RESUMO
Osteoarthritis (OA) is the most common joint disease, characterized by matrix degradation and changes in chondrocyte morphology and metabolism. Literature reported that electromagnetic fields (EMFs) can produce benefits in OA patients, even if EMFs mechanism of action is debated. Human osteoarthritic chondrocytes isolated from femoral heads were cultured in vitro in bidimensional (2-D) flasks and in three-dimensional (3-D) alginate beads to mimic closely cartilage environment in vivo. Cells were exposed 30 min/day for 2 weeks to extremely low-frequency electromagnetic field (ELF) with fixed frequency (100 Hz) and to therapeutic application of musically modulated electromagnetic field (TAMMEF) with variable frequencies, intensities, and waveforms. Cell viability was measured at days 7 and 14, while healthy-cell density, heavily vacuolized (hv) cell density, and cluster density were measured by light microscopy only for 3-D cultures after treatments. Cell morphology was observed for 2-D and 3-D cultures by transmission electron microscopy (TEM). Chondrocyte exposure to TAMMEF enhances cell viability at days 7 and 14 compared to ELF. Light microscopy analysis showed that TAMMEF enhances healthy-cell density, reduces hv-cell density and clustering, compared to ELF. Furthermore, TEM analysis showed different morphology for 2-D (fibroblast-like) and 3-D (rounded shape) cultures, confirming light microscopy results. In conclusion, EMFs are effective and safe for OA chondrocytes. TAMMEF can positively interfere with OA chondrocytes representing an innovative non-pharmacological approach to treat OA.
Assuntos
Condrócitos/efeitos da radiação , Campos Eletromagnéticos , Osteoartrite/terapia , Idoso , Idoso de 80 Anos ou mais , Sobrevivência Celular/efeitos da radiação , Células Cultivadas , Feminino , Humanos , Masculino , Microscopia Eletrônica de Transmissão , Pessoa de Meia-Idade , MúsicaRESUMO
BACKGROUND: The hypoglossal canal is a dual bone canal at the cranial base near the occipital condyles. The filaments of the hypoglossal nerve pass through the canal. It also transmits the meningeal branch of the ascending pharyngeal artery, the venous plexus and meningeal branches of the hypoglossal nerve. The hypoglossal nerve innervates all the intrinsic and extrinsic muscles of the tongue except the palatoglossal and is fundamental in physiological functions as phonation and deglutition. A surgical approach to the canal requires knowledge of the main morphometric data by neurosurgeons. METHODS: The present study was carried out on 50 adult dried skulls: 31 males: age range 18-85 years; 19 females: age range 26-79 years. The skulls came from the ''Leonetto Comparini'' Anatomical Museum. The skulls belonged to people from Siena (Italy) and its surroundings (1882-1932) and, therefore, of European ethnicity. The present study reports (a) the osteological variations in hypoglossal canal (b) the morphometry of hypoglossal canal and its relationship with occipital condyles. One skull had both the right and left hypoglossal canals occluded and, therefore, could not be evaluated. None of the skulls had undergone surgery. RESULTS: We found a double canal in 16% of cases, unilaterally and bilaterally in 2% of cases. The mean length of the right and left hypoglossal canals was 8.46 mm. The mean diameter of the intracranial orifice and extracranial orifice of the right and left hypoglossal canals was 6.12 ± 1426 mm, and 6.39 ± 1495 mm. The mean distance from the intracranial end of the hypoglossal canal to the anterior and posterior ends of occipital condyles was 10,76 mm and 10,81 mm. The mean distance from the intracranial end of the hypoglossal canal to the inferior end of the occipital condyles was 7,65 mm. CONCLUSIONS: The study on the hypoglossal canal adds new osteological and morphometric data to the previous literature, mostly based on studies conducted on different ethnic groups.The data presented is compatible with neuroradiological studies and it can be useful for radiologists and neurosurgeons in planning procedures such as transcondilar surgery. The last purpose of the study is to build an Italian anatomical data base of the dimensions of the hypoglossal canal in dried skulls..
Assuntos
Nervo Hipoglosso , Osso Occipital , Masculino , Adulto , Feminino , Humanos , Adolescente , Adulto Jovem , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Cadáver , Osso Occipital/anatomia & histologia , Osso Occipital/cirurgia , Nervo Hipoglosso/anatomia & histologia , Coração , ItáliaRESUMO
Previous evidence demonstrates that low dose morphine systemic administration induces acute thermal hyperalgesia in normal mice through microOR stimulation of the inositol signaling pathway. We investigated the site of action of morphine and the mechanism of action of microOR activation by morphine to NMDA receptor as it relates to acute thermal hyperalgesia. Our experiments show that acute thermal hyperalgesia is blocked in periaqueductal gray with the microOR antagonist CTOP, the NMDA antagonist MK801 and the protein kinase C inhibitor chelerythrine. Therefore, a site of action of systemically administered morphine low dose on acute thermal hyperalgesic response appears to be located at the periaqueductal gray. At this supraspinal site, microOR stimulation by systemically morphine low dose administration leads to an increased phosphorylation of specific subunit of NMDA receptor. Our experiments show that the phosphorylation of subunit 1 of NMDA receptor parallels the acute thermal hyperalgesia suggesting a role for this subunit in morphine-induced hyperalgesia. Protein kinase C appears to be the key element that links microOR activation by morphine administration to mice with the recruitment of the NMDA/glutamatergic system involved in the thermal hyperalgesic response.
Assuntos
Hiperalgesia/induzido quimicamente , Hiperalgesia/patologia , Morfina , Substância Cinzenta Periaquedutal/fisiologia , Receptores de N-Metil-D-Aspartato/fisiologia , Receptores Opioides mu/fisiologia , Alcaloides/administração & dosagem , Análise de Variância , Animais , Comportamento Animal/efeitos dos fármacos , Benzofenantridinas/administração & dosagem , Maleato de Dizocilpina/administração & dosagem , Relação Dose-Resposta a Droga , Inibidores Enzimáticos , Antagonistas de Aminoácidos Excitatórios/administração & dosagem , Hiperalgesia/prevenção & controle , Masculino , Camundongos , Atividade Motora/efeitos dos fármacos , Medição da Dor/métodos , Substância Cinzenta Periaquedutal/efeitos dos fármacos , Desempenho Psicomotor/efeitos dos fármacos , Tempo de Reação/efeitos dos fármacos , Somatostatina/administração & dosagem , Somatostatina/análogos & derivadosRESUMO
Morphine, the most used compound among narcotic analgesics, has been shown to be endogenously present in different mammalian/invertebrate normal tissues. In this study, we used mice that cannot make dopamine due to a genetic deletion of tyrosine hydroxylase specifically in dopaminergic neurons, to test the hypothesis that endogenous dopamine is necessary to endogenous morphine formation in vivo in mammalian brain. When dopamine was lacking in brain neurons, endogenous morphine was missing in brain mouse whereas it could be detected in brain from wild type rodent at a picogram range. Our data prove for the first time that endogenous dopamine is necessary to endogenous morphine formation in normal mammalian brain. Morphine synthesis appears to be originated from dopamine through L-tyrosine in normal brain tissue. Morphine synthesis is not considered to occur inside the same neuron in normal tissue; released dopamine might be transported into morphinergic neuron and further transformed into morphine. A physiological role for endogenous morphine is suggested considering that dopamine could modulate thermal threshold through endogenous morphine formation in vivo. Thus, dopamine and endogenous opiates/opioid peptides may be interconnected in the physiological processes; yet, endogenous morphine may represent a basic link of this chain.
Assuntos
Encéfalo/metabolismo , Dopamina/deficiência , Morfina/metabolismo , Peptídeos Opioides/biossíntese , Animais , Regulação da Temperatura Corporal/fisiologia , Encéfalo/anatomia & histologia , Dopamina/biossíntese , Camundongos , Camundongos Knockout , Limiar Sensorial/fisiologia , Sensação Térmica/fisiologia , Tirosina/metabolismo , Tirosina 3-Mono-Oxigenase/genéticaRESUMO
The distribution of morphine-containing cells in the central nervous system, adrenal gland, and its presence in blood may serve to demonstrate that this signal molecule can act as a hormone besides its role in cell-to-cell signaling within the brain. This speculative review is the result of a literature evaluation with an emphasis on studies from our laboratory. Opioid peptides and opiate alkaloids have been found to influence cardiac and vascular function. They have also been reported to promote ischemic preconditioning protection in the heart. Given the presence of morphine and the novel mu(3) opiate receptor on vascular endothelial cells, including cardiac and vascular endothelial cells in the median eminence, it would appear that endogenous opiate alkaloids are involved in modulating cardiac function, possible at the hormonal level. This peripheral target tissue, via nitric oxide coupling to mu opiate receptors, may serve to down regulate the excitability of this tissue given the heart's high performance state as compared to that of the saphenous vein, a passive resistance conduit. With this in mind, morphine and other endogenous opiate alkaloids may function as a hormone.
Assuntos
Alcaloides/metabolismo , Vasos Sanguíneos/fisiologia , Endorfinas/fisiologia , Hormônios/fisiologia , Animais , HumanosRESUMO
Neuroblastoma (NB) is the most common extracranial solid cancer in childhood and the most common cancer in infancy. Our purpose was to investigate in vitro how cancer cell survival occurs in presence of morphine in undifferentiated and differentiated SHSY-5Y human neuroblastoma cultured cell line. Exposure of differentiated cells to morphine dose-dependently induced apoptosis in these cells through c-Jun N-terminal kinase (JNK)/caspase pathway. Otherwise, morphine induced activation for mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway, caused positive regulation of cell survival in undifferentiated cells. Therefore, cell differentiation state bimodally affects the cellular regulation activity triggered by morphine in isolated cultured neuroblastoma cells raising concerns about the application of morphine to this type of cancer patients.
Assuntos
Analgésicos Opioides/farmacologia , Apoptose/efeitos dos fármacos , Diferenciação Celular , Sobrevivência Celular/efeitos dos fármacos , Morfina/farmacologia , Proteínas Reguladoras de Apoptose/metabolismo , Proteína 11 Semelhante a Bcl-2 , Caspase 3/metabolismo , Linhagem Celular Tumoral , Ativação Enzimática , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Sistema de Sinalização das MAP Quinases , Proteínas de Membrana/metabolismo , Proteínas Quinases Ativadas por Mitógeno/antagonistas & inibidores , Neuroblastoma , Proteínas Proto-Oncogênicas/metabolismoRESUMO
Pleasure is described as a state or feeling of happiness and satisfaction resulting from an experience that one enjoys. We examine the neurobiological factors underlying reward processes and pleasure phenomena. With regard to possible negative effects of pleasure, we focus on addiction and motivational toxicity. Pleasure can serve cognition, productivity and health, but simultaneously promotes addiction and other negative behaviors. It is a complex neurobiological phenomenon, relying on reward circuitry or limbic activity. These processes involve dopaminergic signaling. Moreover, nicotine, cocaine and alcohol appear to exert their pleasure providing action via endogenous morphinergic mechanisms. Natural rewarding activities are necessary for survival and appetitive motivation, usually governing beneficial biological behaviors like eating, sex and reproduction. Social contacts can further facilitate the positive effects exerted by pleasurable experiences. However, artificial stimulants can be detrimental, since flexibility and normal control of behavior are deteriorated. Additionally, addictive drugs are capable of directly acting on reward pathways, now, in part, via endogenous morphine processes.
Assuntos
Álcoois/metabolismo , Cocaína/metabolismo , Modelos Biológicos , Morfina/metabolismo , Nicotina/metabolismo , Recompensa , Transdução de Sinais , Animais , HumanosRESUMO
Systemic administration of morphine induced a hyperalgesic response in the hot plate test, at an extremely low dose (1-10 microg/kg). We have examined in vivo whether morphine, at an extremely low dose, induces acute central hypernociception following activation of the opioid receptor-mediated PLC/PKC inositol-lipid signaling pathway. The PLC inhibitor U73122 and the PKC blocker, calphostin C, dose dependently prevented the thermal hypernociception induced by morphine. This effect was also prevented by pretreatment with aODN against PLCbeta3 at 2 nmol/mouse and PKCgamma at 2-3 nmol/mouse. Low dose morphine hyperalgesia was dose dependently reversed by selective NMDA antagonist MK801 and ketamine. This study demonstrates the presence of a nociceptive PLCbeta3/PKCgamma/NMDA pathway stimulated by low concentrations of morphine, through muOR1 receptor, in mouse brain. This signaling pathway appears to play an opposing role in morphine analgesia. When mice were treated with a morphine analgesic dose (7 mg/kg), the downregulation of PLCbeta3 or PKCgamma at the same aODN doses used for the prevention of the hyperalgesic effect induced, respectively, a 46% and 67% potentiation in analgesic response. Experimental and clinical studies suggest that opioid may activate pronociceptive systems, leading to pain hypersensitivity and short-term tolerance, a phenomenon encountered in postoperative pain management by acute opioid administration. The clinical management of pain by morphine may be revisited in light of the identification of the signaling molecules of the hyperalgesic pathway.
Assuntos
Analgésicos Opioides , Temperatura Alta , Hiperalgesia/induzido quimicamente , Morfina , Transdução de Sinais , Analgesia , Analgésicos Opioides/administração & dosagem , Analgésicos Opioides/farmacologia , Animais , Comportamento Animal/efeitos dos fármacos , AMP Cíclico/metabolismo , Diglicerídeos/metabolismo , Relação Dose-Resposta a Droga , Regulação para Baixo , Inibidores Enzimáticos/farmacologia , Antagonistas de Aminoácidos Excitatórios/administração & dosagem , Antagonistas de Aminoácidos Excitatórios/farmacologia , Hiperalgesia/fisiopatologia , Hiperalgesia/prevenção & controle , Immunoblotting , Isoenzimas/metabolismo , Masculino , Camundongos , Morfina/administração & dosagem , Morfina/farmacologia , Nociceptores/efeitos dos fármacos , Fosfolipase C beta , Proteína Quinase C/antagonistas & inibidores , Proteína Quinase C/metabolismo , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Fosfolipases Tipo C/antagonistas & inibidores , Fosfolipases Tipo C/metabolismoRESUMO
Endogenous morphine is present in the mammalian brain as determined by gas chromatography/mass spectrometry. The criteria essential for satisfying the definition of morphine as a neurotransmitter are examined. The detection of endogenous morphine-like compounds inside brain neurons by immunocytochemistry and the Ca(+) dependent release of endogenous morphine from rat brain slices provide evidence for its transmitter status. Indirect evidence that endogenous morphine modulates thermonociception and weakens memory through mu opioid receptors again supports a neurotransmitter role for this chemical messenger. Evidence has been found for its endogenous synthesis in animal tissues as well. These findings indicate that endogenous morphine might function as neuromodulator/neurotransmitter agent in the CNS.
Assuntos
Química Encefálica , Sistema Nervoso Central/química , Morfina/análise , Animais , Humanos , Mamíferos , Memória/fisiologia , Morfina/metabolismo , Dor/fisiopatologia , Receptores Opioides mu/fisiologia , Estresse PsicológicoRESUMO
Nitric oxide (NO) signalling is at the forefront of intense research interest because its many effects remain controversial and seemingly contradictory. This paper examines its role as a potential mediator of pain and tolerance. Within this context discussion covers endogenous morphine, documenting its ability to be made in animal tissues, including nervous tissue, and in diverse animal phyla. Supporting morphine as an endogenous signalling molecule is the presence of the newly cloned mu3 opiate receptor subtype found in animal (including human) immune, vascular and neural tissues, which is coupled to NO release. Importantly, this mu opiate receptor subtype is morphine-selective and opioid peptide-insensitive, further highlighting the presence of morphinergic signalling coupled to NO release. These findings provide novel insights into pain and tolerance as morphinergic signalling exhibits many similarities with NO actions. Taken together, a select morphinergic signalling system utilising NO opens the gate for the development of novel pharmaceuticals and/or the use of old pharmaceuticals in new ways.
Assuntos
Dependência de Morfina/metabolismo , Morfina/metabolismo , Dor/metabolismo , Analgésicos/farmacologia , Analgésicos/uso terapêutico , Analgésicos Opioides/uso terapêutico , Animais , Sequência de Bases , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , AMP Cíclico/metabolismo , GMP Cíclico/metabolismo , Diabetes Mellitus/metabolismo , Tolerância a Medicamentos , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Humanos , Injeções Intraventriculares , Dados de Sequência Molecular , Morfina/administração & dosagem , Morfina/uso terapêutico , Dependência de Morfina/prevenção & controle , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase/antagonistas & inibidores , Óxido Nítrico Sintase/metabolismo , Dor/tratamento farmacológico , Dor/psicologia , Receptores Opioides mu/genética , Receptores Opioides mu/metabolismo , Transdução de SinaisRESUMO
BACKGROUND: Morphine is the most used compound among narcotic analgesics. Apart from its presence in the poppy plant, morphine has been shown to be endogenously present in different tissues of mammals and lower animals. MATERIAL/METHODS: The presence of endogenous morphine and codeine was investigated by Gas Chromatography/ Mass Spectrometry (GC/MS) in the brain of non human primate. The release of endogenous morphine from monkey brain slices was studied in vitro in the presence of high potassium concentrations with and without calcium in the medium. RESULTS: Endogenous morphine, and its direct precursor codeine, was for the first time detected by GC/MS in the brain of non human primate. High potassium concentrations depolarized neurons releasing endogenous morphine twofold above basal line levels in a calcium dependent mechanism. CONCLUSIONS: This finding confirms the presence of the endogenous alkaloid throughout the phylogenesis of the nerve system of mammals and lower animals and indicates that endogenous morphine might function as a neuromodulator/neurotransmitter agent in the central nervous system (CNS) of non human primates.
Assuntos
Química Encefálica , Cercopithecus/metabolismo , Codeína/análise , Morfina/análise , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Química Encefálica/efeitos dos fármacos , Codeína/metabolismo , Codeína/farmacologia , Cromatografia Gasosa-Espectrometria de Massas , Masculino , Morfina/metabolismo , Morfina/farmacologiaRESUMO
BACKGROUND: Currently, complementary and alternative medicine (CAM) are experiencing growing popularity, especially in former industrialized countries. However, most of the underlying physiological and molecular mechanisms as well as participating biological structures are still speculative. Specific and non-specific effects may play a role in CAM. Moreover, trust, belief, and expectation may be of importance, pointing towards common central nervous system (CNS) pathways involved in CAM. MATERIAL/METHODS: Four CAM approaches (acupuncture, meditation, music therapy, and massage therapy) were examined with regard to the CNS activity pattern involved. CNS commonalities between different approaches were investigated. RESULTS: Frontal/prefrontal and limbic brain structures play a role in CAM. Particularly, left-anterior regions of the brain and reward or motivation circuitry constituents are involved, indicating positive affect and emotion-related memory processing--accompanied by endocrinologic and autonomic functions--as crucial components of CAM effects. Thus, trust and belief in a therapist or positive therapy expectations seem to be important. However, besides common non-specific or subjective effects, specific (objective) physiological components also exist. CONCLUSIONS: Non-specific CNS commonalities are involved in various CAM therapies. Different therapeutic approaches physiologically overlap in the brain. However, molecular correspondents of the detected CNS analogies still have to be specified. In particular, fast acting autoregulatory signaling molecules presumably play a role. These may also be involved in the placebo response.
Assuntos
Terapias Complementares , Sistema Límbico/efeitos dos fármacos , Morfina/farmacologia , Acupuntura , Animais , Humanos , Meditação , Morfina/metabolismo , MusicoterapiaRESUMO
BACKGROUND: We have identified a novel mu opiate receptor, p3, which is expressed in several human tissues, is selective for opiate alkaloids, insensitive to opioid peptides, and also is coupled to constitutive nitric oxide release. We, and others, have also demonstrated the presence of opiate alkaloids as endogenous substances in various nerve tissues taken from mammals, man and invertebrates. MATERIAL/METHODS: Morphine isolation and identification was achieved by high pressure liquid chromatography coupled to electrochemical detection. This material was finally identified by nano-electrospray ionization quadruple time-of-flight tandem mass spectrometry (Q-TOF MS/MS). Morphine's ability to release nitric oxide from limbic tissues was determined in real-time via an amperometric probe. RESULTS: We demonstrate the presence of morphine in rat brain amygdala at 12.7 +/- 5.4 ng/g wet tissue. Morphine was able to stimulate the release of nitric oxide from hippocampus and amygdalar tissues in a naloxone and L-NAME sensitive manner. Furthermore, rat chow, incubation medium etc, did not contain morphine, eliminating the possibility of contamination. CONCLUSION: This finding provides evidence that morphine biosynthesis occurs in mammalian neural tissues. It also demonstrates that morphine releases nitric oxide in limbic tissues. Given the limbic system involvement in modulating emotion, including experiences related to pain perception, it appears that morphine is involved with this activity.
Assuntos
Tonsila do Cerebelo/química , Morfina/análise , Óxido Nítrico/biossíntese , Receptores Opioides mu/fisiologia , Tonsila do Cerebelo/efeitos dos fármacos , Tonsila do Cerebelo/metabolismo , Animais , Hipocampo/metabolismo , Morfina/metabolismo , Morfina/farmacologia , Ratos , Ratos Sprague-DawleyRESUMO
Memory and the processes of learning in mammals are well known to be affected by opioid agonists such as morphine, which has been proven to interfere and cause amnesia. The presence of endogenous morphine has been demonstrated in various tissues from mammals to invertebrates. In this study, we have investigated the effects caused by in-vivo immunodepletion of endogenous morphine on working memory under different experimental conditions. When mice were submitted to fasting, a stress condition, acquisition and consolidation of memory were significantly impaired compared to controls. This was demonstrated by a decrease in entry latency into the dark room in the retention session of the passive avoidance test. This effect was significantly reversed to baseline values when endogenous morphine was depleted from the extracellular brain space. These findings support a role for endogenous morphine in weakening memory processes under stress conditions.