Toward Structural Health Monitoring with the MyShake Smartphone Network.

The field of structural health monitoring (SHM) faces a fundamental challenge related to accessibility. While analytical and empirical models and laboratory tests can provide engineers with an estimate of a structure's expected behavior under various loads, measurements of actual buildings require the installation and maintenance of sensors to collect observations. This is costly in terms of power and resources. MyShake, the free seismology smartphone app, aims to advance SHM by leveraging the presence of accelerometers in all smartphones and the wide usage of smartphones globally. MyShake records acceleration waveforms during earthquakes. Because phones are most typically located in buildings, a waveform recorded by MyShake contains response information from the structure in which the phone is located. This represents a free, potentially ubiquitous method of conducting critical structural measurements. In this work, we present preliminary findings that demonstrate the efficacy of smartphones for extracting the fundamental frequency of buildings, benchmarked against traditional accelerometers in a shake table test. Additionally, we present seven proof-of-concept examples of data collected by anonymous and privately owned smartphones running the MyShake app in real buildings, and assess the fundamental frequencies we measure. In all cases, the measured fundamental frequency is found to be reasonable and within an expected range in comparison with several commonly used empirical equations. For one irregularly shaped building, three separate measurements made over the course of four months fall within 7% of each other, validating the accuracy of MyShake measurements and illustrating how repeat observations can improve the robustness of the structural health catalog we aim to build.

3D architecture and complex behavior along the simple central San Andreas fault.

The central San Andreas Fault (CSAF) exhibits a simple linear large-scale fault geometry, yet seismic and aseismic deformation features vary in a complex way along the fault. Here we investigate fault zone behaviors using geodetic observation, seismicity and microearthquake focal mechanisms. We employ an improved focal-mechanism characterization method using relative earthquake radiation patterns on 75,164 Ml ≥ 1 earthquakes along a 2-km-wide, 190-km-long segment of the CSAF, from 1984 to 2015. The data reveal the 3D fine-scale structure and interseismic kinematics of the CSAF. Our findings indicate that the first-order spatial variations in interseismic fault creep rate, creep direction, and the fault zone stress field can be explained by a simple fault coupling model. The inferred 3D mechanical properties of a mechanically weak and poorly coupled fault zone provide a unified understanding of the complex fine-scale kinematics, indicating distributed slip deficits facilitating small-to-moderate earthquakes, localized stress heterogeneities, and complex multi-scale ruptures along the fault. Through this detailed mapping, we aim to relate the fine-scale fault architecture to potential future faulting behavior along the CSAF.

Cocaine dose and self-administration history, but not initial cocaine locomotor responsiveness, affects sensitization to the motivational effects of cocaine in rats.

Cocaine addiction is a significant and complex disease. Part of this complexity is caused by the variability of the drug experience early in drug use (initial responsiveness, amount of use, etc.). In rats, individual differences in initial cocaine responsiveness and cocaine self-administration history both predict the development of cocaine sensitization, a putative mechanism contributing to the development of cocaine addiction. Here, we sought to determine the role of these factors and cocaine dose on the development of sensitization to cocaine's motivational effects during the earliest stages of self-administration. Rats were classified as either low or high cocaine responders (LCRs or HCRs, respectively) based on acute cocaine-induced locomotor activity (10 mg/kg i.p.) before learning to self-administer cocaine (0.6 mg/kg/infusion i.v.) under a fixed ratio 1 (FR1) schedule of reinforcement. After acquisition, rats self-administered cocaine (0.6 or 1.2 mg/kg/infusion) under a progressive ratio (PR) schedule of reinforcement either immediately or after an additional five FR1 sessions (0.6 or 1.2 mg/kg/infusion). No LCR/HCR differences in sensitization were observed. However, regardless of LCR/HCR classification, exposure to the higher dose of cocaine produced sensitization to cocaine's motivational effects on the PR schedule (i.e., increased break points) and an escalation of consumption on the FR schedule. Thus, our results reveal a novel model for studying escalation and sensitization very early after acquisition and suggest that sensitization may be important in the earliest stages of the cocaine addiction process.

Global growth of earthquake early warning.

Public-private partnerships provide a method for vastly expanding sensor networks.

Detecting damaged buildings using real-time crowdsourced images and transfer learning.

After significant earthquakes, we can see images posted on social media platforms by individuals and media agencies owing to the mass usage of smartphones these days. These images can be utilized to provide information about the shaking damage in the earthquake region both to the public and research community, and potentially to guide rescue work. This paper presents an automated way to extract the damaged buildings images after earthquakes from social media platforms such as Twitter and thus identify the particular user posts containing such images. Using transfer learning and ~ 6500 manually labelled images, we trained a deep learning model to recognize images with damaged buildings in the scene. The trained model achieved good performance when tested on newly acquired images of earthquakes at different locations and when ran in near real-time on Twitter feed after the 2020 M7.0 earthquake in Turkey. Furthermore, to better understand how the model makes decisions, we also implemented the Grad-CAM method to visualize the important regions on the images that facilitate the decision.

The deterministic nature of earthquake rupture.

Understanding the earthquake rupture process is central to our understanding of fault systems and earthquake hazards. Multiple hypotheses concerning the nature of fault rupture have been proposed but no unifying theory has emerged. The conceptual hypothesis most commonly cited is the cascade model for fault rupture. In the cascade model, slip initiates on a small fault patch and continues to rupture further across a fault plane as long as the conditions are favourable. Two fundamental implications of this domino-like theory are that small earthquakes begin in the same manner as large earthquakes and that the rupture process is not deterministic--that is, the size of the earthquake cannot be determined until the cessation of rupture. Here we show that the frequency content of radiated seismic energy within the first few seconds of rupture scales with the final magnitude of the event. We infer that the magnitude of an earthquake can therefore be estimated before the rupture is complete. This finding implies that the rupture process is to some degree deterministic and has implications for the physics of the rupture process.

Individual differences in initial low-dose cocaine-induced locomotor activity and locomotor sensitization in adult outbred female Sprague-Dawley rats.

Sex and individual differences are important considerations when studying cocaine responsiveness. We have previously shown that male Sprague-Dawley (S-D) rats can be classified as low or high cocaine responders (LCRs or HCRs, respectively) based on their locomotor activity following a single dose of cocaine (10 mg/kg, i.p.). Further, this distinction was found to predict dopamine transporter function, cocaine-induced locomotor sensitization, cocaine conditioned place preference and motivation to self-administer cocaine. Here we investigated whether or not individual differences in cocaine-induced locomotor activity and locomotor sensitization exist in female S-D rats. Female rats exhibited a broad range of locomotor activation following either a 5 or 10 mg/kg cocaine injection, allowing for classification as LCRs or HCRs. When administered over 7 days, both doses induced locomotor sensitization in female LCRs/HCRs. However, the magnitude of effects produced by 5 mg/kg cocaine in female LCRs/HCRs was more comparable to that produced by 10 mg/kg in male LCRs/HCRs, both of which, interestingly, developed sensitization in this study. These findings suggest that female S-D rats, like male S-D rats, can be classified as LCRs/HCRs and highlight the importance of accounting for dose when studying sex and individual differences to the effects of cocaine.

Offspring size plasticity in response to intraspecific competition: an adaptive maternal effect across life-history stages.

When provisioning offspring, mothers balance the benefits of producing a few large, fitter offspring with the costs of decreased fecundity. The optimal balance between offspring size and fecundity depends on the environment. Theory predicts that larger offspring have advantages in adverse conditions, but in favorable conditions size is less important. Thus, if environmental quality varies, selection should favor mothers that adaptively allocate resources in response to local conditions to maximize maternal fitness. In the bryozoan Bugula neritina, we show that the intensity of intraspecific competition dramatically changes the offspring size/performance relationship in the field. In benign or extremely competitive environments, offspring size is less important, but at intermediate levels of competition, colonies from larger larvae have higher performance than colonies from smaller larvae. We predicted mothers should produce larger offspring when intermediate competition is likely and tested these expectations in the field by manipulating the density of brood colonies. Our findings matched expectations: mothers produced larger larvae at high densities and smaller larvae at low densities. In addition, mothers from high-density environments produced larvae that have higher dispersal potential, which may enable offspring to escape crowded environments. It appears mothers can adaptively adjust offspring size to maximize maternal fitness, altering the offspring phenotype across multiple life-history stages.

Individual differences in cocaine-induced locomotor activity in male Sprague-Dawley rats and their acquisition of and motivation to self-administer cocaine.

RATIONALE: Factors that increase an individual's susceptibility to cocaine dependence remain largely unknown. We have previously shown that adult outbred male Sprague-Dawley rats can be classified as either low or high cocaine responders (LCRs or HCRs, respectively) based on their locomotor activity following the administration of a single dose of cocaine (10 mg/kg, i.p.). Furthermore, LCR/HCR classification predicts dopamine transporter function/inhibition, cocaine-induced locomotor sensitization, and cocaine-conditioned place preference. OBJECTIVES: The present study assessed LCR/HCR classification and the development of locomotor sensitization on the latency to acquire cocaine self-administration and motivation to self-administer cocaine. RESULTS: LCRs and HCRs did not differ in their latency to acquire low-dose cocaine self-administration (0.25 mg/kg/infusion over 12 s, fixed ratio 1 schedule of reinforcement). In a follow-up experiment, repeated experimenter-administered injections of cocaine (10 mg/kg, i.p.) resulted in locomotor sensitization for LCRs, but not HCRs; nonetheless, all rats exhibited decreased latency to acquire cocaine self-administration compared to the first experiment. Repeated cocaine preexposure and LCR/HCR classification predicted break point when rats responded for cocaine under a progressive ratio schedule of reinforcement (0.25, 0.5, and 1.0 mg/kg/infusion; multiple exposure>single exposure, LCR>HCR), but there was no interaction between these variables. CONCLUSIONS: Although LCR/HCR classification did not predict the rate of acquisition of cocaine self-administration under these conditions, LCR rats demonstrated greater responding for cocaine after acquisition (PR). Thus, these findings demonstrate the relevance of using the LCR/HCR model when studying susceptibility to cocaine dependence.

Applying Movement Ecology to Marine Animals with Complex Life Cycles.

Marine animals with complex life cycles may move passively or actively for fertilization, dispersal, predator avoidance, resource acquisition, and migration, and over scales from micrometers to thousands of kilometers. This diversity has catalyzed idiosyncratic and unfocused research, creating unsound paradigms regarding the role of movement in ecology and evolution. The emerging movement ecology paradigm offers a framework to consolidate movement research independent of taxon, life-history stage, scale, or discipline. This review applies the framework to movement among life-history stages in marine animals with complex life cycles to consolidate marine movement research and offer insights for scientists working in aquatic and terrestrial realms. Irrespective of data collection or simulation strategy, breaking each life-history stage down into the fundamental units of movement allows each unit to be studied independently or interactively with other units. Understanding these underlying mechanisms of movement within each life-history stage can then be used to construct lifetime movement paths. These paths can allow further investigation of the relative contributions and interdependencies of steps and phases across a lifetime and how these paths influence larger research topics, such as population-level movements.

Quantitative trait loci for sensitivity to acute ethanol and ethanol consummatory behaviors in rats.

Individuals with a low initial response to alcohol (i.e., ethanol) are at greater risk of developing alcohol abuse or dependence later in life. Similar to humans, individual differences in ethanol sensitivity also can be seen in rats, and several laboratories have used these individual differences to generate selectively bred rats that differ in acute ethanol sensitivity. We have worked with two sets of such rats (Inbred High or Low Alcohol Sensitivity strains, IHAS or ILAS, respectively; Inbred Alcohol Tolerant or Non-Tolerant strains, IAT and IANT, respectively) and have confirmed previously mapped quantitative trait loci (QTL) for these acute differences with the use of recombinant congenic lines; however, the relationship between acute sensitivity and ethanol drinking in these rats has yet to be determined. Thus, here we tested the hypothesis that QTLs underlying variation in initial low sensitivity to ethanol also will modulate variation in ethanol drinking behaviors. Separate groups of selectively inbred parent and congenic rats were tested for the loss of righting response (LORR) and also assessed for ethanol consummatory behavior using either operant self-administration or an intermittent-access two-bottle choice procedure. LORR testing confirmed the presence of a LORR duration QTL in all of the congenics; however, the lack of a corresponding difference in blood ethanol concentration at the regaining of the righting response suggests that these QTLs may be mediating a difference in ethanol metabolism rather than in neuronal sensitivity. IHAS/ILAS-derived congenic rats did not differ from parent rats at any point during operant self-administration. IAT/IANT-derived congenic rats showed small, but significant, increases in ethanol consumption relative to the parent strains only during the initial stages of operant self-administration. In contrast to operant testing, IHAS/ILAS-derived congenic rats showed significantly greater ethanol consumption and preference than parent rats during intermittent-access testing. There were not differences, however, between IAT/IANT congenic and parent rats during intermittent access. These data support the hypothesis that there is a genetic relationship between initial ethanol sensitivity and ethanol consumption, at least for the IHAS/ILAS-derived congenic rats. Our current studies, however, cannot eliminate pharmacokinetic or taste preference factors as contributing to the rats' responses, nor can we eliminate the possibility of a linkage effect because of the fairly large size of the QTL intervals; i.e., distinct genes may be mediating the acute sensitivity and drinking responses.

Continuous exposure to the competitive N-methyl-D: -aspartate receptor antagonist, LY235959, facilitates escalation of cocaine consumption in Sprague-Dawley rats.

RATIONALE: Chronic high dose consumption of cocaine is associated with significant negative effects to individual users and society. Nevertheless, the precise mechanisms that mediate increases in cocaine consumption in a drug-using individual are not fully understood. OBJECTIVES: This study used a long access version of the drug self-administration procedure to determine whether escalation of cocaine consumption is mediated by increased activity through N-methyl-D: -aspartate (NMDA) receptors. MATERIALS AND METHODS: Male Sprague-Dawley rats (n = 63) were first trained to self-administer cocaine (0.33 mg/infusion, i.v.) under a fixed-ratio 1 schedule of reinforcement. After training, some rats were implanted with subcutaneous osmotic minipumps filled with vehicle or the competitive NMDA receptor antagonist, LY235959, and subsequently allowed to self-administer cocaine in short (2 h) or long (6 h) access self-administration sessions. RESULTS: Vehicle-treated rats escalated cocaine self-administration across 14 long-access self-administration sessions. Rats treated with LY235959 via osmotic minipump, but not twice daily injections, escalated cocaine self-administration at a greater rate and to a greater degree than vehicle-treated rats. In post-escalation cocaine dose-infusion tests, rats treated continuously with LY235959 self-administered more cocaine (0.08-1.32 mg/infusion) than vehicle-treated rats, regardless of access condition, shifting the dose-infusion curves upward. During extinction sessions, which were conducted after the escalation phase of the study, rats that had long (6 h) access to cocaine stopped responding sooner than rats that had short (2 h) access to cocaine, independent of LY235959 treatment. CONCLUSIONS: These data are consistent with hypo-glutamatergic consequences of repeated cocaine exposure.

Continuous intracerebroventricular infusion of the competitive NMDA receptor antagonist, LY235959, facilitates escalation of cocaine self-administration and increases break point for cocaine in Sprague-Dawley rats.

Although escalation of consumption is an important characteristic of cocaine dependence, the neurobiological mechanisms that mediate this phenomenon have not been fully described. In this study, we used male, Sprague-Dawley rats to measure the effects of acute and continuous intracerebroventricular (ICV) administration of the competitive NMDA receptor antagonist, LY235959, on cocaine self-administration behavior under various schedules of reinforcement and access conditions. Single ICV infusions of LY235959 (0.03-0.3 microg/5 microl) produced dose-dependent and statistically significant decreases in the number of cocaine infusions earned under a progressive ratio schedule of reinforcement. In a second experiment, vehicle or LY235959 (0.2-0.3 microg/day) was continuously administered ICV to rats via surgically-implanted subcutaneous osmotic minipump/intracranial cannula assemblies. Both vehicle- and LY235959-treated rats significantly escalated cocaine self-administration over the 10 long access sessions; however, rats treated with LY235959 escalated cocaine self-administration faster and to a greater degree than vehicle-treated rats. There was a statistically significant increase in cocaine infusions earned under the PR schedule in LY235959-treated rats, but not vehicle-treated rats, after 10 long access cocaine self-administration sessions. These data support the hypothesis that escalation of cocaine consumption is mediated by hypo-glutamatergic tone in the central nervous system and this facilitation of escalation is associated with an increase in motivation to respond for cocaine.

Low and high locomotor responsiveness to cocaine predicts intravenous cocaine conditioned place preference in male Sprague-Dawley rats.

Outbred, male Sprague-Dawley rats can be classified as either low or high cocaine responders (LCRs or HCRs, respectively) based on cocaine-induced locomotor activity in an open-field arena. This difference reflects cocaine's ability to inhibit the striatal dopamine transporter and predicts development of sensitization. To investigate the relationship between initial cocaine locomotor responsiveness and cocaine reward, here we first classified rats as either LCRs or HCRs in a conditioned place preference (CPP) apparatus. Subsequently, we conducted cocaine conditioning trials, twice-daily over 4 days with vehicle and cocaine (10 mg/kg, i.p. or 1 mg/kg, i.v.). When cocaine was administered by the i.p. route, similar to previous findings in the open-field, LCRs and HCRs were readily classified and locomotor sensitization developed in LCRs, but not HCRs. However, cocaine CPP was not observed. In contrast, when cocaine was administered by the i.v. route, the LCR/HCR classification not only predicted sensitization, but also CPP, with only LCR rats exhibiting sensitization and cocaine conditioning. Our findings show that the initial locomotor response to cocaine can predict CPP in male Sprague-Dawley rats under conditions when place conditioning develops, and that LCRs may be more prone to develop conditioning in the context of cocaine reward.

Tomography reveals buoyant asthenosphere accumulating beneath the Juan de Fuca plate.

The boundary between Earth's strong lithospheric plates and the underlying mantle asthenosphere corresponds to an abrupt seismic velocity decrease and electrical conductivity increase with depth, perhaps indicating a thin, weak layer that may strongly influence plate motion dynamics. The behavior of such a layer at subduction zones remains unexplored. We present a tomographic model, derived from on- and offshore seismic experiments, that reveals a strong low-velocity feature beneath the subducting Juan de Fuca slab along the entire Cascadia subduction zone. Through simple geodynamic arguments, we propose that this low-velocity feature is the accumulation of material from a thin, weak, buoyant layer present beneath the entire oceanic lithosphere. The presence of this feature could have major implications for our understanding of the asthenosphere and subduction zone dynamics.

MyShake: A smartphone seismic network for earthquake early warning and beyond.

Large magnitude earthquakes in urban environments continue to kill and injure tens to hundreds of thousands of people, inflicting lasting societal and economic disasters. Earthquake early warning (EEW) provides seconds to minutes of warning, allowing people to move to safe zones and automated slowdown and shutdown of transit and other machinery. The handful of EEW systems operating around the world use traditional seismic and geodetic networks that exist only in a few nations. Smartphones are much more prevalent than traditional networks and contain accelerometers that can also be used to detect earthquakes. We report on the development of a new type of seismic system, MyShake, that harnesses personal/private smartphone sensors to collect data and analyze earthquakes. We show that smartphones can record magnitude 5 earthquakes at distances of 10 km or less and develop an on-phone detection capability to separate earthquakes from other everyday shakes. Our proof-of-concept system then collects earthquake data at a central site where a network detection algorithm confirms that an earthquake is under way and estimates the location and magnitude in real time. This information can then be used to issue an alert of forthcoming ground shaking. MyShake could be used to enhance EEW in regions with traditional networks and could provide the only EEW capability in regions without. In addition, the seismic waveforms recorded could be used to deliver rapid microseism maps, study impacts on buildings, and possibly image shallow earth structure and earthquake rupture kinematics.

Escalation of cocaine consumption in short and long access self-administration procedures.

BACKGROUND: Escalation of consumption is a hallmark of cocaine addiction. Many animal models reveal escalation by increasing the duration of drug access (e.g., 6-24 h/day) after longer histories of self-administration. We recently developed a method that reveals escalation early post-acquisition under shorter access conditions. However, whether or not rats will escalate cocaine consumption both early post-acquisition under short access (2 h/day) conditions, and later under long access (6 h/day) conditions, has not been demonstrated. METHODS: All rats acquired cocaine self-administration (0.8 mg/kg, i.v.) under 2 h conditions, and then continued 2h self-administration for an additional 13 sessions. Then, rats were assigned either to 2 or 6h conditions, and self-administered cocaine (0.8 mg/kg, i.v.) for an additional 19 sessions. In addition, four cocaine-induced locomotor activity measurements were taken for each rat: before cocaine exposure, after non-contingent cocaine administration, and after escalation in the short and long access experimental phases. RESULTS: Following acquisition, rats displayed a robust escalation of intake during 2 h sessions. Rats that self-administered cocaine in continued 2h sessions exhibited stable intake, whereas rats that self-administered cocaine in 6h sessions further escalated intake. Despite the second escalation in 6h rats, cocaine-induced locomotor activity did not differ between 2 and 6h rats. CONCLUSIONS: Escalation of cocaine self-administration can occur in the same rats both early post-acquisition, and later under long access conditions. Importantly, this early post-acquisition period provides a new opportunity to determine the mechanisms first involved in the escalation phenomenon.

Continuous exposure to dizocilpine facilitates the acquisition and escalation of cocaine consumption in male Sprague-Dawley rats.

BACKGROUND: Blocking N-methyl-d-aspartate (NMDA) glutamate receptors (NMDARs) prevents cocaine locomotor sensitization, but facilitates escalation of cocaine self-administration and produces ambiguous effects on acquisition of cocaine self-administration. This study used a recently described model of acquisition and escalation to test the hypothesis that continuous NMDAR antagonism functionally increases the effects of a given dose of cocaine. METHODS: We assessed acquisition of cocaine self-administration (0.6 mg/kg/infusion) in rats treated continuously with either vehicle or the NMDAR antagonist dizocilpine (0.4 mg/kg/day) for 14 consecutive 2h fixed ratio 1 (FR1) sessions. In a separate experiment that assessed the effect of dizocilpine treatment on escalation of cocaine self-administration, rats acquired cocaine self-administration (0.6 mg/kg/infusion) prior to vehicle or dizocilpine treatment. Then, immediately post-acquisition, rats were treated continuously with either vehicle or dizocilpine and allowed to self-administer either 0.6 or 1.2mg/kg/infusion cocaine for an additional seven consecutive 2h FR1 sessions. RESULTS: Relative to vehicle-treated rats, a significantly greater percentage of dizocilpine-treated rats acquired cocaine self-administration. During the escalation experiment, both vehicle- and dizocilpine-treated rats escalated intake of 1.2mg/kg/infusion cocaine. Whereas vehicle-treated rats exhibited stable intake of 0.6 mg/kg/infusion cocaine, dizocilpine-treated rats escalated intake of this moderate cocaine dose to levels indistinguishable from intake levels produced by self-administration of the high cocaine dose (i.e., 1.2mg/kg/infusion). CONCLUSIONS: These findings suggest that chronic NMDAR blockade potentiates, rather than attenuates, cocaine's effects and argue for reconsideration of the role of NMDARs in cocaine "addiction-like" behavior.

Antinociceptive effects of the selective delta opioid agonist SNC80 alone and in combination with mu opioids in the squirrel monkey titration procedure.

RATIONALE: The nonpeptidic compound SNC80 [(+)-4[(alphaR)-alpha-((2S, 5R)-4-allyl-2, 5,-dimethyl-l-piperazinyl)-3-methoxybenzyl]- N, N-diethylbenzamide], has a high degree of selectivity for delta opioid receptors. Moreover, compounds with delta opioid activity have been shown to enhance the effects of mu agonists under certain conditions. OBJECTIVES: The present study examined the effects of SNC80 alone and in combination with the mu opioid agonists, morphine, butorphanol, and buprenorphine to determine whether SNC80 would enhance their antinociceptive effects. METHODS: In the squirrel monkey shock titration procedure increasing levels of shock are delivered to the monkey's tail in incremental steps and responses on a lever decrease shock intensity. The level at which monkeys maintain the shock (median shock level, MSL) and rate of responding (RR) are examined. RESULTS: SNC80 alone did not consistently alter responding under the titration procedure; however, morphine, butorphanol, and buprenorphine increased MSL without decreasing RR markedly. SNC80 (0.1-3.0 mg/kg) enhanced the effects of single doses of morphine, butorphanol, and buprenorphine that either did not increase or produced very small increases in MSL when administered alone. Interestingly, SNC80 enhanced the effects of morphine, butorphanol, and buprenorphine on MSL without decreasing RR. CONCLUSIONS: SNC80 does not produce antinociceptive effects in the squirrel monkey titration procedure but can enhance the effects of selected doses of morphine, butorphanol, and buprenorphine on MSL without decreasing RR. These data suggest that SNC80-induced enhancement of the antinociceptive effects of mu opioids is dependent on dose, time, and method of administration and is not the result of sedation or motor dysfunction.

Pharmacological properties of JDTic: a novel kappa-opioid receptor antagonist.

Biological studies were conducted on (3R)-7-Hydroxy-N-[(1S)-1-[[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]methyl]-2-methylpropyl]-1,2,3,4-tetrahydro-3-isoquinoline-carboxamide (JDTic), the first potent kappa-selective opioid receptor antagonist not derived from an opiate class of compounds. In the mouse tail-flick test, JDTic, administered subcutaneously (s.c.), blocked anticociceptive activity for up to 2 weeks. When JDTic was administered either s.c. or p.o. 24 h before the selective KOP (kappa)-opioid receptor agonist, enadoline, AD(50s) of 4.1 and 27.3, respectively, were obtained. A time-course study of JDTic versus enadoline indicated significant antagonist p.o. activity up to 28 days. In contrast, JDTic, s.c., failed to antagonize the analgesic effects of the selective MOP mu-opioid receptor agonist, sufentanil. In the squirrel monkey shock titration antinociception test, JDTic given intramuscularly (i.m.) shifted the trans-3,4-dichloro-N-methyl-N-(2-[1-pyrrolidinyl] cyclohexyl) benzeneacetamide (U50,488) dose-effect curve to the right. In the U50,488-induced diuresis rat test, JDTic, s.c., suppressed diuretic activity with a greater potency than that of nor-binaltorphimine (nor-BNI). Thus, JDTic is a potent long- and orally acting selective kappa-opioid antagonist.