RESUMEN
BACKGROUND: Self-inflicted injury, including cutting or burning, is the most frequent reason for psychiatric visits to medical emergency departments. This behavior, particularly when there is no apparent suicidal intent, is poorly understood from both biological and clinical perspectives. OBJECTIVE: To examine the role of endogenous opioids and monoamine neurotransmitters in non-suicidal self-injury (NSSI). METHODS: We compared cerebrospinal fluid (CSF) levels of endogenous opioids, 5 hydroxyindolacetic acid (5-HIAA) and homovanillic acid (HVA) in individuals with a history of repetitive non-suicidal self-injury with a diagnostically-matched group of individuals who had never engaged in non-suicidal self-injury. History of suicidal behavior, demographic background and psychopathology was assessed. All patients were diagnosed with a Cluster B personality disorder (i.e. borderline, antisocial, narcissistic or histrionic) (N=29) and had a history of at least one suicide attempt. Fourteen participants had a history of repeated non-suicidal self-injurious behavior (NSSI) in adulthood and 15 did not (no NSSI). RESULTS: The NSSI group had significantly lower levels of CSF beta-endorphin and met-enkephalin when compared with the non-NSSI group. CSF dynorphin, HVA and 5-HIAA levels did not differ. Severity of depression, hopelessness and overall psychopathology was greater in the NSSI group. CONCLUSION: beta-endorphin and met-enkephalin, opioids acting upon receptors involved in mediating stress-induced and physical pain analgesia respectively, are implicated in NSSI. Serotonergic and dopaminergic dysfunctions do not appear to be related to NSSI. Based on our findings, we propose a model of non-suicidal self-injury. Our results suggest that drugs acting on the opioid system warrant exploration as pharmacological treatments for NSSI.
Asunto(s)
Dinorfinas/líquido cefalorraquídeo , Encefalina Metionina/líquido cefalorraquídeo , Ácido Homovanílico/síntesis química , Ácido Hidroxiindolacético/líquido cefalorraquídeo , Trastornos de la Personalidad/líquido cefalorraquídeo , Conducta Autodestructiva/líquido cefalorraquídeo , Intento de Suicidio/psicología , betaendorfina/líquido cefalorraquídeo , Adolescente , Adulto , Anciano , Nivel de Alerta/fisiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Trastornos de la Personalidad/psicología , Valores de Referencia , Conducta Autodestructiva/psicología , Adulto JovenRESUMEN
The diversity of peptide ligands for a particular receptor may provide a greater dynamic range of functional responses, while maintaining selectivity in receptor activation. Dynorphin A (Dyn A), and dynorphin B (Dyn B) are endogenous opioid peptides that activate the kappa-opioid receptor (KOR). Here, we characterized interactions of big dynorphin (Big Dyn), a 32-amino acid prodynorphin-derived peptide consisting of Dyn A and Dyn B, with human KOR, mu- (hMOR) and delta- (hDOR) opioid receptors and opioid receptor-like receptor 1 (hORL1) expressed in cells transfected with respective cDNA. Big Dyn and Dyn A demonstrated roughly similar affinity for binding to hKOR that was higher than that of Dyn B. Dyn A was more selective for hKOR over hMOR, hDOR and hORL1 than Big Dyn, while Dyn B demonstrated low selectivity. In contrast, Big Dyn activated G proteins through KOR with much greater potency, efficacy and selectivity than other dynorphins. There was no correlation between the rank order of the potency for the KOR-mediated activation of G proteins and the binding affinity of dynorphins for KOR. The rank of the selectivity for the activation of G proteins through hKOR and of the binding to this receptor also differed. Immunoreactive Big Dyn was detected using the combination of radioimmunoassay (RIA) and HPLC in the human nucleus accumbens, caudate nucleus, hippocampus and cerebrospinal fluid (CSF) with the ratio of Big Dyn and Dyn B being approximately 1:3. The presence in the brain implies that Big Dyn, along with other dynorphins, is processed from prodynorphin and secreted from neurons. Collectively, the high potency and efficacy and the relative abundance suggest that Big Dyn may play a role in the KOR-mediated activation of G proteins.
Asunto(s)
Unión Competitiva/fisiología , Sistema Nervioso Central/metabolismo , Dinorfinas/líquido cefalorraquídeo , Receptores Opioides kappa/metabolismo , Animales , Unión Competitiva/efectos de los fármacos , Sistema Nervioso Central/efectos de los fármacos , Líquido Cefalorraquídeo/metabolismo , Dinorfinas/química , Dinorfinas/genética , Endorfinas/líquido cefalorraquídeo , Endorfinas/química , Endorfinas/genética , Guanosina 5'-O-(3-Tiotrifosfato)/metabolismo , Humanos , Ligandos , Ratones , Ratones Noqueados , Vías Nerviosas/efectos de los fármacos , Vías Nerviosas/metabolismo , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Dolor/genética , Dolor/metabolismo , Dolor/fisiopatología , Radioinmunoensayo , Ensayo de Unión Radioligante , Receptores Opioides/efectos de los fármacos , Receptores Opioides/metabolismo , Receptores Opioides delta/efectos de los fármacos , Receptores Opioides delta/metabolismo , Receptores Opioides kappa/efectos de los fármacos , Receptores Opioides mu/efectos de los fármacos , Receptores Opioides mu/metabolismo , Receptor de NociceptinaRESUMEN
Recent studies suggest that the endogenous opioid peptide, dynorphin, is an important mediator of progesterone negative feedback on GnRH pulse frequency in the ewe. These experiments tested this hypothesis by examining the effects of progesterone on dynorphin A concentrations in cerebrospinal fluid (CSF) collected from the third ventricle and expression of preprodynorphin (PPD) mRNA in hypothalamic nuclei. CSF was collected every 10 min for 5 h in three groups of ewes: 1) ovary-intact ewes during the luteal phase (d 6-7 of estrous cycle); 2) ewes 6-7 d after ovariectomy (OVX); and 3) OVX ewes treated for 6-7 d with implants that produced luteal-phase progesterone levels. Diencephalic tissue from these ewes was then collected and processed for in situ hybridization using an ovine cDNA probe against PPD. Progesterone treatment increased dynorphin A concentrations in CSF over that observed in untreated OVX ewes; CSF dynorphin A concentrations in ovary-intact ewes were midway between the other groups. OVX significantly decreased the number of PPD mRNA-expressing cells in the preoptic area (POA), anterior hypothalamic area (AHA), and arcuate nucleus (ARC), with no change seen in any other PPD-expressing nuclei. Progesterone treatment of OVX ewes restored PPD expression in the POA and AHA to levels seen in luteal-phase animals but had no effect on PPD expression in the ARC. These results are consistent with the hypothesis that progesterone acts via dynorphin neurons to inhibit pulsatile GnRH secretion and point to dynorphin neurons in the POA, AHA, and ARC as potential mediators of this action during the luteal phase.
Asunto(s)
Dinorfinas/líquido cefalorraquídeo , Dinorfinas/genética , Hipotálamo/metabolismo , Progesterona/fisiología , Precursores de Proteínas/genética , ARN Mensajero/análisis , Animales , Femenino , Ovariectomía , Progesterona/sangre , OvinosRESUMEN
Our study addressed the hypothesis that spinal release of endogenous opioids underlies Delta9-tetrahydrocannabinol (Delta9-THC)-induced antinociception in Freund's adjuvant-induced arthritic and nonarthritic rats. The paw-pressure test was used to assess the antinociceptive effects of Delta9-THC versus those of morphine, and opioid and cannabinoid receptor-selective antagonists were used to characterize the involved receptors. Cerebrospinal fluid was collected after Delta9-THC injection (i.p.) for the measurement of endogenous opioid peptides. Our results indicate that morphine or Delta9-THC is equally potent and efficacious in both nonarthritic and arthritic rats. Delta9-THC-induced antinociception is attenuated by the kappa opioid receptor antagonist, nor-binaltorphimine, in arthritic rats only. Delta9-THC induces increased immunoreactive dynorphin A (idyn A) levels in nonarthritic rats while decreasing idyn A in arthritic rats. We hypothesize that the elevated idyn A level in arthritic rats contributes to hyperalgesia by interaction with N-methyl-D-aspartate receptors, and that Delta9-THC induces antinociception by decreasing idyn A release.
Asunto(s)
Artritis Experimental/prevención & control , Dronabinol/farmacología , Naltrexona/análogos & derivados , Dolor/fisiopatología , Animales , Artritis Experimental/inducido químicamente , Artritis Experimental/fisiopatología , Antagonistas de Receptores de Cannabinoides , Relación Dosis-Respuesta a Droga , Dronabinol/líquido cefalorraquídeo , Dronabinol/uso terapéutico , Dinorfinas/líquido cefalorraquídeo , Encefalina Leucina/líquido cefalorraquídeo , Encefalina Metionina/líquido cefalorraquídeo , Adyuvante de Freund/administración & dosificación , Inyecciones Intradérmicas , Inyecciones Intraperitoneales , Masculino , Morfina/antagonistas & inhibidores , Morfina/farmacología , Mycobacterium/inmunología , Naloxona/farmacología , Naltrexona/farmacología , Antagonistas de Narcóticos , Dolor/tratamiento farmacológico , Dimensión del Dolor/efectos de los fármacos , Piperidinas/farmacología , Pirazoles/farmacología , Ratas , Ratas Sprague-Dawley , Receptor Cannabinoide CB1/antagonistas & inhibidores , Receptor Cannabinoide CB1/uso terapéutico , Receptores Opioides/clasificación , Receptores Opioides/uso terapéutico , RimonabantRESUMEN
Dynorphin A(1-13), a tridecapeptide of the endogenous opioid peptides, has modest effects in reducing mild opiate withdrawal in humans. Previous studies revealed that dynorphin also potentiates the analgesic effect of morphine in morphine-tolerant rats and mice. The therapeutic potential of dynorphin A(1-13) is limited due to extensive metabolism by human metabolic enzymes resulting in an in vivo half-life of less than one minute. Chemical modifications of dynorphin A(1-13), such as N-methylation of Tyr1 and amidation of the C-terminus have been shown to be effective in protecting against the proteolytic enzymes in human plasma. This article is a general review of the metabolism of dynorphin A(1-13) in human plasma and CSF.
Asunto(s)
Dinorfinas/metabolismo , Fragmentos de Péptidos/metabolismo , Animales , Barrera Hematoencefálica , Dinorfinas/sangre , Dinorfinas/líquido cefalorraquídeo , Humanos , Fragmentos de Péptidos/sangre , Fragmentos de Péptidos/líquido cefalorraquídeoRESUMEN
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)(-).
Asunto(s)
Lesiones Encefálicas/fisiopatología , Dinorfinas/metabolismo , Isoenzimas/metabolismo , Naltrexona/análogos & derivados , Péptidos Opioides/metabolismo , Prostaglandina-Endoperóxido Sintasas/metabolismo , Vasodilatación/efectos de los fármacos , Animales , Animales Recién Nacidos , Lesiones Encefálicas/enzimología , Ciclooxigenasa 2 , Dinorfinas/antagonistas & inhibidores , Dinorfinas/líquido cefalorraquídeo , Dinorfinas/farmacología , Activación Enzimática , Femenino , Ácido Glutámico/farmacología , Indometacina/farmacología , Isoenzimas/antagonistas & inhibidores , Masculino , N-Metilaspartato/farmacología , Naltrexona/farmacología , Nitrobencenos/farmacología , Péptidos Opioides/líquido cefalorraquídeo , Piamadre/irrigación sanguínea , Sulfonamidas/farmacología , Superóxidos/metabolismo , Porcinos , NociceptinaRESUMEN
Intrathecal infusion of the neuropeptide FF analogue, [D-Tyr1, (NMe)Phe3]neuropeptide FF (1DMe; 0.1 microm-0.1 mm) in anaesthetized rats produced a concentration-dependent decrease in the spinal outflow of dynorphin A (1-8)-like material, which persisted for at least 90 min after treatment with 10 microm-0.1 mm of the compound. Co-administration of d-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP; 1 microm) to block spinal micro-opioid receptors did not modify this effect, whereas naltrindole (10 microm) totally prevented it and nor-binaltorphimine (10 microm) reduced the post-effect. These data suggest that 1DMe triggers the release of endogenous opioids that stimulate mainly delta-opioid receptors, and secondarily kappa-opioid receptors, thereby exerting a negative influence on dynorphin A (1-8)-like material outflow. Because dynorphin has pronociceptive properties, such a decrease in spinal dynorphin A (1-8)-like material release might underlie the long-lasting antinociceptive effects of intrathecally administered neuropeptide FF and analogues.
Asunto(s)
Dinorfinas/líquido cefalorraquídeo , Naltrexona/análogos & derivados , Oligopéptidos/administración & dosificación , Fragmentos de Péptidos/líquido cefalorraquídeo , Somatostatina/análogos & derivados , Médula Espinal/efectos de los fármacos , Animales , Relación Dosis-Respuesta a Droga , Dinorfinas/metabolismo , Inyecciones Espinales , Masculino , Modelos Animales , Naltrexona/administración & dosificación , Antagonistas de Narcóticos/administración & dosificación , Fragmentos de Péptidos/metabolismo , Perfusión , Radioinmunoensayo , Ratas , Ratas Sprague-Dawley , Receptores Opioides delta/efectos de los fármacos , Receptores Opioides kappa/efectos de los fármacos , Receptores Opioides mu/antagonistas & inhibidores , Somatostatina/administración & dosificación , Médula Espinal/metabolismoRESUMEN
OBJECTIVE: To explore the modulating effects of extradural injection of Mailuoning on analgesic function. METHODS: Twenty patients of lumbar intervertebral disk prolapse were treated by extradural injection of Mailuoning, the spontaneous release of dynorphin A (Dyn-A) in cerebrospinal fluid (CSF) before and after treatment were measured and compared with that of the 20 cases in the control group to determine the therapeutic effect of Mailuoning. RESULTS: After treatment, the concentration of Dyn-A in CSF in the treated group increased remarkably, but displayed no significant difference to normal healthy group (P > 0.05), while that in the control group there was significant difference between them (P < 0.01). CONCLUSION: Mailuoning has the modulatory effect on analgesia function and lumbar intervertral disk prolapse was treated by means of its Dyn-A elevating action.
Asunto(s)
Analgésicos/administración & dosificación , Medicamentos Herbarios Chinos/administración & dosificación , Dinorfinas/líquido cefalorraquídeo , Desplazamiento del Disco Intervertebral/tratamiento farmacológico , Vértebras Lumbares , Fitoterapia , Adulto , Anciano , Femenino , Humanos , Inyecciones Epidurales , Desplazamiento del Disco Intervertebral/líquido cefalorraquídeo , Masculino , Persona de Mediana EdadRESUMEN
Previous research in this laboratory concerning delta9-tetrahydrocannabinol-induced spinal antinociception indicated the critical role of dynorphin A-(1-17) in spinal antinociception following acute intrathecal (i.t.) administration. In the present study, tolerance development to delta9-tetrahydrocannabinol-induced spinal antinociception attenuated delta9-tetrahydrocannabinol-induced modulation of immunoreactive dynorphin A-(1-17). These data indicate that at lower doses of drug, desensitization of the cannabinoid receptor inhibits stimulation of downstream dynorphinergic neurons. However, at higher doses of drug, desensitization is overcome and spinal dynorphin A concentrations are increased by delta9-tetrahydrocannabinol. Antinociception in the absence of elevated dynorphin A-(1-17) levels in the tolerant rat suggests that factors other than the attenuated dynorphin release are components of antinociception in the tolerant state. The shift from the critical role of dynorphin A in cannabinoid antinociception vs. that in the non-tolerant state may indicate tolerance also at the kappa-opioid receptor, a role as yet undetermined.
Asunto(s)
Analgésicos/farmacología , Dronabinol/farmacología , Dinorfinas/metabolismo , Analgésicos/administración & dosificación , Animales , Relación Dosis-Respuesta a Droga , Dronabinol/administración & dosificación , Tolerancia a Medicamentos , Dinorfinas/líquido cefalorraquídeo , Inyecciones Espinales , Masculino , Radioinmunoensayo , Ratas , Ratas Sprague-Dawley , Tiempo de Reacción/efectos de los fármacos , Receptores Opioides kappa/efectos de los fármacos , Sustancia P/metabolismoRESUMEN
Intrathecal administration of anandamide, delta9-tetrahydrocannabinol (THC) and (-)-3-[2-hydroxy-4-(1,1-dimethyheptyl)ptyl)phenyl]-4-(3-hydr oxypropyl)-cicloexan-1-ol (CP55,940) induced spinal antinociception accompanied by differential kappa-opioid receptor involvement and dynorphin A peptide release. Antinociception using the tail-flick test was induced by the classical cannabinoid THC and was blocked totally by 17,17'-bis(cyclopropylmethyl)-6',6,7,7'-tetrahydro-4,5,4'5'-diepoxy++ +-6,6'-(imino)[7,7'-bimorphinan]-3,3',14,14'-tetrol (norbinaltorphimine) indicating a significant and critical kappa-opioid receptor component. The endogenous cannabinoid, anandamide and the non-classical bicyclic cannabinoid, CP55,940, induced non-nor-BNI-sensitive effects. The N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-3-pyrazo le-carboxamide (SR141716A)-mediated attenuation of spinal antinociception imparted by the various cannabinoids indicates cannabinoid CB1 receptor involvement. THC-induced an enhancement of immunoreactive dynorphin A release which coincided with the onset, but not duration antinociception. The release of dynorphin A was also attenuated by SR141716A suggesting it is cannabinoid CB1 receptor-mediated. These data indicate a critical role for dynorphin A release in the initiation of the antinociceptive effects of the cannabinoids at the spinal level.
Asunto(s)
Cannabinoides/farmacología , Dinorfinas/efectos de los fármacos , Analgésicos/farmacología , Animales , Cannabinoides/antagonistas & inhibidores , Ciclohexanoles/farmacología , Dimetilsulfóxido/farmacología , Dronabinol/farmacología , Dinorfinas/líquido cefalorraquídeo , Inyecciones Espinales , Masculino , Naltrexona/análogos & derivados , Naltrexona/farmacología , Antagonistas de Narcóticos/farmacología , Nociceptores/efectos de los fármacos , Dolor/prevención & control , Dimensión del Dolor , Piperidinas/farmacología , Pirazoles/farmacología , Ratas , Ratas Sprague-Dawley , RimonabantRESUMEN
Because methionine enkephalin contributes to and dynorphin opposes dilation during a 10-min hypoxic exposure, opioids modulate pial artery dilation to this stimulus. However, such modulation may be dependent on the duration of hypoxia. The present study was designed to characterize the modulation of hypoxic pial dilation by opioids as a function of stimulus duration in newborn pigs equipped with a closed cranial window. Hypoxic dilation was decremented in both moderate and severe groups (PO2 approximately 35 and 25 mmHg, respectively) during 20-min and 40-min exposure periods compared with the response during 5 or 10 min of stimulation (24 +/- 1, 25 +/- 1, 18 +/- 1, and 14 +/- 1% for 5, 10, 20, and 40 min of moderate hypoxia; means +/- SE). Moderate and severe hypoxia had no effect on cerebral spinal fluid (CSF) methionine enkephalin or dynorphin concentration during a 5-min exposure period. During a 10-min exposure, however, both opioids were increased in CSF. During 20- and 40-min exposure periods, CSF dynorphin continued to increase, whereas methionine enkephalin steadily decreased (962 +/- 18, 952 +/- 21, 2,821 +/- 15, 2,000 +/- 81, and 1,726 +/- 58 pg/ml methionine enkephalin for control, 5, 10, 20, and 40 min of moderate hypoxia, respectively). The mu-opioid (methionine enkephalin) antagonist beta-funaltrexamine had no influence on dilation during the 5-min exposure, decremented the 10- and 20-min exposures, but had no effect on 40-min exposure hypoxic dilation. Whereas the kappa-opioid (dynorphin) antagonist norbinaltorphimine similarly had no effect on a 5-min exposure dilation, it, in contrast, potentiated 10-, 20-, and 40-min exposure hypoxic dilations (23 +/- 1 vs. 23 +/- 1, 24 +/- 1 vs. 32 +/- 1, 16 +/- 1 vs. 24 +/- 2, and 13 +/- 1 vs. 23 +/- 3% for 5, 10, 20, and 40-min hypoxic dilation before and after norbinaltorphimine). These data show that opioids do not modulate hypoxic pial dilation during short but do so during longer exposure periods. Moreover, hypoxic pial dilation is diminished during longer exposure periods. Decremented hypoxic pial dilation during longer exposure periods results, at least in part, from decreased release of methionine enkephalin and accentuated release of dynorphin. These data suggest that the relative role of opioids in hypoxic pial dilation changes with the stimulus duration.
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Hipoxia Encefálica/fisiopatología , Péptidos Opioides/fisiología , Piamadre/irrigación sanguínea , Vasodilatación , Animales , Arterias , Dinorfinas/líquido cefalorraquídeo , Encefalina Metionina/líquido cefalorraquídeo , Femenino , Hipoxia Encefálica/líquido cefalorraquídeo , Masculino , Naltrexona/análogos & derivados , Naltrexona/farmacología , Antagonistas de Narcóticos/farmacología , Porcinos , Vasodilatación/efectos de los fármacosAsunto(s)
Catecolaminas/metabolismo , Caballos/metabolismo , Hidrocortisona/sangre , Péptidos/análisis , Hipófisis/metabolismo , Hormona Adrenocorticotrópica/sangre , Hormona Adrenocorticotrópica/líquido cefalorraquídeo , Animales , Arginina Vasopresina/sangre , Arginina Vasopresina/líquido cefalorraquídeo , Catecolaminas/sangre , Catecolaminas/líquido cefalorraquídeo , Cateterismo/veterinaria , Cromatografía Líquida de Alta Presión/veterinaria , Dopamina/sangre , Dopamina/líquido cefalorraquídeo , Dinorfinas/sangre , Dinorfinas/líquido cefalorraquídeo , Encefalina Metionina/sangre , Encefalina Metionina/líquido cefalorraquídeo , Femenino , Caballos/sangre , Caballos/líquido cefalorraquídeo , Masculino , Norepinefrina/sangre , Norepinefrina/líquido cefalorraquídeo , Péptidos/sangre , Péptidos/líquido cefalorraquídeo , Radioinmunoensayo/veterinaria , Valores de Referencia , betaendorfina/sangre , betaendorfina/líquido cefalorraquídeoRESUMEN
E-2078 is a dynorphin A (1-8) analog, [N-methyl-Tyr1, N-methyl-Arg7-D-Leu8] dynorphin A (1-8) ethylamide. Its ability to cross the blood-brain barrier was examined in rhesus monkeys using matrix-assisted laser desorption/ionization mass spectrometry. In vivo studies were carried out by i.v. injecting E-2078, 10 mg/kg, a dose that had been found to be antinociceptive, to rhesus monkeys. Blood and cerebrospinal fluid samples were collected at various time points after the injection. It was found that E-2078 was stable in vivo in rhesus monkey blood. No biotransformation products were detected in the blood. Mass spectrometric analysis of the cerebrospinal fluid samples collected after E-2078 injection detected the presence of E-2078, indicating that E-2078 had crossed the blood-brain barrier. These findings are consistent with the possibility that systemically administered E-2078 could produce centrally mediated behavioral and physiological effects.
Asunto(s)
Analgésicos no Narcóticos/farmacocinética , Barrera Hematoencefálica , Dinorfinas/farmacocinética , Fragmentos de Péptidos/farmacocinética , Analgésicos no Narcóticos/sangre , Analgésicos no Narcóticos/líquido cefalorraquídeo , Animales , Biotransformación , Dinorfinas/sangre , Dinorfinas/líquido cefalorraquídeo , Recuento de Eritrocitos , Femenino , Macaca mulatta , Masculino , Fragmentos de Péptidos/sangre , Fragmentos de Péptidos/líquido cefalorraquídeo , Estándares de Referencia , Espectrometría de Masa por Láser de Matriz Asistida de Ionización DesorciónRESUMEN
In-vitro incubation of human cerebrospinal fluid (CSF) obtained from patients ranging from 22-78 years with 10 microM of dynorphin A1-13 (Dyn A1-13) resulted in several cleavage products. Dyn A1-12 and A2-13 were identified as the major CSF metabolites by matrix-assisted laser desorption mass spectrometry (LD-MS). Further metabolites were Dyn A1-6, A2-12 and A4-12. LD-MS further suggested the formation of Dyn A1-8, A1-7, A1-10, A7-10, A3-12, A7-12, A3-13, A7-13 and A8-13. The metabolic half-life of Dyn A1-13 at 37 degrees C was approximately 2.5 h (range 1.75-8.5 h), compared to less than one minute in plasma. The half-life of Dyn A1-13 decreased markedly with age or age-associated processes (n = 20, r2 = 0.498). Noncompartmental kinetic analysis in the absence or presence of enzyme inhibitors (leucinethiol 10 microM, captopril 100 microM and GEMSA 20 microM) suggested that Dyn A1-13 is mainly metabolized by carboxypeptidase to A1-12 (51%) and by aminopeptidases to A2-13 (35%). The generation of A1-6 (13%) was only detected under enzyme inhibition. The extent of conversion into the main metabolites did not follow an age-associated trend, thus over-all enzyme levels but no specific enzymatic systems are elevated with age.
Asunto(s)
Envejecimiento/líquido cefalorraquídeo , Dinorfinas/líquido cefalorraquídeo , Fragmentos de Péptidos/líquido cefalorraquídeo , Adulto , Anciano , Aminopeptidasas/antagonistas & inhibidores , Aminopeptidasas/metabolismo , Carboxipeptidasas/antagonistas & inhibidores , Carboxipeptidasas/metabolismo , Cromatografía Líquida de Alta Presión , Dinorfinas/sangre , Inhibidores Enzimáticos/farmacología , Femenino , Semivida , Humanos , Masculino , Espectrometría de Masas , Persona de Mediana Edad , Fragmentos de Péptidos/sangreRESUMEN
The role of the opioid receptor-endogenous opioid peptide system in mediating analgesia induced by nitrous oxide has been a controversial subject. Most previous studies provided only indirect evidence either to support or refute the involvement of opioid receptors and/or endogenous opioid peptides. To provide more direct evidence, we measured concentrations of five naturally occurring endogenous opioid peptides in third ventricular cerebrospinal fluid from eight acclimated dogs with chronically implanted ventricular catheters. Paired samples of cerebrospinal fluid were obtained from each animal when breathing room air or 66-75 vol% nitrous oxide in oxygen through a face mask. Endogenous opioid peptides were physically separated using reversed phase high-performance liquid chromatography and quantified using radioimmunoassays. Nitrous oxide inhalation increased cerebrospinal fluid concentrations of met5-enkephalin from a control value of 0.30 +/- 0.07 (mean +/- SEM, n = 8) to 42.4 +/- 8.1 pmol/mL (P = 0.0006). Increases ranged from 28 to more than 400 times the control value. Met5-enkephalin-arg6-phe7 concentrations also increased from 14.5 +/- 2.5 to 57.6 +/- 17.8 pmol/mL (P = 0.018). No significant changes were noted in concentrations of dynorphin A, dynorphin B, or beta-endorphin. These results directly support the hypothesis that nitrous-oxide-induced analgesia involves the proenkephalin-derived family of endogenous opioid peptides.
Asunto(s)
Encefalina Metionina/análogos & derivados , Encefalina Metionina/líquido cefalorraquídeo , Óxido Nitroso/farmacología , Analgesia , Animales , Cromatografía Líquida de Alta Presión , Perros , Dinorfinas/líquido cefalorraquídeo , Femenino , Masculino , Radioinmunoensayo , betaendorfina/líquido cefalorraquídeoRESUMEN
The present study was designed to investigate the contribution of opioids and nitric oxide (NO) to hypoxia-induced pial vasodilation. Newborn pigs equipped with a closed cranial window were used to measure pial arteriolar diameter and to collect cortical periarachnoid cerebrospinal fluid (CSF) for assay of opioids and guanosine 3',5'-cyclic monophosphate (cGMP). Hypoxia-induced pial dilation was potentiated by norbinaltorphimine, 10(-6) M, a kappa-opioid antagonist (25 +/- 2 vs. 33 +/- 3%, n = 5), but was blunted by beta-funaltrexamine, 10(-8) M, a mu-opioid antagonist (28 +/- 2 vs. 19 +/- 1%, n = 5). Hypoxia-induced vasodilation was associated with increased CSF methionine enkephalin, a mu-opioid agonist (884 +/- 29 vs. 2,638 +/- 387 pg/ml, n = 5). N omega-nitro-L-arginine (L-NNA), an NO synthase inhibitor (10(-6) M), also blunted hypoxia-induced vasodilation that was further diminished by coadministration of L-NNA and beta-funaltrexamine (26 +/- 2, 14 +/- 1, and 9 +/- 1%, respectively, n = 5). Reversal of the above order of antagonist administration resulted in similar inhibition of hypoxia-induced pial dilation. Hypoxia-induced vasodilation was also associated with an increase in CSF cGMP that was attenuated by L-NNA (2.1 +/- 0.1- vs. 1.1 +/- 0.2-fold change in CSF cGMP, n = 5). Sodium nitroprusside (10(-6) M) increased CSF cGMP and methionine enkephalin concentration similar to hypoxia. These data suggest that hypoxia-induced pial arterial vasodilation, in part, is due to NO and/or cGMP-induced methionine enkephalin release as well as the direct action of NO.
Asunto(s)
Arginina/análogos & derivados , Arterias Cerebrales/fisiología , Dinorfinas/líquido cefalorraquídeo , Encefalina Metionina/líquido cefalorraquídeo , Hipoxia/fisiopatología , Óxido Nítrico/fisiología , Vasodilatación/fisiología , Aminoácido Oxidorreductasas/antagonistas & inhibidores , Análisis de Varianza , Animales , Animales Recién Nacidos , Arginina/farmacología , Arteriolas/efectos de los fármacos , Arteriolas/fisiología , Arteriolas/fisiopatología , Arterias Cerebrales/efectos de los fármacos , Arterias Cerebrales/fisiopatología , GMP Cíclico/líquido cefalorraquídeo , Encefalina Ala(2)-MeFe(4)-Gli(5) , Encefalinas/farmacología , Femenino , Masculino , Músculo Liso Vascular/efectos de los fármacos , Músculo Liso Vascular/fisiología , Músculo Liso Vascular/fisiopatología , Naltrexona/análogos & derivados , Naltrexona/farmacología , Óxido Nítrico/antagonistas & inhibidores , Óxido Nítrico Sintasa , Nitroarginina , Nitroprusiato/farmacología , Receptores Opioides kappa/antagonistas & inhibidores , Receptores Opioides mu/agonistas , Receptores Opioides mu/antagonistas & inhibidores , Porcinos , Vasodilatación/efectos de los fármacosRESUMEN
BACKGROUND: Limited neurobiological data have implicated central arginine vasopressin in the pathobiology of obsessive-compulsive disorder (OCD). Based on twin, family genetic, and pharmacological studies, some forms of OCD are etiologically related to Tourette's syndrome. The role of arginine vasopressin and related compounds such as oxytocin in Tourette's syndrome has not been previously explored. METHODS: To compare cerebrospinal fluid (CSF) levels of arginine vasopressin and oxytocin, we collected CSF at midday in a standardized fashion from a total of 83 individuals (29 patients with OCD, 23 patients with Tourette's syndrome, and 31 normal controls). We also collected family study data on each subject to determine which subjects had a family history positive for Tourette's syndrome, OCD, or related syndromes. RESULTS: In contrast to previous reports, we report similar concentrations of arginine vasopressin for all three groups but increased oxytocin levels in patients with OCD. Remarkably, this increase was observed only in a subset of patients with OCD (n = 22) independently identified as being without a personal or family history of tic disorders (P = .0003). In this subgroup of patients, the CSF oxytocin level was correlated with current severity of OCD (n = 19, r = .47, P < .05). CONCLUSIONS: A possible role for oxytocin in the neurobiology of a subtype of OCD is suggested by the elevated CSF levels of oxytocin and by the correlation between CSF oxytocin levels and OCD severity. These findings reinforce the value of family genetic data in identifying biologically homogeneous (and perhaps more etiologically homogeneous) groups of patients with OCD. Together with emerging pharmacological data showing differential responsiveness to treatment of tic-related OCD vs non-tic-related OCD, these data also argue strongly for the incorporation of tic-relatedness as a variable in biological and behavioral studies of patients with OCD.
Asunto(s)
Trastorno Obsesivo Compulsivo/líquido cefalorraquídeo , Oxitocina/líquido cefalorraquídeo , Adolescente , Adulto , Edad de Inicio , Arginina Vasopresina/líquido cefalorraquídeo , Arginina Vasopresina/fisiología , Aminas Biogénicas/líquido cefalorraquídeo , Comorbilidad , Dinorfinas/líquido cefalorraquídeo , Familia , Femenino , Humanos , Ácido Hidroxiindolacético/líquido cefalorraquídeo , Masculino , Trastornos Mentales/epidemiología , Persona de Mediana Edad , Trastorno Obsesivo Compulsivo/epidemiología , Trastorno Obsesivo Compulsivo/fisiopatología , Escalas de Valoración Psiquiátrica , Índice de Severidad de la Enfermedad , Síndrome de Tourette/líquido cefalorraquídeo , Síndrome de Tourette/epidemiología , Síndrome de Tourette/fisiopatología , Triptófano/líquido cefalorraquídeoRESUMEN
In lumbar cerebrospinal fluid (CSF) obtained from patients with chronic tension-type headache (CTH), the concentrations of beta-endorphin, met-enkephalin, dynorphin, cholecystokinin (CCK), calcitonin gene-related peptide (CGRP), and somatostatin were measured before and after 8 weeks of treatment with sulpiride or paroxetine. We previously reported higher than normal met-enkephalin concentrations in CTH. The present study reveals normal basal concentrations of CCK, CGRP and somatostatin and slightly decreased dynorphin in the same patients. Treatment with sulpiride or paroxetine did not change the concentration of any of the neuropeptides measured. These data suggest central changes in opioid systems but not in other peptide systems (CCK, CGRP, somatostatin) involved in nociceptive processing at the level of the spinal cord dorsal horn/nucleus caudalis of the trigeminal nerve in CTH. Such central changes might be pathophysiologically important or merely secondary to other more important occurrences. The lack of changes in neuropeptide concentrations during drug treatment makes planning of studies involving CSF analysis easier, but also limits the probability of obtaining information on specific neuropeptide systems through CSF analysis.
Asunto(s)
Neuropéptidos/líquido cefalorraquídeo , Paroxetina/farmacología , Sulpirida/farmacología , Cefalea de Tipo Tensional/tratamiento farmacológico , Adulto , Anciano , Metabolismo Basal , Péptido Relacionado con Gen de Calcitonina/líquido cefalorraquídeo , Colecistoquinina/líquido cefalorraquídeo , Enfermedad Crónica , Antagonistas de los Receptores de Dopamina D2 , Dinorfinas/líquido cefalorraquídeo , Femenino , Humanos , Masculino , Persona de Mediana Edad , Somatostatina/líquido cefalorraquídeo , Cefalea de Tipo Tensional/líquido cefalorraquídeoRESUMEN
We investigated whether central pain mechanisms including the endogenous antinociceptive system are involved in functional abdominal pain--that is, abdominal pain without abnormal findings at routine examinations. beta-Endorphin, met-enkephalin immunoreactivity, and dynorphin immunoreactivity were measured in cerebrospinal fluid (CSF) from nine patients with long-lasting functional abdominal pain and nine pain-free controls undergoing minor surgery while under spinal analgesia. Furthermore, pain sensitivity was evaluated with an ischaemic pain test comparing 21 functional abdominal pain patients with two control groups: 1) 24 patients with organic abdominal pain due to duodenal ulcer, gallstone, or urinary tract calculi, and 2) 13 healthy pain-free controls. The CSF beta-endorphin concentration was significantly decreased in the functional abdominal pain group as compared with nine matched controls (P = 0.01). Met-enkephalin and dynorphin immunoreactivities were normal. This part of the investigation was suspended after nine patients had been tested, because of post-lumbar-puncture headache. With regard to pain sensitivity, no significant difference between the three groups was shown, but subdivision of the functional abdominal pain group showed that individuals with pain and no symptoms of irritable bowel syndrome (IBS) were significantly more sensitive to pain than functional abdominal pain patients with IBS and healthy controls (P = 0.04).