Volume 10, Issue 3, June 2008
ß-endorphin, deltorphin II, [D-Ala2 , Phe4 , Gly5 – ol-enkephalin (DAGO) as well as endomorphin-1 and endomorphin-2 injected intracerebroventricularly (icv.) induced gastroprotective action. It has been raised that endogenous opioids may have a central role in maintaining gastric mucosal integrity. Therefore we aimed to study the role of endogenous opioid system in the gastroprotective action induced by activation of 2- adrenoceptors, nociceptin- and cannabinoid- receptors. Our results suggest that the non-selective opioid receptor antagonist naloxone (27 nmol icv.) and the -opioid receptor antagonist naltrindole (5 nmol icv.) abolished the mucosal protective effect of 2-adrenoceptor agonists clonidine (470 pmol icv.) and rilmenidine (45 pmol icv.), nociceptin (1 nmol icv.) and the cannabinoid receptor agonist anandamide (110 nmol icv.). Based on our findings it can be raised that opioid system besides its well known regulatory functions might be involved in maintenance of gastric mucosal integrity.
KEYWORDS: gastroprotection, opioid system, clonidine, rilmenidine, nociceptin, anandamide, rat
As it is well known opioids are the most powerful drugs used for acute and chronic pain, although, their several serious side effects, such as respiratory depression, mental clouding, constipation, and tolerance dependence producing capacity, as well as large interpatient variability in responses limit their safe everyday use. Furthermore, the treatment of certain types of pain (e.g. neuropathic pain) is not very satisfactorily managed. Consequently, there is a continuous need to find analgesics efficient against chronic neuropathic pain and avoid these side actions and still retain opioid like potency. There are several possible way to find new targets for these purposes. Recently opioid receptors have been identified on peripheral processes of sensory neurons. These findings provide new insights into intrinsic mechanisms of pain control and suggest innovative strategies for developing drugs and alternative approaches to pain treatment. In the effort to discover better analgesic drugs for chronic pain, attention is being paid to specific ion channels at the periphery, include members of transient receptor potential family (TRPV1, capsaicin receptors), as well as P2x receptors, sensitive to purines released from tissue injury. A special tetradotoxin-resistant, voltage dependent type of sodium channel is associated with dorsal root ganglia neurons is blocked by mexiletine, used in chronic pain. A synthetic peptide analogue of marine snail toxin ziconitine blocks N-type calcium channels. GABA and NMDA receptors are also involved in the antinociceptive actions of gabapentin and ketamine, respectively. Furthermore nicotine and analogues (epibatidine) induce analgesia through nicotinic ACh receptors. We studied mostly the peripheral targets of hydrophilic heterocyclic opioids in antinociceptive processes.
Keywords: antinociception, acute and chronic pain, neuropathic pain, opioids, receptors, ionchannels
One of the first neurobiological theories of major depression was the monoamine deficiency hypothesis. The classic monoamine theory of depression suggested that a deficit in monoamine neurotransmitters in the synaptic cleft was the main and primary cause of depression. Recent and newer versions and modifications of the primary classic theory also mainly included this postulate, while other theories of depression preferred departing from the monoamine-based model altogether. Unfortunately, the clear neurobiology of major depression remains an elusive issue, despite intense research. It is clearly held that most, if not all, antidepressant pharmacotherapies treatments produce their therapeutic antidepressant effects, at least in part, by modulating monoamine systems (noradrenergic, serotonergic, and dopaminergic) by a selective or a multi-acting way; however, much less is known about the neurobiological pathology of these monoamine systems in depression. Much of the past 10-15 years of research in the biology of mood disorders has led to considerable evidence in depression implicating multiple system pathology, including abnormalities of monoamine as well as other neurotransmitter systems. These approaches and findings have led researchers to propose broader theories regarding the neurobiology of depression, just like a spreading disorder of specific neuronal networks in the brain. A model for the pathophysiology of depression ill be discussed in the next pages, after describing the main components of depression pathogenesis. Suggestion is that the primary defect emerges in the cross-regulation and vulnerability of special monoaminergic and non-monoaminergic neural networks, which leads to a decrease in the tonic release of neurotransmitters in their projection areas, altering postsynaptic sensitivity, and following, overexaggerated responses to acute increases in the presynaptic firing rate and transmitter release. It is proposed that the primary defect should be involved, in the noradrenergic innervation spreading from the locus coeruleus (LC). Dysregulation of the LC projection activities may lead in turn to malfunction of serotonergic and dopaminergic neurotransmission. Failure of the LC function could explain the basic impairments in the processing of novel information, intensive processing of irrational beliefs, and anxiety. Consecutive deficits in the serotonergic neurotransmission may contribute to the mood changes and reduction in the mesotelencephalic dopaminergic activity to loss of motivation, and anhedonia. Malfunction and dysregulation of CRF and other neuropeptides such as neuropeptide Y, galanin and substance P may reinforce the LC dysfunction and thus further weaken the adaptive ability to stressful stimuli. The new SNRI antidepressants seem to be more superior and effective in the treatment of major depression and in the prophylaxis of recurrent depressive episodes because of their coexistent noradrenergic activity.
Keywords: major depression, locus coeruleus, noradrenaline, serotonine, corticotropin releasing factor, neuropeptid Y, substance P, galanin
Psychopharmacology was born some 50 years ago as a relatively narrow clinical discipline with LSD-25 and chlorpromazine, among a few others, being the early prototypes. In the course of its development, psychopharmacology grew into a wider scientific discipline as psychoactive drugs were assumed to interact with biochemical processes at the synapses to influence transmission of activities among neurons in producing their effects. Thus biochemistry and neuropharmacology have been adopted as collaborative disciplines and this larger field was named neuropsychopharmacology. More recently it has been recognized that, at the clinical level, neuropsychopharmacology has also extensive contact with social issues so that there is an increasing emphasis on translational research in recent announcements from the National Institute of Mental Health in the USA to facilitate and encourage collaboration among clinicians, basic science and social science researchers. To help the process of translational research in mental health, a new organizing principle is proposed based on a novel concept of Psychonucleotides (PNs). There are two types of PNs: Simple PNs (SPN) and Complex ones (CPN) and they are seen as temporary modules mediating meaning between the linguistic and neuronal levels in the brain. As the proposed mediating takes the integrative processes of the whole brain into consideration the development of large scale neuronal theories for translational research should became easier and more comprehensive by going beyond the focus on the cognitive cortex and taking also emotional and social processes into consideration.
Keywords: psychopharmacology, psychonucleotides, translational research, biological bases
Zsuzsa Halmai, Eszter Dömötör , Gabriella Balogh , Andrea Sárosi , Gábor Faludi , Anna Székely
Depression is a frequent, wide spectrum disease causing substantial suffering. Quantitative tools for measuring depression are rather important both at the clinical and non-clinical state. BDI (Beck Depression Inventory) the HADS (Hospital Anxiety and Depression Scale) and the BHS (Beck Hopelessness Scale) are used both in clinical practice and research. Primary aim of these questionnaires is the diagnosis of clinical depression, however, screening for less severe stages of depression, and realization of predisposition to depression is also important. Based on results from recent twin-studies genetic factors of depression are significant. Moreover, discovering genetic risk factors of depression is a challenging task of psychogenetic association studies. Creating new endophenotypes, those units of our phenotypic makeup which can be objectively measured and are linked to certain genetic components, is an important step in completion of this challenge. The primary goal of the present study was to characterize predisposition to depression with endophenotypes suitable for genetic association analysis. To achieve this goal 170 participants filled out the BDI and HADS questionnaires in the first stage of the study (99 were diagnosed with clinical depression, and 71 were healthy adults). Psychometric properties of these questionnaires were assessed, reliability of the Hungarian version of both scales proved to be satisfactory. Using items from these tools we derived a common factor structure in order to create a new, short measure (the DS1K) of the depression construct ready to be used as endophenotype in psychogenetic association studies. Usability of the DS1K was assessed based on data from 144 healthy adults. The measure proved to be highly reliable (Cronbach-alpha = 0.88) and valid (correlation with the BDI and HADS scales were high and significant).
Keywords: depression scale, Beck, HADS, DS1K, psychometric properties, endophenotype
Depressed patients draw small figures in the left upper corner of sheet in House-Tree-Person (H-T-P) Test. This type of drawing rarely was drawn by patients without melancholic complains. In the Crisis Intervention Department at the Budapest Social Center (Hungary), 5 homeless male patients between 42-67 years of ages were found with depressive type of drawing in the H-T-P Test, but without melancholy. One had alcoholic encephalopathy with mild cognitive disorder, four had alcoholic or vascular types of dementia. Three had severe apathy. One was euphoric, undiscriminating with logorhea, but reported depression without sadness in Beck Depression Inventory. One had retarded thinking. Psycho-organic signs were well demonstrated in demented patients’ drawings. Four patients represented human figures without hands, which symbolized helplessness. Apathy frequently was reported to be the only syndrome in psycho-organic, chronic fatigue, burn out syndromes, or even in exhaustive depression and sickness-behaviour, but it could not be classified in ICD-10 or DSM-IV-TR. Apathy, like depression, responded to antidepressive treatments, therefore, this similarity of syndromes could be responsible for our lethargic patients’ depressive type of drawings. Furthermore, clinically abortive depressions perhaps could be demonstrated only by nonverbal drawing test. Psycho-organic and depressive signs of drawings were reported to be independent of each other, therefore, dementia could not cause our patients’ depressive type of drawings. So, H-T-P Drawing Test was a useful nonverbal method of psycho-organic patients’ investigation, which demonstrated depression in patients without verbally manifest melancholic illness.
Keywords: depression, apathy, psychoorganic syndrome, dementia, H-T-P Drawing Test