Alex Gray

The involvement of the opioidergic system in the antinociceptive mechanism of action of antidepressant compounds

Debate exists as to the nature of antidepressant‐induced antinociception. It is unclear whether antidepressants are inherently antinociceptive, are able to potentiate opioid antinociception or both. We have used the acetic acid induced abdominal constriction assay in mice to investigate antidepressant‐induced antinociception. All the antidepressants tested (s.c.) produced dose‐dependent protection against acetic acid‐induced abdominal constriction. Similarly, morphine and aspirin were also effective antinociceptive agents in this nociceptive assay. Opioid antagonists, naloxone (0.5 mg kg−1, s.c.) and naltrindole (1 mg kg−1, s.c.), shifted the dose‐response relationships to the right for each of the antidepressant agents (dothiepin, amitriptyline, sibutramine, (+)‐oxaprotiline and paroxetine). In this context the naloxone dose‐ratios were 1.95, 3.90, 2.32, 4.50 and 2.65, with naltrindole dose‐ratios of 4.36, 17.00, 4.28, 11.48 and 2.65 were obtained, respectively. Naloxone also shifted the morphine dose‐response relationship to the right, by a factor of 2.62, whilst naltrindole had no effect upon morphine antinociception. Aspirin antinociception remained unaffected by both opioid antagonists. The enkephalin catabolism inhibitor acetorphan, by itself, produced no activity in this test at a dose of 10 mg kg−1 (s.c.). However, at higher doses, acetorphan produced a linear dose‐response relationship against acetic acid‐induced abdominal constriction. When acetorphan was administered before either the antidepressants or morphine, there was a clear potentiation of the antidepressant‐ or morphine‐induced antinociception. However, acetorphan had no effect on aspirin antinociception. Since neither of the opioid antagonists were able to attenuate, nor was acetorphan able to potentiate, aspirin antinociception, we concluded that the mechanism of antidepressant‐induced antinociception is different from that of the non‐steroidal anti‐inflammatory drugs. These data are consistent with the view that antidepressants may induce endogenous opioid peptide release, as shown by the acetorphan study. In this context, the ability of naltrindole to displace the antidepressant dose‐response relationship to the right without affecting morphine antinociception, implicates the δ‐opioid receptor and endogenous opioid peptides in antidepressant‐induced antinociception.

The KRAFT architecture for knowledge fusion and transformation

This paper describes the Knowledge Reuse And Fusion/Transformation (KRAFT) architecture which supports the fusion of knowledge from multiple, distributed, heterogeneous sources. The architecture uses constraints as a common knowledge interchange format, expressed against a common ontology. Knowledge held in local sources can be transformed into a common constraint language, and fused with knowledge from other sources. The fused knowledge is then used to solve some problem or deliver some information to a user. Problem solving in KRAFT typically exploits pre-existing constraint solvers. KRAFT uses an open and flexible agent architecture in which knowledge sources, knowledge fusing entities and users are all represented by independent KRAFT agents, communicating using a messaging protocol. Facilitator agents perform matchmaking and brokerage services between the various kinds of agent. KRAFT is being applied to an example application in the domain of network data services design.

Do α2-adrenoceptors play an integral role in the antinociceptive mechanism of action of antidepressant compounds?

Antidepressants are analgesic in the absence or presence of depression. The underlying mechanisms probably involve a complex interplay between several neurotransmitter systems and neuroreceptors. Alpha-adrenoceptors play an important role in pain processing and alpha2-adrenoceptor agonists have been used in clinical pain management so we have investigated whether alpha-adrenoceptor sub-types mediate the antinociceptive activity of antidepressants. Thus, the abdominal constriction assay in mice was used to examine the antinociceptive responses of a diverse range of antidepressants following alpha1- or alpha2-adrenoceptor antagonism. The antidepressants or monoamine reuptake inhibitors included the serotonin selective reuptake inhibitor paroxetine, the serotonin-noradrenaline reuptake inhibitor sibutramine, the resolved (+)- and (-)-enantiomers of the noradrenaline reuptake inhibitor oxaprotiline, plus the tricyclics amitriptyline and dothiepin. All these compounds have been previously shown to be antinociceptive in this paradigm. The respective alpha1- and alpha2-adrenoceptor antagonists prazosin and RX821002 ([2-(2-methoxy-1,-4-benzodioxan-2-yl)-2-imidazoline]) did not produce antinociception though at 1.0 mg kg(-1); s.c., RX821002 but not prazosin blocked clonidine antinociception. The antinociceptive activity produced by sub-maximal doses of amitriptyline, dothiepin, sibutramine, paroxetine, (+)- and (-)-oxaprotiline were all blocked by RX821002 but not by prazosin. Additionally, both morphine and aspirin antinociception was resistant to alpha1- and alpha2-adrenoceptor antagonism. Thus, alpha2- rather than alpha1-adrenoceptors may play an integral role in antidepressant antinociception irrespective of the propensity for inhibiting reuptake of not only noradrenaline but also serotonin. It is probable, however, that other differing pharmacological properties of some antidepressants, such as opioid-like activity, may complicate any empirical correlation between monoamine uptake and analgesia.

Contrasting actions of acute or chronic paroxetine and fluvoxamine on morphine withdrawal-induced place conditioning

The acute and chronic effects of paroxetine and fluvoxamine on naloxone withdrawal-induced place aversion in morphine dependent rats were investigated. Acutely administered fluvoxamine (25 mg/kg s.c. given 30 min prior to naloxone withdrawal pairing) and chronic daily paroxetine (10 mg/kg s.c.) coadministration with a morphine induction protocol, both attenuated morphine withdrawal place aversion. Conversely, acutely administered paroxetine (up to 25 mg/kg s.c.) or chronic daily fluvoxamine (10 mg/kg s.c.) coadministration with morphine did not modify subsequent withdrawal place aversion. Previous radioligand binding studies indicate that fluvoxamine has opioid-displacing properties. It is suggested therefore that acute fluvoxamine may have decreased withdrawal aversion, probably through serotonin and also, in part, via an opioid-like mechanism whereas chronic paroxetine decreased withdrawal aversion by a serotonergic mechanism, but it is not clear whether opioid systems play any role in the action of paroxetine.

Personalizing web information for patients: linking patient medical data with the web via a patient personal knowledge base

This paper describes ongoing study that examines problems with existing patient health information sources and investigates an approach for linking (i.e. integrating) data from a patient’s medical record(s) with relevant health information on the web. The aim is to provide patients with simplified, customized and controlled access to web information. Data from patient medical records are extracted and linked with relevant health information on the web through a web search service. These are made available to patients through a web portal that we refer to as the patient knowledge base (PatientKB). Our integration approach utilizes term semantics (i.e. meaning) to enrich the web search and simplify medical terms for patients. In the current implementation, patients have guided, secure and relatively customized access to basic and relevant web information on their diagnoses. Future implementation will attempt to achieve further customization, extensibility and safety features. This paper investigates how ideas presented in an earlier study can be implemented.

Effect of alprazolam on opiate withdrawal: a combined behavioural and microdialysis study

Benzodiazepines are commonly abused concurrently with opioids. The pharmacological rationale for this remains unknown. The present study has addressed behaviourally and neurochemically the action of alprazolam on the naloxone-precipitated morphine withdrawal syndrome in male rats. In naloxone (1 mg kg-1 i.p.)-precipitated morphine withdrawn rats, alprazolam (2.5 mg kg-1 s.c.) reduced the severity of the affective component, as measured by squeal on touch hostility, and the physical sequelae of opioid withdrawal. The microdialysis study in anaesthetized rats identified an increase in noradrenaline levels in hippocampal dialysates in rats undergoing naloxone-precipitated opioid withdrawal. Acute treatment with alprazolam (2.5 mg kg-1 s.c.) 20 min before administration of naloxone prevented the previously identified increase in noradrenaline in hippocampal dialysates. The only observable effect alprazolam induced in non-morphine-dependent rats was a 15% reduction in spontaneous locomotor activity. In conclusion, one interpretation of the data suggests that alprazolam decreases the withdrawal syndrome in rats through dampening down the previously identified hyperactivity of the locus coeruleus.

Providing confusion: the need for education not information in chronic care.

Patient information is one aspect of meeting the needs of health service users; it is meant to empower patients and their carers in making informed decisions and managing their health needs. Mary Dixon-Woods described two types of discourse in patient education: the first is more concerned with making patients comply with their doctors orders and the second is about empowering patients and rejecting direction. This article looks at the aims of the two and shows that neither is capable of supporting highly successful best practice within medicine. Instead, a hybrid set of strategic aims are proposed for patient education created by merging the two discourses in the same way that John Dewey merged the child-centred and child-led schools of thought in education. These hybrid strategic aims for patient education are then used to develop requirements for an information system to support patient education, using a mixture of system centric and user centric approaches.

Genetic Programming within Civil Engineering

Genetic programming is a relatively new method of evolutionary computing with few published applications in civil engineering. This paper both describes and demonstrates how GP can be applied to structural optimisation and design problems to produce results that offer significant improvements over traditional GA based methods. The paper concludes by presenting the direction of the work currently being undertaken at Cardiff University, which includes the conceptual design of frame structures and the visualisation of results using VRML/X3D to produce virtual reality simulations that can be used as a collaborative design environment over the Internet.

The bottom-up approach to defining life: deciphering the functional organization of biological cells via multi-objective representation of biological complexity from molecules to cells

In silico representation of cellular systems needs to represent the adaptive dynamics of biological cells, recognizing a cells multi-objective topology formed by temporally cohesive intracellular structures. The design of these models needs to address the hierarchical and concurrent nature of cellular functions and incorporate the ability to self-organize in response to transitions between healthy and pathological phases, and adapt accordingly. The functions of biological systems are constantly progressing, due to the ever changing demands of their environment. Biological systems meet these demands by pursuing objectives, aided by their constituents, giving rise to biological functions. A biological cell is organized into an objective/task hierarchy. These objective hierarchy corresponds to the nested nature of temporally cohesive structures and representing them will facilitate in studying pleiotropy and polygeny by modeling causalities propagating across multiple interconnected intracellular processes. Although biological adaptations occur in physiological, developmental and reproductive timescales, the paper is focused on adaptations that occur within physiological timescales, where the biomolecular activities contributing to functional organization, play a key role in cellular physiology. The paper proposes a multi-scale and multi-objective modeling approach from the bottom–up by representing temporally cohesive structures for multi-tasking of intracellular processes. Further the paper characterizes the properties and constraints that are consequential to the adaptive dynamics in biological cells.

Mapping the Integrated Care Pathway into BPM for Health Case Management

Teamwork, collaboration and coordination are key aspects of the patient-centric approach taken by modern healthcare. Although many projects have been and are currently being undertaken to improve support for health care professionals, adequate support for teamwork, communication and coordination has yet to be achieved. The delivery of the healthcare service is very challenging as it involves heterogeneous distributed systems, multi-professionals and dependent tasks among each. In addition, the treatment journey of each patient is unique as a decision is usually made according to several constraints related to the patient, medical condition, patient’s choice, available resources and/or doctor’s consultation decision. We believe that, in order to provide the required support, it is necessary to explicitly acknowledge the patient’ s medical state within their treatment journey. This project proposes the use of a Business Process Management (BPM) system that uses associations between patients, health care professionals, and the Integrated Care Pathway (ICP) to provide improved support for healthcare professionals as individuals and members of integrated care teams. Moreover, mapping the ICP into the BPM system will help support the implementation of best practice according to the national guidelines. By leveraging the information contained in these associations, and understanding the patient progress along the dynamic care pathway, this proposal provides tailored context-based actions. This includes automated notifications, alerts, scheduling and timers, as well as supporting treatment continuity and tracking as the patient progresses through their treatment journey. Clinicians’ and developers’ feedback on this proposal has been very positive.