RESUMEN
BACKGROUND AND PURPOSE: Single-prolonged stress (SPS), a rat model of post-traumatic stress disorder (PTSD), also induces long-lasting hyperalgesia associated with hypocortisolism and elevated nociceptin/orphanin FQ (N/OFQ) levels in serum and CSF. Here, we determined the effect of JTC-801 (N-(4-amino-2-methylquinolin-6-yl)-2-(4-ethylphenoxymethyl) benzamide monohydrochloride), a nociceptin/orphanin FQ peptide (NOP) receptor antagonist, on symptoms of pain and anxiety in rats after SPS exposure, and examined N/OFQ-NOP receptor system changes. EXPERIMENTAL APPROACH: Male Sprague Dawley rats received JTC-801 (6 mg kg(-1) i.p., once daily) during days 7-21 of SPS. The ability of JTC-801 to inhibit N/OFQ-stimulated [(35) S]-GTPγS binding was confirmed in rat brain membranes. Anxiety-like behaviour and pain sensitivity were monitored by changes in elevated plus maze performance and withdrawal responses to thermal and mechanical stimuli. Serum corticosterone and N/OFQ content in CSF, serum and brain tissues were determined by radioimmunoassay; NOP receptor protein and gene expression in amygdala, hippocampus and periaqueductal grey (PAG) were examined by immunoblotting and real-time PCR respectively. KEY RESULTS: JTC-801 treatment reversed SPS-induced mechanical allodynia, thermal hyperalgesia, anxiety-like behaviour and hypocortisolism. Elevated N/OFQ levels in serum, CSF, PAG and hippocampus at day 21 of SPS were blocked by JTC-801; daily JTC-801 treatment also reversed NOP receptor protein and mRNA up-regulation in amygdala and PAG. CONCLUSION AND IMPLICATIONS: JTC-801 reversed SPS-induced anxiety- and pain-like behaviours, and NOP receptor system up-regulation. These findings suggest that N/OFQ plays an important role in hyperalgesia and allodynia maintenance after SPS. NOP receptor antagonists may provide effective treatment for co-morbid PTSD and pain. LINKED ARTICLES: This article is part of a themed section on Opioids: New Pathways to Functional Selectivity. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-2.
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Aminoquinolinas/uso terapéutico , Ansiedad/tratamiento farmacológico , Benzamidas/uso terapéutico , Antagonistas de Narcóticos/uso terapéutico , Dolor/tratamiento farmacológico , Receptores Opioides/metabolismo , Trastornos por Estrés Postraumático/tratamiento farmacológico , Aminoquinolinas/farmacología , Amígdala del Cerebelo/efectos de los fármacos , Amígdala del Cerebelo/metabolismo , Animales , Ansiedad/metabolismo , Benzamidas/farmacología , Modelos Animales de Enfermedad , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Calor , Hiperalgesia/tratamiento farmacológico , Hiperalgesia/metabolismo , Masculino , Antagonistas de Narcóticos/farmacología , Péptidos Opioides/sangre , Péptidos Opioides/líquido cefalorraquídeo , Péptidos Opioides/metabolismo , Dolor/metabolismo , Sustancia Gris Periacueductal/efectos de los fármacos , Sustancia Gris Periacueductal/metabolismo , Ratas Sprague-Dawley , Receptores Opioides/genética , Trastornos por Estrés Postraumático/metabolismo , Receptor de Nociceptina , NociceptinaRESUMEN
Fritless SPE on-line coupled to CE with UV and MS detection (SPE-CE-UV and SPE-CE-MS) was evaluated for the analysis of opioid peptides. A microcartridge of 150 µm id was packed with a C18 sorbent (particle size > 50 µm), which was retained between a short inlet capillary and a separation capillary (50 µm id). Several experimental parameters were optimized by SPE-CE-UV using solutions of dynorphin A (DynA), endomorphin 1 (End1), and methionine-enkephaline (Met). A microcartridge length of 4 mm was selected, sample was loaded for 10 min at 930 mbar and the retained peptides were eluted with 67 nL of an acidic hydro-organic solution. Using SPE-CE-MS, peak area and migration time repeatabilities for the three opioid peptides were 12-27% and 4-5%, respectively. SPE recovery was lower for the less hydrophobic DynA (22%) than for End1 (66%) and Met (78%) and linearity was satisfactory in all cases between 5 and 60 ng/mL. The LODs varied between 0.5 and 1.0 ng/mL which represent an enhancement of two orders of magnitude when compared with CE-MS. Cerebrospinal fluid (CSF) samples spiked with the opioid peptides were analyzed to demonstrate the applicability to biological samples. Peak area and migration time repeatabilities were similar to the standard solutions and the opioid peptides could be detected down to 1.0 ng/mL.
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Electroforesis Capilar/métodos , Espectrometría de Masas/métodos , Péptidos Opioides/líquido cefalorraquídeo , Extracción en Fase Sólida/instrumentación , Extracción en Fase Sólida/métodos , Diseño de Equipo , Humanos , Límite de Detección , Modelos Lineales , Reproducibilidad de los ResultadosRESUMEN
Endogenous opioid peptides enkephalin and dynorphin are major co-transmitters of striatofugal pathways of the basal ganglia. They are involved in the genesis of levodopa-induced dyskinesia and in the modulation of direct and indirect striatal output pathways that are disrupted in Parkinson's disease. One pharmacologic approach is to develop synthetic glycopeptides closely resembling endogenous peptides to restore their normal functions. Glycosylation promotes penetration of the blood-brain barrier. We investigated CNS penetration of the opioid glycopeptide MMP-2200, a mixed δ/µ-agonist based on leu-enkephalin, as measured by in vivo microdialysis and subsequent mass spectrometric analysis in awake, freely moving rats. The glycopeptide (10 mg/kg) reaches the dorsolateral striatum (DLS) rapidly after systemic (i.p.) administration and is stably detectable for the duration of the experiment (80 min). The detected level at the end of the experiment (around 250 pM) is about 10-fold higher than the level of the endogenous leu-enkephalin, measured simultaneously. This is one of the first studies to directly prove that glycosylation of an endogenous opioid peptide leads to excellent blood-brain barrier penetration after systemic injection, and explains robust behavioral effects seen in previous studies by measuring how much glycopeptide reaches the target structure, in this case the DLS.
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Glicopéptidos/líquido cefalorraquídeo , Glicopéptidos/farmacocinética , Péptidos Opioides/líquido cefalorraquídeo , Péptidos Opioides/farmacocinética , Animales , Masculino , Microdiálisis , Ratas , Ratas Sprague-DawleyRESUMEN
Nociceptin/Orphanin FQ (N/OFQ) appears to contribute to the development of morphine tolerance, as blockade of its actions will block or reverse the process. To better understand the contribution of N/OFQ to the development of morphine tolerance, this study examined the effect of chronic morphine treatment on levels of N/OFQ and levels and activity of the N/OFQ peptide (NOP) receptor in spinal cord (SC) from male and female rats. Both male and female Wistar rats showed less responsiveness to morphine after subcutaneous injection of escalating doses of morphine (10, 20, 40, 60 and 80 mg/kg, respectively) twice daily for five consecutive days. Male rats were more tolerant to the antinociceptive actions of morphine than females. The N/OFQ content of SC extracts was higher in females than in males, regardless of treatment; following chronic morphine treatment the difference in N/OFQ levels between males and females was more pronounced. N/OFQ content in cerebrospinal fluid (CSF) was reduced 40% in male and 16% in female rats with chronic morphine exposure, but increased in periaqueductal grey of both sexes. Chronic morphine treatment increased NOP receptor levels 173% in males and 137% in females, while decreasing affinity in both. Chronic morphine increased the efficacy of N/OFQ-stimulated [³5S]GTPγS binding to SC membranes from male rats, consistent with increased receptor levels. Taken together, these findings demonstrate sex differences in N/OFQ-NOP receptor expression and NOP receptor activity following chronic morphine treatment. They also suggest interplay between endogenous N/OFQ and chronic morphine treatment that results in nociceptive modulation.
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Analgésicos Opioides/farmacología , Morfina/farmacología , Péptidos Opioides/fisiología , Médula Espinal/efectos de los fármacos , Animales , Tolerancia a Medicamentos , Femenino , Guanosina 5'-O-(3-Tiotrifosfato)/metabolismo , Cinética , Masculino , Plasticidad Neuronal/efectos de los fármacos , Péptidos Opioides/líquido cefalorraquídeo , Dimensión del Dolor/efectos de los fármacos , Sustancia Gris Periacueductal/metabolismo , Células del Asta Posterior/efectos de los fármacos , Radioinmunoensayo , Ratas , Ratas Wistar , Tiempo de Reacción/efectos de los fármacos , Caracteres Sexuales , NociceptinaRESUMEN
Theoretical and practical aspects of a problem of adaptation to military-professional work are considered. Neurophysiological mechanisms of adaptation of military men to conditions of hot mountain-desert climate are revealed. Condition of the opioidergic system is shown at fighting stress, and its role in occurrence of illness of adaptation is described. Influence of extreme factors of a hot climate mountain-desert district is accompanied by infringement of interhemisphere mutual relations and psychosomatic changes.
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Adaptación Fisiológica , Adaptación Psicológica , Medicina Militar , Clima Desértico , Electroencefalografía , Humanos , Masculino , Péptidos Opioides/líquido cefalorraquídeo , Estrés Psicológico/fisiopatologíaRESUMEN
Expression and release of nociceptin/orphanin FQ (N/OFQ) are elevated in the substantia nigra reticulata of 6-hydroxydopamine-hemilesioned rats, suggesting a pathogenic role for N/OFQ in Parkinson's disease. In this study, we investigated whether elevation of N/OFQ expression in 6-hydroxydopamine-hemilesioned rats selectively occurs in substantia nigra and whether hypomotility following acute haloperidol administration is accompanied by a rise in nigral N/OFQ levels. Moreover, to prove a link between N/OFQ and idiopathic Parkinson's disease in humans, we measured N/OFQ levels in the cerebrospinal fluid of parkinsonian patients undergoing surgery for deep brain stimulation. In situ hybridization demonstrated that dopamine depletion was associated with increase of N/OFQ expression in substantia nigra (compacta +160%, reticulata +105%) and subthalamic nucleus (+45%), as well as reduction in caudate putamen (-20%). No change was observed in globus pallidus, nucleus accumbens, thalamus, and motor cortex. Microdialysis coupled to the bar test allowed to demonstrate that acute administration of haloperidol (0.8 and 3 mg/kg) increased nigral N/OFQ levels (maximally of +47% and +53%, respectively) in parallel with akinesia. A correlation with preclinical studies was found by analyzing N/OFQ levels in humans. Indeed, N/OFQ levels were found to be approximately 3.5-fold elevated in the cerebrospinal fluid of parkinsonian patients (148 fmol/ml) compared with nonparkinsonian neurologic controls (41 fmol/ml). These data represent the first clinical evidence linking N/OFQ to idiopathic Parkinson's disease in humans. They strengthen the pathogenic role of N/OFQ in the modulation of parkinsonism across species and provide a rationale for developing N/OFQ receptor antagonists as antiparkinsonian drugs.
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Encéfalo/metabolismo , Regulación de la Expresión Génica/fisiología , Péptidos Opioides/metabolismo , Enfermedad de Parkinson/patología , Adrenérgicos/toxicidad , Adulto , Anciano , Anciano de 80 o más Años , Análisis de Varianza , Animales , Antipsicóticos/farmacología , Conducta Animal/efectos de los fármacos , Encéfalo/efectos de los fármacos , Modelos Animales de Enfermedad , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Haloperidol/uso terapéutico , Humanos , Masculino , Microdiálisis/métodos , Persona de Mediana Edad , Péptidos Opioides/líquido cefalorraquídeo , Péptidos Opioides/genética , Oxidopamina/toxicidad , Enfermedad de Parkinson/líquido cefalorraquídeo , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/etiología , Ratas , Ratas Sprague-Dawley , Adulto Joven , NociceptinaRESUMEN
Single neonatal treatment (imprinting) with 20 microg benzpyrene results in significant increase of the brain serotonin level in the striatum, while in the other four regions (cortex, brainstem, hippocampus, hypothalamus) when measured in adults can be detected. The nocistatin level of cerebrospinal fluid (CSF) significantly decreases, while there is no change in the plasma nocistatin level. The results call attention to the comprehensive imprinting effect of benzpyrene, which in addition to receptorial, hormonal and sexual behavioral disturbances causes lasting differences in the brain serotonin and nocistatin levels, probably influencing mood and pain tolerance.
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Envejecimiento/metabolismo , Benzopirenos/farmacología , Encéfalo/efectos de los fármacos , Péptidos Opioides/metabolismo , Serotonina/metabolismo , Envejecimiento/sangre , Envejecimiento/líquido cefalorraquídeo , Animales , Animales Recién Nacidos , Ganglios Basales/efectos de los fármacos , Ganglios Basales/metabolismo , Encéfalo/crecimiento & desarrollo , Encéfalo/metabolismo , Tronco Encefálico/efectos de los fármacos , Tronco Encefálico/metabolismo , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/metabolismo , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Hipotálamo/efectos de los fármacos , Hipotálamo/metabolismo , Masculino , Péptidos Opioides/sangre , Péptidos Opioides/líquido cefalorraquídeo , Ratas , Ratas WistarRESUMEN
Neuropeptides nociceptin/orphanin FQ (N/OFQ) and nocistatin (NST) are related to pain modulation. The amounts of these peptides and their precursor protein, prepronociceptin (ppN/OFQ) in the brain, spinal cord and serum samples of rats with partial sciatic nerve ligation (PSNL) were compared with those in naïve rats using radioimmunoassay (RIA). There was a significant rise in the levels of ppN/OFQ, N/OFQ and NST in the brains of PSNL rats. Their spinal cords showed significantly increased ppN/OFQ and NST levels but no change in N/OFQ levels. The PSNL rats also had increased serum NST (statistically significant) and N/OFQ (statistically insignificant) with decreased ppN/OFQ suggesting important roles of these peptides in neuropathic pain mechanism.
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Péptidos Opioides/metabolismo , Dolor/metabolismo , Precursores de Proteínas/metabolismo , Receptores Opioides/metabolismo , Animales , Anticuerpos/inmunología , Encéfalo/metabolismo , Hiperalgesia/metabolismo , Masculino , Modelos Animales , Péptidos Opioides/sangre , Péptidos Opioides/líquido cefalorraquídeo , Dimensión del Dolor , Precursores de Proteínas/sangre , Precursores de Proteínas/líquido cefalorraquídeo , Radioinmunoensayo , Ratas , Ratas Sprague-Dawley , Receptores Opioides/sangre , Nervio Ciático/metabolismo , Nervio Ciático/cirugía , Médula Espinal/metabolismo , NociceptinaRESUMEN
Weanling female rats were stressed (by water and food deprivation for two days) and three months later the following indexes were studied: 5-HT and 5-HIAA levels in five brain regions, blood plasma and cerebrospinal fluid (CSF), sexual activity and nocistatin level of the plasma and CSF. The 5-HIAA content of hypothalamus and brainstem was significantly decreased (in the brainstem with one third) and in the striatum significantly increased. Plasma nocistatin level was significantly increased. Meyerson index and lordosis quotient were similar to control, but the estrus frequency almost doubled in the stressed animals. Much more defense reactions were observed in the stressed females during trials of mating. The results demonstrate that, 1) the perinatal period is not only sensitive to the remote-effects of stress but later could also be stress-sensitive critical periods, and 2) the continuously differentiating (e.g. bone marrow) cells are sensitive to late imprinting by stress, as well as to the brain and the sexual system.
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Química Encefálica , Encéfalo/metabolismo , Serotonina/metabolismo , Conducta Sexual Animal , Estrés Fisiológico/psicología , Animales , Femenino , Ácido Hidroxiindolacético/análisis , Ácido Hidroxiindolacético/sangre , Ácido Hidroxiindolacético/líquido cefalorraquídeo , Masculino , Péptidos Opioides/sangre , Péptidos Opioides/líquido cefalorraquídeo , Ratas , Ratas Wistar , Serotonina/análisis , Serotonina/sangre , Serotonina/líquido cefalorraquídeo , DesteteRESUMEN
The neuropeptide nociceptin/orphanin FQ (N/OFQ) is the endogenous ligand for the opioid-like receptor ORL-1 and is thought to be involved in pain transmission and modulation. Human studies have not yet defined its role in pain patients. The aims of this study were 1) to verify the presence of N/OFQ in the cerebrospinal fluid (CSF) of human controls and patients with chronic noncancer pain, including those treated with intrathecally administered morphine, and 2) to determine whether pain or treatment with long-term intrathecal morphine influences its levels. The CSF of 27 patients (nine controls and 18 with chronic noncancer pain, of whom 12 were treated chronically with intrathecally administered morphine and six were opioid naïve) was analyzed, blindly, with radioimmunoassay methods. N/OFQ was detected in all patients. Mean CSF concentrations were lowest in the morphine-treated group and highest in the untreated chronic pain patients (12.06+/-1.19 and 57.41+/-10.06 fmol/ml, respectively), and the difference between the morphine-treated group and controls was statistically significant (44.72+/-13.56 fmol/ml, P<0.05). The presence of N/OFQ peptide in human CSF may correlate with biological activities that are influenced by different pain states and long-term intrathecal-morphine treatment. Further studies should verify whether the determination of this peptide CSF level may provide information on opioid treatment efficacy and on the presence of opioid tolerance.
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Morfina/administración & dosificación , Péptidos Opioides/líquido cefalorraquídeo , Dimensión del Dolor/efectos de los fármacos , Dolor/líquido cefalorraquídeo , Dolor/tratamiento farmacológico , Anciano , Analgésicos Opioides/administración & dosificación , Biomarcadores/líquido cefalorraquídeo , Enfermedad Crónica , Femenino , Humanos , Inyecciones Espinales , Masculino , Persona de Mediana Edad , Dolor/diagnóstico , Dimensión del Dolor/métodos , NociceptinaRESUMEN
Nocistatin (NST) and nociceptin/orphanin FQ (NCP) are two important bio-peptides derived from the precursor protein prepronociceptin (ppNCP), involved in several central nervous system (CNS) functions including pain transmission. Since the actual form of human NST in CNS is not fully characterized, we studied the structure of NST from human brain tissue and cerebrospinal fluid (CSF) samples. NST and NCP were isolated from human brain and CSF samples by affinity chromatography combined with HPLC. Mass spectrometry was used for the identification and characterization of the peptides. The total NST immunoreactivity was detected as 11.5+/-2.3 pmol/g tissue for the brain and 0.44 pmol/ml for the pooled CSF sample after the HPLC purification by radioimmunoassay. The presence of two different forms of mature nocistatin (NST-17 and NST-30) and a possible N-terminal methionine cleaved NST-29 were confirmed by both radioimmunoassay and mass spectrometry. Affinity chromatography, HPLC and mass spectrometry methods used in this study were highly sensitive and suitable for identification of actual chemical structures and quantification of very small amounts of peptides in biological samples. The present findings may help further for search for new treatment of neuropathic pain, which is often poorly managed by current therapies.
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Química Encefálica , Neuropéptidos/aislamiento & purificación , Péptidos Opioides/líquido cefalorraquídeo , Péptidos Opioides/aislamiento & purificación , Precursores de Proteínas/líquido cefalorraquídeo , Precursores de Proteínas/aislamiento & purificación , Secuencia de Aminoácidos , Animales , Cromatografía de Afinidad , Cromatografía Líquida de Alta Presión , Humanos , Metionina/química , Datos de Secuencia Molecular , Neuropéptidos/líquido cefalorraquídeo , Neuropéptidos/química , Neuropéptidos/metabolismo , Péptidos Opioides/antagonistas & inhibidores , Péptidos Opioides/metabolismo , Péptidos Opioides/fisiología , Dolor/metabolismo , Dolor/fisiopatología , Isoformas de Proteínas/antagonistas & inhibidores , Isoformas de Proteínas/líquido cefalorraquídeo , Isoformas de Proteínas/aislamiento & purificación , Isoformas de Proteínas/fisiología , Precursores de Proteínas/metabolismo , Radioinmunoensayo , Receptores Opioides/aislamiento & purificación , Receptores Opioides/metabolismo , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción , NociceptinaRESUMEN
Fluid percussion brain injury elevates the cerebrospinal fluid (CSF) concentration of the opioid nociceptin/orphanin FQ (N/OFQ), which potentiates vasoconstriction to the prostaglandins U 46619, a thromboxane A(2) mimic, and prostaglandin (PG)F(2a). This study investigated the role of the extracellular signal-regulated kinase (ERK), p38, and c-Jun N-terminal kinase (JNK) isoforms of mitogen activated protein kinase (MAPK) in potentiated prostaglandin vasoconstriction after brain injury and the relationship of brain injury induced release of N/OFQ to MAPK. Pial artery diameter was measured with a video microscaler by observation through a glass coverslip cranial window placed in the parietal cortex of newborn pigs. Brain injury potentiated U 46619 induced pial artery vasoconstriction but U 0126 and SB 203580 (10(-6) and 10(-5) M, respectively) (ERK and p38 MAPK inhibitors) blocked the potentiation. In contrast, administration of SP 600125 (10(-6) and 10(-5) M) (JNK MAPK inhibitor) only attenuated brain injury induced U 46619 potentiation and such responses were significantly different than that in the presence of either U 0126 or SB 203580 after FPI. Co-administration of N/OFQ (10(-10) M), the CSF concentration observed after brain injury, with U 46619 or PGF(2a) under non brain injury conditions potentiated prostaglandin vasoconstriction but U 0126 and SB 203580 blocked such potentiation. Administration of SP 600125 modestly attenuated prostaglandin potentiation by N/OFQ. These data show that activation of ERK and p38 primarily contribute to potentiation of prostaglandin constriction after brain injury. These data suggest that N/OFQ differentially activates ERK, p38, and JNK MAPK to contribute to potentiated prostaglandin vasoconstriction after fluid percussion brain injury.
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Lesiones Encefálicas/fisiopatología , Circulación Cerebrovascular/fisiología , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Péptidos Opioides/farmacología , Prostaglandinas/farmacología , Vasoconstricción/fisiología , Animales , Lesiones Encefálicas/enzimología , Circulación Cerebrovascular/efectos de los fármacos , Modelos Animales de Enfermedad , Interacciones Farmacológicas , Activación Enzimática , Inhibidores Enzimáticos/farmacología , Quinasas MAP Reguladas por Señal Extracelular/antagonistas & inhibidores , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Femenino , Proteínas Quinasas JNK Activadas por Mitógenos/antagonistas & inhibidores , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Masculino , Proteínas Quinasas Activadas por Mitógenos/antagonistas & inhibidores , Péptidos Opioides/líquido cefalorraquídeo , Porcinos , Vasoconstricción/efectos de los fármacos , Proteínas Quinasas p38 Activadas por Mitógenos/antagonistas & inhibidores , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , NociceptinaRESUMEN
The presence of the opioids, beta-endorphin, met-enkephalin, and endomorphin, and of corticotropin-releasing factor (CRF) and the CRF family member, urocortin (Ucn), is described in cerebrospinal fluid-contacting neurons in the brain of the amphibian, Xenopus laevis.
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Hormona Liberadora de Corticotropina/líquido cefalorraquídeo , Neuronas/metabolismo , Péptidos Opioides/líquido cefalorraquídeo , Xenopus laevis/líquido cefalorraquídeo , Animales , UrocortinasRESUMEN
BACKGROUND: The mechanism(s) of nociceptive dysfunction and potential roles of opioid neurotransmitters are unresolved in the chronic pain syndromes of fibromyalgia and chronic low back pain. METHODS: History and physical examinations, tender point examinations, and questionnaires were used to identify 14 fibromyalgia, 10 chronic low back pain and 6 normal control subjects. Lumbar punctures were performed. Met-enkephalin-Arg6-Phe7 (MEAP) and nociceptin immunoreactive materials were measured in the cerebrospinal fluid by radioimmunoassays. RESULTS: Fibromyalgia (117.6 pg/ml; 85.9 to 149.4; mean, 95% C.I.; p = 0.009) and low back pain (92.3 pg/ml; 56.9 to 127.7; p = 0.049) groups had significantly higher MEAP than the normal control group (35.7 pg/ml; 15.0 to 56.5). MEAP was inversely correlated to systemic pain thresholds. Nociceptin was not different between groups. Systemic Complaints questionnaire responses were significantly ranked as fibromyalgia > back pain > normal. SF-36 domains demonstrated severe disability for the low back pain group, intermediate results in fibromyalgia, and high function in the normal group. CONCLUSIONS: Fibromyalgia was distinguished by higher cerebrospinal fluid MEAP, systemic complaints, and manual tender points; intermediate SF-36 scores; and lower pain thresholds compared to the low back pain and normal groups. MEAP and systemic pain thresholds were inversely correlated in low back pain subjects. Central nervous system opioid dysfunction may contribute to pain in fibromyalgia.
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Encefalina Metionina/análogos & derivados , Fibromialgia/líquido cefalorraquídeo , Dolor de la Región Lumbar/líquido cefalorraquídeo , Péptidos Opioides/líquido cefalorraquídeo , Adulto , Anciano , Enfermedad Crónica , Encefalina Metionina/líquido cefalorraquídeo , Síndrome de Fatiga Crónica/complicaciones , Femenino , Fibromialgia/complicaciones , Humanos , Masculino , Persona de Mediana Edad , Dolor/fisiopatología , Dimensión del Dolor , NociceptinaRESUMEN
STUDY DESIGN: Cerebrospinal fluid biomarkers were evaluated in a setup using established pig models to mimic clinical disc herniation. OBJECTIVES: To investigate biomarkers for nerve tissue injury, inflammation, and pain in cerebrospinal fluid after mechanical compression and/or nucleus pulposus application to spinal nerve roots. SUMMARY OF BACKGROUND DATA: The association between mechanical compression, biochemical effects of nucleus pulposus, and nerve root injury in degenerative disc disorders is incompletely investigated. METHODS: The unilateral S1 nerve root was exposed in 20 pigs. The animals were divided into four groups (n = 5 each): 1) slow-onset mechanical compression with an ameroid constrictor; 2) autologous nucleus pulposus application; 3) mechanical compression plus nucleus pulposus; and 4) sham operation. After 1 week, 6 mL of cerebrospinal fluid was collected, and four structural nerve proteins, neurofilaments, S-100, glial fibrillary acidic protein, neuron-specific enolase, the proinflammatory cytokine interleukin-8, the neurotransmitter nociceptin, and substance P endopeptidase activity were analyzed using immunoassays. RESULTS: The concentration of neurofilament was increased in the mechanical compression group (17.0 microg/L +/- 5.0) and in the mechanical compression plus nucleus pulposus group (19.8 +/- 12.1 microg/L) compared with the sham group (0.9 +/- 0.9 microg/L) and the nucleus pulposus group (0.4 +/- 0.1 microg/L) (P < 0.01 for both). The concentration of nociceptin was increased significantly in the mechanical compression group (24.0 +/- 8.6 fm/mL) and in the mechanical compression plus nucleus pulposus group (31.2 +/- 6.6 fm/mL) compared with the sham group (7.0 +/- 1.3 fm/mL) (P < 0.05 and P < 0.01, respectively). A correlation was found between concentrations of neurofilament and nociceptin (r = 0.50, P < 0.05). There were no intergroup differences regarding glial fibrillary acidic protein, neuron-specific enolase, S-100, interleukin-8, or substance P endopeptidase activity. CONCLUSIONS: The present study demonstrates increased concentrations of neurofilament and nociceptin in cerebrospinal fluid after nerve root compression. A simultaneous application of nucleus pulposus did not increase the response.
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Proteínas del Líquido Cefalorraquídeo/análisis , Disco Intervertebral/química , Proteínas del Tejido Nervioso/líquido cefalorraquídeo , Neuralgia/líquido cefalorraquídeo , Raíces Nerviosas Espinales/lesiones , Extractos de Tejidos/toxicidad , Animales , Biomarcadores , Proteína Ácida Fibrilar de la Glía/líquido cefalorraquídeo , Interleucina-8/líquido cefalorraquídeo , Vértebras Lumbares , Metaloendopeptidasas/líquido cefalorraquídeo , Neuralgia/etiología , Proteínas de Neurofilamentos/líquido cefalorraquídeo , Péptidos Opioides/líquido cefalorraquídeo , Fosfopiruvato Hidratasa/líquido cefalorraquídeo , Presión/efectos adversos , Proteínas S100/líquido cefalorraquídeo , Raíces Nerviosas Espinales/efectos de los fármacos , Estrés Mecánico , Porcinos , Extractos de Tejidos/farmacología , NociceptinaRESUMEN
The discovery of the endogenous opioid peptide systems and their subsequent identification in human cerebrospinal fluid near 30 years ago triggered an intensive research to evaluate the function of these compounds in the clinical perspective. However, for this purpose it was necessary to develop reliable techniques with high sensitivity and reproducibility. Furthermore, it was necessary to assess the chemical nature of the opioid activity present in CSF. Therefore, research on opioid peptides in CSF have to a considerable extent been directed to attempts to characterize the peptide activity present in this fluid in order to identify suitable markers of activity in any particular opioid peptide system. In the clinic these markers have been used in attempts to correlate alterations in peptide levels to various neurological diseases. This article reviews the past and ongoing research on opioid peptide systems in CSF from human with particular emphasis on their relevance in the clinical perspective.
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Péptidos Opioides/líquido cefalorraquídeo , Animales , Cromatografía , Enfermedad , Femenino , Humanos , Masculino , Espectrometría de Masas , Neuropéptidos/química , Péptidos/química , Embarazo , Radioinmunoensayo , Receptores Opioides/metabolismo , Sensibilidad y EspecificidadRESUMEN
Four weeks old (weanling) female rats were treated with the tricyclic antidepressant and histamine/serotonin receptor blocker mianserin for studying its faulty hormonal imprinting effect. Measurements were done four months later. Brain serotonin levels significantly decreased in four regions (hippocampus, hypothalamus, striatum and brainstem), without any change in the cortex. Sexual activity of the treated and control rats was similar. Cerebrospinal fluid nocistatin level was one magnitude higher in the treated rats, than in the controls. The density of uterine estrogen receptors was significantly reduced, while binding capacity of glucocorticoid receptors of liver and thymus remained at control level. The results call attention to the possibility of 1. a broad spectrum imprinting at the time of weaning by a receptor level acting non-hormone molecule 2. imprinting of the brain in a non-neonatal period of life and 3. a very durable (lifelong?) effect of the late imprinting with an antidepressant.
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Química Encefálica/efectos de los fármacos , Impronta Psicológica/efectos de los fármacos , Mianserina/farmacología , Péptidos Opioides/líquido cefalorraquídeo , Antagonistas de la Serotonina/farmacología , Serotonina/análisis , Animales , Dexametasona/metabolismo , Femenino , Ratas , Ratas Wistar , Receptores de Estrógenos/análisis , Conducta Sexual Animal/efectos de los fármacos , DesteteRESUMEN
In earlier experiments endorphin treatment of newborn rats caused the decrease of brain serotonin content, increasing aggressivity, enhanced sexual activity of females and changes in the binding capacity of uterine estrogen receptors at adult age, however nociceptin content of the cerebrospinal fluid was not changed. In the present experiment neonatal treatment of male and female rats was done with a single dose of 3 microg beta-endorphin and in five months old rats the level of nociceptin antagonist nocistatin was determined by radioimmunoassay in the cerebrospinal fluid. In both genders the amount of nocistatin was one magnitude higher in the endorphin treated groups. There was also a significant difference between the male and female nocistatin level in the treated and non-treated groups alike, with the advantage of females. The results call attention to the possibility of influencing pain-tolerance for life, by the pain-provoked endorphin levels during delivery.
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Péptidos Opioides/líquido cefalorraquídeo , betaendorfina/farmacología , Animales , Animales Recién Nacidos , Femenino , Masculino , Radioinmunoensayo , Ratas , Ratas WistarRESUMEN
A single dose (3 microg) beta-endorphin was administered to newborn female and male rats (hormonal imprinting). In adult age (at 5 months) sexual behavior, steroid hormone binding capacity and brain serotonin content was studied. Females' sexual activity (lordosis quotient) significantly decreased and more animals protested against mounting (ratio of kicking and crying 21/24 vs. 8/24; p < 0.001). Males' sexual activity did not change, however more males were aggressive (4/10 vs. 1/10). Uterine estrogen receptor density significantly increased and affinity decreased. There was no change in the binding capacity of thymic glucocorticoid receptors. In the brain, five regions were studied for serotonin content. There was a gender difference in serotonin level and the intragroup differences were also high. In the endorphin treated males the serotonin level was significantly lower than in the controls. In the endorphin treated females the intragroup scattering has been significantly reduced. Nociceptin content of the cerebrospinal fluid was not changed. The experiments call attention to the possibility of adjustment of sexual and behavioral sphere by the individually different endorphin surge during labor.
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Animales Recién Nacidos/psicología , Química Encefálica/efectos de los fármacos , Impronta Psicológica/efectos de los fármacos , Serotonina/metabolismo , Conducta Sexual Animal/efectos de los fármacos , betaendorfina/farmacología , Agresión/efectos de los fármacos , Animales , Cromatografía Líquida de Alta Presión , Citosol/efectos de los fármacos , Citosol/metabolismo , Dexametasona/metabolismo , Estradiol/metabolismo , Femenino , Cinética , Masculino , Péptidos Opioides/líquido cefalorraquídeo , Ratas , Ratas Wistar , Receptores de Estrógenos/metabolismo , Receptores de Glucocorticoides/metabolismo , Caracteres Sexuales , Timo/efectos de los fármacos , Timo/crecimiento & desarrollo , Timo/metabolismo , Útero/efectos de los fármacos , Útero/crecimiento & desarrollo , Útero/metabolismo , NociceptinaRESUMEN
Previous studies have observed that the recently described endogenous opioid, nociceptin/orphanin FQ (NOC/oFQ), contributes to impairment of N-methyl-D-aspartate (NMDA)-induced cerebrovasodilation following fluid percussion brain injury (FPI) via a cyclooxygenase (COX)-dependent generation of superoxide anion (O(2)(-)). This study was designed to investigate the relationship between NOC/oFQ, another opioid, dynorphin, and activation of the COX-2 isoform of the enzyme in such impaired dilation to NMDA after FPI in piglets equipped with a closed cranial window. Superoxide dismutase (SOD)-inhibitable nitroblue tetrazolium (NBT) reduction was determined as an index of O(-)(2) generation. Under non-brain injury conditions, NOC/oFQ (10(-10) M), the CSF concentration observed after FPI, increased CSF dynorphin, while the NOC/oFQ antagonist [F/G] NOC/oFQ (1-13) NH(2) attenuated the stimulated release of dynorphin following FPI (34 +/- 3 and 97 +/- 6 vs. 36 +/- 3 and 68 +/- 8 pg/mol for CSF dynorphin before and after FPI in untreated and NOC/oFQ antagonist-pretreated animals). FPI increased SOD-inhibitable NBT reduction, but pretreatment with norbinaltorphimine, a dynorphin antagonist, or NS398, a COX-2 inhibitor, blunted such reduction (1 +/- 1 vs. 19 +/- 3 vs. 4 +/- 1 vs. 4 +/- 1 pmol/mm(2) for control, FPI, FPI-norbinaltorphimine and FPI-NS398, respectively). Under non-brain injury conditions, dynorphin, in a concentration observed in CSF after FPI, also increased SOD-inhibitable NBT reduction, which was blunted by NS398. NMDA-induced pial artery dilation was reversed to vasoconstriction following FPI, but pretreatment with norbinaltorphimine or NS398 partially protected such responses (9 +/- 1 and 16 +/- 1, control; - 8 +/- 1 and - 13 +/- 2, FPI; 6 +/- 1 and 12 +/- 1% FPI-norbinaltorphimine for NMDA 10(-8), 10(-6) M, respectively). These data show that NOC/oFQ modulates the CSF release of dynorphin after FPI. These data also show that dynorphin contributes to O(2)(-) generation after FPI via COX-2 activation. These data additionally indicate that dynorphin and COX-2 activation contribute to impairment of NMDA pial artery dilation after FPI. Finally, these data suggest that NOC/oFQ impairs NMDA dilation postinsult via the sequential release of dynorphin, activation of COX-2, and generation of O(2)(-).