, related to the technical procedure, to our knowledge, perioperative Addisonian crisis from vertebral augmentation has not been reported in the literature. OBJECTIVE: To report an Addisonian crisis perioperative to vertebral augmentation. DESIGN: Case report. METHOD: Retrospective case review. RESULTS: The patient had a history of adrenal insufficiency treated previously with steroids. He developed an L3 vertebral compression fracture, failed conservative therapy and was eventually referred for vertebral augmentation. Immediately after starting the procedure, the patient developed profound hypotension unresponsive to intravenous fluids and vasopressors, consistent with Addisonian crisis. After intravenous steroids had resolved the Addisonian crisis, he underwent vertebral augmentation without further complication. CONCLUSION: Addisonian crisis may be triggered by vertebral augmentation. Practitioners need to recognize immediately this potentially lethal disorder in patients with known or suspected adrenal insufficiency and treat with intravenous hydrocortisone.

Exogenous contrast agent improves sensitivity of gradient-echo functional magnetic resonance imaging at 9.4 T.

Relative to common clinical magnetic field strengths, higher fields benefit functional brain imaging both by providing additional signal for high-resolution applications and by improving the sensitivity of endogenous contrast due to the blood oxygen level dependent (BOLD) mechanism, which has limited detection power at low magnetic fields relative to the use of exogenous contrast agent. This study evaluates the utility of iron oxide contrast agent for gradient echo functional MRI at 9.4 T in rodents using cocaine and methylphenidate as stimuli. Relative to the BOLD method, the use of high iron doses and short echo times provided a roughly twofold global increase in functional sensitivity, while also suppressing large vessel signal and reducing susceptibility artifacts. Furthermore, MRI measurements of the functional percentage change in cerebral blood volume (CBV) showed excellent agreement with results obtained at much lower magnetic field strengths, demonstrating that MRI estimates of this quantity are roughly independent of magnetic field when appropriate techniques are employed. The derived field dependencies for relative sensitivity and MRI estimates of the percentage change in CBV suggest that the benefits provided by exogenous agents will persist even at much higher magnetic fields than 9.4 T.

Functional response of tumor vasculature to PaCO2: determination of total and microvascular blood volume by MRI.

In order to identify differences in functional activity, we compared the reactivity of glioma vasculature and the native cerebral vasculature to both dilate and constrict in response to altered P(a)CO(2). Gliomas were generated by unilateral implantation of U87MGdEGFR human glioma tumor cells into the striatum of adult female athymic rats. Relative changes in total and microvascular cerebral blood volume were determined by steady state contrast agent-enhanced magnetic resonance imaging for transitions from normocarbia to hypercarbia and hypocarbia. Although hypercarbia induced a significant increase in both total and microvascular blood volume in normal brain and glioma, reactivity of glioma vasculature was significantly blunted in comparison to normal striatum; glioma total +/- CBV increased by 0.6 +/- 0.1%/mm Hg CO(2) whereas normal striatum increased by 1.5 +/- 0.2%/mm Hg CO(2), (P <.0001, group t-test). Reactivity of microvascular blood volume was also significantly blunted. In contrast, hypocarbia decreased both total and microvascular blood volumes more in glioma than in normal striatum. These results indicate that cerebral blood vessels derived by tumor-directed angiogenesis do retain reactivity to CO(2). Furthermore, reduced reactivity of tumor vessels to a single physiological perturbation, such as hypercarbia, should not be construed as a generalized reduction of functional activity of the tumor vascular bed.

Osteoid osteoma: elevation of cardiac and respiratory rates at biopsy needle entry into tumor in 10 patients.

PURPOSE: To evaluate changes in cardiac and respiratory rates in a consecutive series of patients who underwent percutaneous treatment for lesions presumed to be osteoid osteoma in whom general anesthesia was established. MATERIALS AND METHODS: Changes in cardiac and respiratory rates were evaluated after establishment of stable general anesthesia in 14 patients who underwent needle biopsy and radio-frequency treatment. Cardiac and respiratory rates were recorded at penetration of skin, muscle, periosteum, cortex, and tumor. Treatment was performed before the biopsy report was available. RESULTS: Biopsy results revealed osteoid osteoma in 10 patients, chondroblastoma in one, and a herniation pit in one. Results in the two remaining patients were nondiagnostic and were excluded. Puncture of skin, muscle, and periosteum caused no detectable change. However, in the 10 patients with biopsy-proved osteoid osteoma, puncture of the tumor caused the mean cardiac rate to increase an average of 26 beats per minute (40%) to 91 (range, 62-114; P <.001) and the mean respiratory rate to increase an average of 12 breaths per minute (50%) to a mean of 37 (range, 25-52; P <.001). These changes occurred within seconds of tumor puncture and were often the first indication to the surgeon that the tumor had been entered. In the two patients with other diagnoses at biopsy, no such change was apparent. CONCLUSION: Mean cardiac and respiratory rates increase significantly at needle puncture of osteoid osteoma.