No abstract

Opioid drugs produce their pharmacological effects by activating inhibitory guanine nucleotide-binding regulatory protein-linked , ␦, and opioid receptors. One major effector for these receptors is adenylyl cyclase, which is inhibited upon receptor activation. However, little is known about which of the ten known forms of adenylyl cyclase are involved in mediating opioid actions. Here we show that all of the major behavioral effects of morphine, including locomotor activation, analgesia, tolerance, reward, and physical dependence and withdrawal symptoms, are attenuated in mice lacking adenylyl cyclase type 5 (AC5), a form of adenylyl cyclase that is highly enriched in striatum. Furthermore, the behavioral effects of selective or ␦ opioid receptor agonists are lost in AC5 ؊/؊ mice, whereas the behavioral effects of selective opioid receptor agonists are unaffected. These behavioral data are consistent with the observation that the ability of a or ␦ opioid receptor agonist to suppress adenylyl cyclase activity was absent in striatum of AC5 ؊/؊ mice. Together, these results establish AC5 as an important component of and ␦ opioid receptor signal transduction mechanisms in vivo and provide further support for the importance of the cAMP pathway as a critical mediator of opioid action. striatum ͉ opioid receptors ͉ analgesia ͉ addiction ͉ cAMP M orphine and most other opioid drugs are widely used clinically because of their potent analgesic effects, but this use is limited by their addiction liability. Both the analgesic and addicting actions of morphine and related drugs are initiated by their binding to , and to a lesser extent, ␦ opioid receptors (1-5). In contrast, other opioid drugs, such as U69593 and U50488H, activate opioid receptors, which generally produce distinct, and in some cases opposite, behavioral effects (6-8).Activation of all three types of opioid receptors is translated into physiological responses via coupling to inhibitory guanine nucleotide-binding regulatory protein, which then acts through several effectors, including most prominently inhibition of adenylyl cyclase, activation of G protein-linked inwardly rectifying K ϩ channels (GIRKs), and inhibition of voltage-gated Ca 2ϩ channels (2, 9). Regulation of G protein-linked inwardly rectifying K ϩ channels has been most closely related to the acute electrophysiological effects of , ␦, and opioid receptor activation of target cells (10, 11), whereas inhibition of adenylyl cyclase, and subsequent inhibition of the cAMP pathway, has been implicated mostly in longer term adaptations to repeated opiate administration (12, 13). Thus, up-regulation of adenylyl cyclase and other components of the cAMP pathway within specific regions of the central and peripheral nervous system has been shown to contribute to tolerance and dependence, and to changes in reward mechanisms, after repeated opioid administration.Despite the important role for adenylyl cyclase in mediating the actions of opioid drugs, little information is available concerning which type of th...

ObjectiveTo compare by 7 Tesla (7T) magnetic resonance imaging (MRI) in patients with focal epilepsy who have non-lesional clinical MRI scans with healthy controls.Methods37 patients with focal epilepsy, based on clinical and electroencephalogram (EEG) data, with non-lesional MRIs at clinical field strengths and 21 healthy controls were recruited for the 7T imaging study. The MRI protocol consisted of high resolution T1-weighted, T2-weighted and susceptibility weighted imaging sequences of the entire cortex. The images were read by two neuroradiologists, who were initially blind to clinical data, and then reviewed a second time with knowledge of the seizure onset zone.ResultsA total of 25 patients had findings with epileptogenic potential. In five patients these were definitely related to their epilepsy, confirmed through surgical intervention, in three they co-localized to the suspected seizure onset zone and likely caused the seizures. In seven patients the imaging findings co-localized to the suspected seizure onset zone but were not the definitive cause, and ten had cortical lesions with epileptogenic potential that did not localize to the suspected seizure onset zone. There were multiple other findings of uncertain significance found in both epilepsy patients and healthy controls. The susceptibility weighted imaging sequence was instrumental in guiding more targeted inspection of the other structural images and aiding in the identification of cortical lesions.SignificanceInformation revealed by the improved resolution and enhanced contrast provided by 7T imaging is valuable in noninvasive identification of lesions in epilepsy patients who are non-lesional at clinical field strengths.

ontinuous electroencephalography (CEEG) monitoring is used increasingly to assess brain function in critically ill patients. Substantial efforts have been made to standardize critical care EEG terminology and to associate EEG patterns with clinical course and outcome. [1][2][3][4][5] One of the main indications for CEEG is to detect electrographic seizures. Most electroencephalographers use a definition of seizures that includes a minimal duration of 10 seconds, 2-7 which reflects the typical duration of partial seizures in patients with chronic epilepsy. [8][9][10] Rhythmic ictal-appearing patterns lasting less than 10 seconds have been described in neonates under different acronyms: brief rhythmic discharges (BRDs), brief electroencephalography rhythmic discharges (BERDs), and brief ictal rhythmic discharges (BIRDs). [11][12][13] In neonates, these patterns encompass discharges of any frequency, including less than 4 Hz, because they are common in this age group. Rhythmic delta activity and periodic discharges with a frequency of less than 4 Hz are common in critically ill patients but are usually not considered to be ictal. 3,5 Ictal discharges in children and adults often have a higher frequency than those in neonates. The occurrence of brief rhythmic discharges with a frequency higher than 4 Hz has never been studied in these older age groups.In this study, we sought to investigate the prevalence, significance, and prognostic implication of these discharges. In addition, we propose the acronym B(I)RDs (brief potentially ictal rhythmic discharges; the parentheses in the acronym indicate that their ictal nature is equivocal) in a group of critically ill patients. IMPORTANCE Brief potentially ictal rhythmic discharges, termed B(I)RDs, have been described mainly in neonates, and their significance in adults remains unclear.OBJECTIVE To describe the incidence of B(I)RDs in critically ill patients and investigate their association with seizures and outcome. DESIGN, SETTING, AND PARTICIPANTSWe reviewed the records of prospectively identified patients with B(I)RDs and patients serving as controls matched for age (±5 years) and primary diagnosis. MAIN OUTCOMES AND MEASURESThe prevalence of seizures during continuous electroencephalography and functional outcome, as measured by the Glasgow Outcome Scale, were determined. RESULTSWe identified B(I)RDs in 20 patients (2%). The pattern most often consisted of very brief (1-3 seconds) runs of sharply contoured theta activity without obvious evolution. All patients with B(I)RDs had cerebral injury, and in cases with a single focal lesion (11 [55%]), B(I)RDs were localized in the same region in all but 2 cases (18%). Patients with B(I)RDs were more likely to have seizures during continuous electroencephalography than were patients without B(I)RDs (15 of 20 [75%] vs 10 of 40 [25%]; P < .001), and 9 patients with B(I)RDs (60%) had only subclinical seizures. Brief potentially ictal rhythmic discharges were identified before seizures in all but 1 case (93%) and ceased in all 12 ...

Impaired consciousness in epilepsy has a significant negative impact on patient quality of life, yet is difficult to study objectively. Here we develop an improved prospective Responsiveness in Epilepsy Scale (RES-II) and report initial results compared to the earlier version of the scale (RES). RES-II is simpler to administer and includes both verbal and nonverbal test items. We evaluated 75 seizures (24 patients) with RES and 34 seizures (11 patients) with RES-II based on video-EEG review. The error rate per seizure by test administrators improved markedly from a mean of 2.01±0.04 with RES to 0.24±0.11 with RES-II. Performance during focal seizures showed a bimodal distribution, corresponding to the traditional complex partial vs. simple partial seizure classification. We conclude that RES-II has improved accuracy and testing efficiency compared to the original RES. Prospective objective testing will ultimately lead to a better understanding of the mechanisms of impaired consciousness in epilepsy.