Clinical Neuroscience

[Antinociception by endogenous ligands at peripheral level]

HORVÁTH Gyöngyi, MÉCS László

MAY 20, 2011

Clinical Neuroscience - 2011;64(05-06)

[It is well known that a multitude of ligands and receptors are involved in the nociceptive system, and some of them increase, while others inhibit the pain sensation both peripherally and centrally. These substances, including neurotransmitters, neuromodulators, hormones, cytokines etc., may modify the activity of nerves involved in the pain pathways. It is also well known that the organism can express very effective antinociception in different circumstances, and during such situations the levels of various endogenous ligands change. Accordingly, a very exciting field of pain research relates to the roles of endogenous ligands. The peripheral action may possibly be extremely important, because low doses of the endogenous ligands may reduce pain without disphoric side-effects, and without the abused potential typical of centrally acting ligands. This review provides a comprehensive overview of the endogenous ligands that can induce antinociception, discusses their effects on different receptors and focuses on their action at peripheral level. We found 17 different endogenous ligands which produced antinociception after their topical administration. The results suggest an important direction for the development of pain strategies that focus on the local administrations of different endogenous ligands.]



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[Neuropsychiatry - in Hungary and other countries]


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[Practical neurology and neuroanatomy Komoly Sámuel, Palkovits Miklós]


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[The role of sleep dynamics and delta homeostasis in cognitive functions]


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Clinical Neuroscience

[Our clinical experience with zonisamide in resistant generalized epilepsy syndromes]

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[Purpose - Zonisamide is licensed in the European Union for adjunctive therapy for partial epilepsy, but its efficacy in generalized epilepsy was less explored. Methods - This prospective observational study included 47 patients (mean age 29 years, range 3-50) with different resistant generalized epilepsy syndromes: idiopathic generalized syndromes (IGE) 15 patients, (juvenile myoclonic epilepsy four, absence epilepsy four, myoclonic absence two, unclassified IGE five), progressive myoclonic epilepsy type 1 (PME1) four, severe myoclonic epilepsy of infancy (SMEI) three, borderline SMEI three, Lennox-Gastaut syndrome/secondary generalized epileptic encephalopties 23 patients. All patients were followed up for at least six months. The mean dose given was 367 mg/day (range 100-600 mg/day), the patients received at least one and no more than two concomitant AE. Response was defined as more than 50% seizure reduction or seizure freedom. Results - The best effect was achieved in PME one, all the patients were responders. Myoclonic seizures were reduced 80%, none of the patients had generalized tonic clonic (GTC) seizures. In two of the four patients all other antiepileptics were tapered of (including piracetam), so they were GTC seizure and almost myoclonia free on zonisamide only. Responder rates were in GEFS ± SME 62.5%, in resistant IGE 62.5%, and in epileptic encephalopathies 33.3% patients. Tolerance after initial efficacy developed in six patients. Adverse effects were mild: weight loss, somnolence and confusion were repeatedly reported. Three patients reported cognitive improvement. Conclusion - Clinical benefit of a broad spectrum antiepileptic zonisamide extends across seizure types, ages and epilepsy syndromes. The efficacy in PME proved to be excellent.]

Clinical Neuroscience

[In memoriam Professor Rozália Kálmánchey (1946-2011)]


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Clinical Neuroscience


KNYIHÁR Erzsébet, CSILLIK Bertalan

[Traditional concept holds that the pain unit consists of three neurons. The first of these, the primary nociceptive neuron, starts with the nociceptors and terminates in the dorsal spinal cord. The second one, called spinothalamic neuron, crosses over in front of the central canal and connects the dorsal horn with the thalamus. The third one, called thalamo- cortical neuron, terminates in the “pain centres” of the cerebral cortex. While this simplistic scheme is useful for didactic purposes, the actual situation is more complex. First, in the periphery it is only nociception that occurs, while pain is restricted to the levels of thalamus and the cortex. Second, pain results from interactions of excitation and inhibition, from divergence and convergence and from attention and distraction, in a diffuse and plastic system, characteristic for all levels of organization. This study describes the major cytochemical markers of primary nociceptive neurons followed by the presentation of recent data on the functional anatomy of nociception and pain, with special focus on the intrinsic antinociceptive system and the role of nitrogen oxide, opiate receptors, nociceptin and nocistatin. In addition to the classic intrinsic antinociceptive centres such as the periaqueductal gray matter and the raphe nuclei, roles of several recently discovered members of the antinociceptive system are discussed, such as the pretectal nucleus, the reticular formation, the nucleus accumbens, the nucleus tractus solitarii, the amygdala and the reticular thalamic nucleus, this latter being a coincidence detector and a centre for attention and distraction. The localisation of cortical centres involved in the generation of pain are presented based on the results of studies using imaging techniques, and the structural basis of corticospinal modulation is also outlined. Seven levels of nociception and pain are highlighted where pharmacological intervention may be successful, 1. the peripheral nociceptor, 2. the spinal ganglion, 3. the multisynaptic system of the dorsal horn, 4. the modulatory system of the brain stem, 5. the antinociceptive system, 6. the multisynaptic system of the thalamus, and 7. the cortical evaluating and localisation system that is also responsible for descending (inhibiting) control. The many levels of nociception and pain opens new ways both for pharmacological research and the general practitioner aiming to alleviate pain.]

Lege Artis Medicinae

[The pain-trigger role of cytokines in the nervous system – the direct analgesic effect of anti-cytokine therapy ]


[Nociceptive, neuropathic and central me­chanisms are involved in the perception, transmission and processing of chronic pain and shaping of cerebral pain image. Alar­mins – molecules alarming defence and signing the presence of pathogens and tissue damage - trigger a series of pathogenic events resulting in inflammatory pain stimuli. Proinflammatory cytokines play a determining role in the pain perception at the level of the nervous system. Continuous inflammatory stimuli while sensitizing the periferic and central neurons activate the pain-related cerebral areas and develop the complex pain image, the pain matrix. Ce­reb­ral functional connections are operating in networks and can be visualized by functional MRI. Cytokines activate the neurons directly or indirectly by other neuromediators. Cytokine receptors are expressed on no­ciceptors and even on higher-level neurons and on various non-neural cells, such as microglia and astrocytes. The most ubiquitous cytokines are the Tumour Necrosis Factor and Interleukin 6 in the nervous sys­tem. The signaling pathways are the Nuclear Factor κB and the Janus-kinase enzyme system. The proinflammatory cytokines and the Janus-kinase are therefore primary therapeutic targets. Anti-cytokine biologicals and small molecular kinase inhibitors decrease the pain and improve functional activity in rheumatoid arthritis. Decrease of pain was more pronounced than expected only from the decrease of the clinical biomarkers of inflammation. The early and ra­pid painkiller effect of targeted biological and chemical-biological response modifiers is attributed to their direct analgesic effect on the brain.]

Clinical Neuroscience

[Evidence for the expression of parathyroid hormone 2 receptor in the human brainstem (in English language)]

BAGÓ G. Attila, PALKOVITS Miklós, USDIN B. Ted, SERESS László, DOBOLYI Árpád

[Background and purpose - The parathyroid hormone 2 receptor (PTH2R) is a G protein coupled receptor. Pharmacological and anatomical evidence suggests that the recently identified tuberoinfundibular peptide of 39 residues is, and parathyroid hormone and parathyroid hormone-related peptide are not, its endogenous ligand. Initial functional studies suggest that the PTH2R is involved in the regulation of viscerosensory information processing. As a first step towards clinical applications, herein we describe the presence of the PTH2R in the human brainstem. Material and methods - Total RNA was isolated from postmortem human cortical and brainstem samples for RT-PCR. Good quality RNA, as assessed on formaldehyde gel, was reverse transcribed. The combined cDNA products were used as template in PCR reactions with primer pairs specific for the human PTH2R. In addition, PTH2R immunolabelling was performed on free floating sections of the human medulla oblongata using fluorescent amplification immunochemistry. Results - Specific bands in the RT-PCR experiments and sequencing of PCR products demonstrated the expression of PTH2R mRNA in the human brainstem. A high density of PTH2R-immunoreactive fibers was found in brain regions of the medulla oblongata including the nucleus of the solitary tract, the spinal trigeminal nucleus, and the dorsal reticular nucleus of the medulla. Conclusion - Independent demonstration of the presence of PTH2R mRNA and immunoreactivity supports the specific expression of the PTH2R in the human brainstem. The distribution of PTH2R-immunoreactive fibers in viscerosensory brain regions is similar to that reported in mouse and rat suggesting a similar role of the PTH2R in human as in rodents. This finding will have important implications when experimental data obtained on the function of the TIP39-PTH2R neuromodulator system in rodents are to be utilized in human.]

Clinical Neuroscience

[Antinociceptive effect of vinpocetine - a comprehensive survey]


[Blockade of retrograde transport of nerve growth factor (NGF) in a peripheral sensory nerve is known to induce transganglionic degenerative atrophy (TDA) of central sensory terminals in the upper dorsal horn of the related, ipsilateral segments(s) of the spinal cord. The ensuing temporary blockade of transmission of nociceptive impulses has been utilized in the therapy of intractable pain, using transcutaneous iontophoresis of the microtubule inhibitors vincristin and vinblastin, drugs which inhibit retrograde transport of NGF. Since microtubule inhibition might inhibit (at least theoretically) mitotic processes in general, we sought to find a drug which inhibits retrograde transport of NGF without microtubule inhibition. Vinpocetine, a derivate of vincamine, which does not interfere with microtubular function, was found to inhibit retrograde axoplasmic transport of NGF in peripheral sensory nerves, similarly to vincristin and vinblastin. Blockade of NGF transport is followed by transganglionic degenerative atrophy in the segmentally related, ipsilateral superficial spinal dorsal horn, characterized by depletion of the marker enzymes of nociception, fluoride resistant acid phosphatase (FRAP) and thiamine monophosphatase (TMP) from the Rolando substance and by decrease of the pain-related neuropeptides substance P (SP) and calcitonin gene-related peptide (CGRP) from lamina I-II-III. Based upon these findings, it has been suggested that vinpocetine may result in a locally restricted decrease of nociception. Herewith, the structural and behavioral effects of perineurally administered vinpocetine are discussed. Nociception, induced by intraplantar injection of formalin, was mitigated by perineural application of vinpocetine; also formalin-induced expression of c-fos in the ipsilateral, segmentally related superficial dorsal horn, was prevented by this treatment. Since vinpocetine is not a microtubule inhibitor, its mode of action is enigmatic. It is assumed that the effect of vinpocetine might be related to interaction with membrane-trafficking proteins, such as signalling endosomes and the endocytosis-mediating „pincher” protein, involved in retrograde axoplasmic transport of NGF, or to interaction with glial elements, recently reported to be involved in the modulation of pain in the spinal cord. Based on animal experiments it is assumed that the temporary, locally restricted decrease of nociception, induced by vinpocetine applied via transcutaneous iontophoresis, might open up new avenues in the clinical treatment of intractable pain.]

Lege Artis Medicinae



[The use of opioids to relieve strong, unbearable pain is a method that has been known for thousands of years and is still effective today. In contrast to the earlier view, opioids today are not only given to cancer patients. The application area of morphine derivatives is generally the relief of exceptionally strong pain regardless of the diagnosis, but opiates are undoubtedly most commonly used to treat cancer-related or strong acute pain. Strong pain reducers are used much more in developed countries for the treatment of non-cancer related severe pain refractory to other approaches. Today the use of opiates and their derivatives (fentanyl, oxycodon) for non-cancer related pain relief is recognized by the national health insurance in that it allows general practitioners to prescribe them, upon the recommendation of a neurosurgeon, orthopaedic surgeon, traumatologist or rheumatologist, with a significant 90% subsidy for six months to ensure easy access for patients in severe, refractory pain due to degenerative musculoskelatal diseases (ICD: M47, M48, M16.9, M17.9, M54.4, M51.0, M51.1). The indications of opioid use, however, are not limited to strong nociceptive pain since they are also effective in certain types of peripheral neuropathic pain. In brief, a basic principle of the use of major analgetics is that their indication is primarily based on the intensity of pain and not on the nature of the disease, even though the latter has a major influence on the clinician's strategy of pain relief.]