RESUMEN
Opioid use disorders (OUDs) are diseases of the brain with behavioral, psychological, neurobiological, and medical manifestations. Vulnerability to OUDs can be affected by factors such as genetic background, environment, stress, and prolonged exposure to µ-opioid agonists for analgesia. Two standard-of-care maintenance medications, methadone and buprenorphine-naloxone, have a long-term positive influence on health of persons with opioid addiction. Buprenorphine and another medication, naltrexone, have also been approved for administration as monthly depot injections. However, neither medication is used as widely as needed, due largely to stigma, insufficient medical education or training, inadequate resources, and inadequate access to treatment. Ongoing directions in the field include (i) personalized approaches leveraging genetic factors for prediction of OUD vulnerability and prognosis, or for targeted pharmacotherapy, and (ii) development of novel analgesic medicines with new neurobiological targets with reduced abuse potential, reduced toxicity, and improved effectiveness, especially for chronic pain states other than cancer pain.
Asunto(s)
Investigación Biomédica , Trastornos Relacionados con Opioides/terapia , Analgésicos Opioides/química , Encéfalo/metabolismo , Humanos , Trastornos Relacionados con Opioides/epidemiología , Salud Pública , Receptores Opioides mu/metabolismoRESUMEN
Illicit use of prescription opioid analgesics (e.g., oxycodone) in adolescence is a pressing public health issue. Our goal was to determine whether oxycodone self administration differentially affects striatal neurotransmitter receptor gene expression in the dorsal striatum of adolescent compared to adult C57BL/6J mice. Groups of adolescent mice (4 weeks old, n=12) and of adult mice (11 weeks old, n=11) underwent surgery during which a catheter was implanted into their jugular veins. After recovering from surgery, mice self administered oxycodone (0.25 mg/kg/infusion) 2 h/day for 14 consecutive days or served as yoked saline controls. Mice were sacrificed within 1h after the last self-administration session and the dorsal striatum was isolated for mRNA analysis. Gene expression was analyzed with real time PCR using a commercially available neurotransmitter receptor PCR array containing 84 genes. We found that adolescent mice self administered less oxycodone than adult mice over the 14 days. Monoamine oxidase A (Maoa) and neuropeptide Y receptor 5 mRNA levels were lower in adolescent mice than in adult mice without oxycodone exposure. Oxycodone self administration increased Maoa mRNA levels compared to controls in both age groups. There was a positive correlation of the amount of oxycodone self administered in the last session or across 14 sessions with Maoa mRNA levels. Gastrin-releasing peptide receptor mRNA showed a significant Drug × Age interaction, with point-wise significance. More genes in the dorsal striatum of adolescents (19) changed in response to oxycodone self administration compared to controls than in adult (4) mice. Overall, this study demonstrates that repeated oxycodone self administration alters neurotransmitter receptors gene expression in the dorsal striatum of adolescent and adult mice.
Asunto(s)
Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/metabolismo , Narcóticos/farmacología , Oxicodona/farmacología , Receptores de Neurotransmisores/metabolismo , Factores de Edad , Animales , Cuerpo Estriado/crecimiento & desarrollo , Comportamiento de Búsqueda de Drogas/fisiología , Expresión Génica/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos C57BL , Monoaminooxidasa/metabolismo , Narcóticos/administración & dosificación , Trastornos Relacionados con Opioides/metabolismo , Oxicodona/administración & dosificación , ARN Mensajero/genética , ARN Mensajero/metabolismo , Reacción en Cadena en Tiempo Real de la Polimerasa , Receptores de Neuropéptido Y/metabolismo , AutoadministraciónRESUMEN
The focus of this review is primarily on recent developments in bidirectional translational research on the addictions, within the Laboratory of the Biology of Addictive Diseases at The Rockefeller University. This review is subdivided into major interacting aspects, including (a) Investigation of neurobiological and molecular adaptations (e.g., in genes for the opioid receptors or endogenous neuropeptides) in response to cocaine or opiates, administered under laboratory conditions modeling chronic patterns of human self-exposure (e.g., chronic escalating "binge"). (b) The impact of such drug exposure on the hypothalamic-pituitary-adrenal (HPA) axis and interacting neuropeptidergic systems (e.g., opioid, orexin and vasopressin). (c) Molecular genetic association studies using candidate gene and whole genome approaches, to define particular systems involved in vulnerability to develop specific addictions, and response to pharmacotherapy. (d) Neuroendocrine challenge studies in normal volunteers and current addictive disease patients along with former addicts in treatment, to investigate differential pharmacodynamics and responsiveness of molecular targets, in particular those also investigated in the experimental and molecular genetic approaches as described above.
Asunto(s)
Investigación Biomédica/métodos , Trastornos Relacionados con Sustancias , Animales , Investigación Biomédica/tendencias , Humanos , Sistema Hipotálamo-Hipofisario/metabolismo , Sistema Hipotálamo-Hipofisario/fisiopatología , Narcóticos/uso terapéutico , Sistema Hipófiso-Suprarrenal/metabolismo , Sistema Hipófiso-Suprarrenal/fisiopatología , Receptores Opioides , Trastornos Relacionados con Sustancias/metabolismo , Trastornos Relacionados con Sustancias/fisiopatología , Trastornos Relacionados con Sustancias/terapiaRESUMEN
RATIONALE: Recent preclinical behavioral and neurobiological research has characterized important behavioral features and has identified neurobiological substrates that may underlie nicotine reinforcement and addiction. OBJECTIVE: To examine recent advances on nicotine exposure in preclinical models, from three perspectives: (a) the chronopharmacokinetics of nicotine, (b) behavioral studies on nicotine reinforcement, withdrawal, and reinstatement/relapse, and (c) effects of nicotine on neurobiological substrates after repeated exposure. RESULTS: Preclinical studies can be used to operationally model selected aspects of nicotine reinforcement, withdrawal, and reinstatement or relapse. These may be used to investigate the functional in vivo consequences of acute and long-term changes in neuronal acetylcholine receptor populations that follow nicotine exposure. Behavioral studies focusing on distinct stages of nicotine exposure (e.g., active reinforcement vs. cessation or reinstatement) may also be used in parallel with studies on dopaminergic function, a proposed substrate for the reinforcing effects of nicotine, and of opioid receptor function, a possible site of neuroadaptations secondary to nicotine exposure. CONCLUSIONS: While no single current animal model may capture the experience of human smoking or nicotine addiction, increasingly, separate animal models are capturing the full spectrum of behavioral and neurobiological dimensions of this complex condition.
Asunto(s)
Estimulantes Ganglionares/farmacología , Nicotina/farmacología , Agonistas Nicotínicos/farmacología , Animales , Conducta Animal/efectos de los fármacos , Ritmo Circadiano , Dopamina/metabolismo , Estimulantes Ganglionares/farmacocinética , Sistema Límbico/metabolismo , Modelos Animales , Neuronas/metabolismo , Nicotina/farmacocinética , Agonistas Nicotínicos/farmacocinética , Receptores Nicotínicos/metabolismo , Receptores Opioides/metabolismo , Refuerzo en Psicología , Fumar/metabolismo , Fumar/psicología , Síndrome de Abstinencia a Sustancias/metabolismo , Síndrome de Abstinencia a Sustancias/psicología , Trastornos Relacionados con Sustancias/genética , Trastornos Relacionados con Sustancias/metabolismo , Trastornos Relacionados con Sustancias/psicologíaRESUMEN
GR89,696 is a synthetic kappa-opioid receptor agonist, recently reported to have an agonist profile consistent with selectivity at the proposed "kappa(2)" subtype. The present studies evaluated the effects of GR89,696 in vitro (i.e., in radioligand binding and [(35)S]guanosine-5'-O-(3-thio)triphosphate assays) and in vivo in rhesus monkeys, in assays used to study kappa-opioid agonists (i.e., thermal antinociception, sedation and muscle relaxation, diuresis, and increases in serum prolactin levels, as well as ethylketocyclazocine and U69,593 discrimination). Furthermore, the sensitivity of GR89,696 to naltrexone and nor-binaltorphimine (nor-BNI) antagonism was compared with that of U50,488 and U69,593, ligands selective for the proposed "kappa(1)" subtype. Overall, GR89,696 displayed the profile of a highly potent kappa-opioid agonist, following parenteral administration in rhesus monkeys. GR89,696 was less sensitive than U50,488 and U69,593 to naltrexone or nor-BNI antagonism, consistent with an action through the proposed kappa(2) receptor subtype.
Asunto(s)
Bencenoacetamidas , Piperazinas/farmacología , Pirrolidinas/farmacología , Receptores Opioides kappa/agonistas , Analgésicos no Narcóticos/farmacología , Analgésicos Opioides/farmacología , Animales , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/metabolismo , Discriminación en Psicología/efectos de los fármacos , Diuresis/efectos de los fármacos , Etilcetociclazocina/farmacología , Femenino , Guanosina 5'-O-(3-Tiotrifosfato)/farmacología , Macaca mulatta , Masculino , Membranas/efectos de los fármacos , Membranas/metabolismo , Relajación Muscular/efectos de los fármacos , Naltrexona/análogos & derivados , Naltrexona/farmacología , Dimensión del Dolor/efectos de los fármacos , Prolactina/sangre , Ensayo de Unión Radioligante , Receptores Opioides kappa/efectos de los fármacos , Mecánica Respiratoria/efectos de los fármacosRESUMEN
Kappa-opioid receptor agonists may have pharmacotherapeutic potential in the management of psychostimulant abuse, due to their ability to modulate dopamine receptor systems involved in drug reinforcement. kappa-Opioid receptor agonists also modulate dopamine receptor function in the hypothalamic tuberoinfundibular system, which has inhibitory control over an anterior pituitary hormone, prolactin. Prolactin levels may thus be a "biomarker" for the ability of kappa-opioid receptor agonists (e.g., (+)-(5 alpha,7 alpha,8 beta)-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4.5]dec-8-yl]-benzeneacetamide (U69,593)) to modulate a dopamine receptor system in vivo in primates. The effectiveness of dopamine D(2)-like receptor agonists (quinpirole and (+/-)-7-hydroxy-dipropylaminotetralin (7-OH-DPAT); 0.0032-0.1 mg/kg) in preventing U69,593-induced prolactin release was studied in intact female rhesus monkeys. Quinpirole and 7-OH-DPAT inhibited U69,593-induced prolactin release (ID(50) values: 0.013 and 0.0072 mg/kg, respectively). However, the dopamine D(1)-receptor agonist (+/-)-6-chloro-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazapine (SKF 82958; 1 mg/kg) did not inhibit U69,593-induced prolactin release under the same conditions. In contrast, the largest doses of quinpirole or 7-OH-DPAT presently studied (0.1 mg/kg), did not decrease sedation caused by U69,593 (0.01, 0.032 mg/kg), a prominent effect of centrally penetrating kappa-opioid receptor agonists. The sedative effect of U69,593 (0.032 mg/kg) was prevented by naltrexone (0.32 mg/kg), consistent with kappa-opioid receptor mediation of this effect. These studies suggest that prolactin release is a valid biomarker for the ability of kappa-opioid receptor agonists to modulate dopamine D(2)-like receptor function, and may also be used to quantify dopamine D(2)-like receptor agonist potency in primates.
Asunto(s)
Bencenoacetamidas , Agonistas de Dopamina/farmacología , Prolactina/efectos de los fármacos , Receptores de Dopamina D2/agonistas , Receptores Opioides kappa/agonistas , Animales , Conducta Animal/efectos de los fármacos , Benzazepinas/farmacología , Sedación Consciente , Relación Dosis-Respuesta a Droga , Femenino , Macaca mulatta , Masculino , Prolactina/sangre , Pirrolidinas/farmacología , Quinpirol/farmacología , Tetrahidronaftalenos/farmacologíaRESUMEN
RATIONALE: The dynorphins are endogenous opioid peptides with relative binding selectivity for kappa-receptors. It is unclear whether the dynorphins share the pharmacological profile observed with synthetic kappa-agonists in primates. OBJECTIVE: The main objective of this study was to compare the effects of s.c. E-2078, a stable dynorphin A(1-8) analog, with two synthetic kappa-opioid ligands, spiradoline (a reference arylacetamide kappa-agonist) and ICI204,448 (a "peripherally selective" kappa-agonist) in behavioral and neuroendocrine endpoints in rhesus monkeys. METHODS: Dose-effect curves were determined for s.c. E-2078, spiradoline and ICI204,448 in causing overt sedation and muscle relaxation (as detected in observational rating scales), in increasing latency to retrieve and consume a food pellet and in increasing serum levels of the anterior pituitary hormone, prolactin, in intact female rhesus monkeys. RESULTS: E-2078 and ICI204,448 (0.1-3.2 mg/kg) caused increases in sedation and muscle relaxation scores, but were less potent and apparently less effective than spiradoline (0.001-0.1 mg/kg) up to the highest doses presently studied. All three agonists were equieffective and approximately equipotent in increasing the latency to retrieve and consume a pellet. Furthermore, E-2078 (0.001-0.032 mg/kg) was equipotent and equieffective with spiradoline in increasing serum prolactin levels, whereas ICI204,448 was less potent, but slightly more effective than the former two agonists. The effects of E-2078 on serum prolactin levels were surmountably antagonized by quadazocine (1 mg/kg) and naltrexone (0.1 mg/kg). CONCLUSIONS: The present studies show that serum prolactin levels are a highly sensitive, quantitative endpoint to study the potency and effectiveness of systemically administered E-2078, and show that the dynorphins may be potent and effective in causing some, but not all, the effects that are observed after the administration of synthetic kappa-agonists.
Asunto(s)
Dinorfinas/farmacología , Hipnóticos y Sedantes/farmacología , Fragmentos de Péptidos/farmacología , Prolactina/sangre , Animales , Azocinas/farmacología , Relación Dosis-Respuesta a Droga , Dinorfinas/administración & dosificación , Dinorfinas/antagonistas & inhibidores , Femenino , Hipnóticos y Sedantes/administración & dosificación , Hipnóticos y Sedantes/antagonistas & inhibidores , Inyecciones Subcutáneas , Macaca mulatta , Masculino , Actividad Motora/efectos de los fármacos , Relajación Muscular/efectos de los fármacos , Naltrexona/farmacología , Antagonistas de Narcóticos/farmacología , Fragmentos de Péptidos/administración & dosificación , Fragmentos de Péptidos/antagonistas & inhibidores , Pirrolidinas/farmacología , Receptores Opioides kappa/agonistas , Factores de TiempoRESUMEN
These studies investigated whether serum prolactin levels could be a quantitative marker of the apparent efficacy of kappa-opioid receptor ligands in primates. The effects of s.c. bremazocine and U50,488 (trans-(+/-)-3, 4-Dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]-benzeneacetamid e; agonists), nalorphine (partial agonist) and nalmefene (antagonist) on prolactin levels were studied in intact female rhesus monkeys. The above compounds, except nalmefene, increased prolactin levels, and their actions conformed to sigmoidal dose-effect curves. The rank order of the compounds' maximum effects in this neuroendocrine endpoint is similar to that in cloned kappa-receptors in vitro, and in a presently studied thermal antinociception assay in vivo. Prolactin may therefore be a quantitative marker of the apparent efficacy of kappa-opioid receptor ligands in primates.
Asunto(s)
Analgésicos/farmacología , Narcóticos/farmacología , Prolactina/efectos de los fármacos , Receptores Opioides kappa/efectos de los fármacos , Animales , Biomarcadores/sangre , Femenino , Ligandos , Macaca mulatta , Prolactina/sangre , Receptores Opioides kappa/agonistas , Receptores Opioides kappa/antagonistas & inhibidoresRESUMEN
Systemic administration of nor-binaltorphimine (nor-BNI) produces a long-lasting kappa-opioid receptor (kappaOR) antagonism and has kappa(1)-selectivity in nonhuman primates. The aim of this study was to establish the pharmacological basis of central kappaOR antagonism in rhesus monkeys (Macaca mulatta). After intracisternal (i.c.) administration of small doses of nor-BNI, the duration and selectivity of nor-BNI antagonism were evaluated against two kappaOR agonists, (trans)-3, 4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]benzeneacetamide (U50,488) and bremazocine. Thermal antinociception was measured in the warm water (50 degrees C) tail-withdrawal assay and sedation was evaluated by observers blind to treatment conditions. Following i.c. pretreatment with 0.32 mg nor-BNI, a 5- to 10-fold rightward shift of the U50,488 baseline dose-effect curve was observed in antinociception. In contrast, this dose of nor-BNI only produced an insignificant 2-fold shift against bremazocine. Pretreatment with a smaller dose (0.032 mg) of nor-BNI produced a 3-fold shift of U50, 488, which lasted for 7 days, but failed to alter the potency of bremazocine. This differential antagonism profile of i.c. nor-BNI also was observed in sedation ratings. In addition, the centrally effective dose of nor-BNI (0.32 mg), when administered s.c. in the back, did not antagonize either U50,488- or bremazocine-induced antinociception and sedation. After i.c. pretreatment with the same dose, nor-BNI also did not antagonize the peripherally mediated effect of U50,488 against capsaicin-induced thermal nociception in the tail. These results indicate that i.c. nor-BNI produces central kappaOR antagonism and support the notion of two functional kappaOR subtypes in the central nervous system. Moreover, it provides a valuable pharmacological basis for further characterizing different sources of kappaOR-mediated effects, namely, from central or peripheral nervous system receptors.
Asunto(s)
Analgésicos Opioides/farmacología , Sistema Nervioso Central/efectos de los fármacos , Cisterna Magna/fisiología , Naltrexona/análogos & derivados , Antagonistas de Narcóticos/farmacología , Sistema Nervioso Periférico/efectos de los fármacos , Receptores Opioides kappa/antagonistas & inhibidores , 3,4-Dicloro-N-metil-N-(2-(1-pirrolidinil)-ciclohexil)-bencenacetamida, (trans)-Isómero/administración & dosificación , 3,4-Dicloro-N-metil-N-(2-(1-pirrolidinil)-ciclohexil)-bencenacetamida, (trans)-Isómero/farmacología , Analgésicos/farmacología , Animales , Benzomorfanos/farmacología , Relación Dosis-Respuesta a Droga , Femenino , Calor , Inyecciones , Macaca mulatta , Masculino , Naltrexona/administración & dosificación , Naltrexona/farmacología , Antagonistas de Narcóticos/administración & dosificaciónRESUMEN
The effects of i.v. dynorphin A(1-17) and its main nonopioid biotransformation fragment, dynorphin A(2-17), were compared in rhesus monkeys with those of the selective kappa-opioid agonist, U69, 593, in assays of operant behavior, thermal antinociception, and neuroendocrine function (prolactin release). Dynorphin A(1-17) (0. 1-3.2 mg/kg i.v.) and U69,593 (0.001-0.032 mg/kg s.c.) decreased rates of schedule-controlled (fixed ratio 20) food-reinforced responding, whereas dynorphin A(2-17) (1-3.2 mg/kg i.v.) was ineffective. Pretreatment studies with the opioid antagonist quadazocine (0.32 mg/kg s.c.) revealed that the operant effects of dynorphin A(1-17) were not mediated by kappa- or micro-opioid receptors. A different profile was observed in the warm water tail withdrawal assay of thermal antinociception, where both dynorphin A(1-17) and A(2-17) (0.032-3.2 mg/kg i.v., n = 4) were modestly effective in 50 degrees C water, and both were ineffective in 55 degrees C water. By comparison, U69,593 (0.032-0.18 mg/kg s.c.) was maximally effective in 50 degrees C water and partially effective in 55 degrees C. kappa-opioid agonists increase serum levels of prolactin in animals and humans. Dynorphin A(1-17) (ED(50) = 0.0011 mg/kg i.v.), similar to U69,593 (ED(50) = 0.0030 mg/kg i.v.), was very potent in increasing serum prolactin levels in follicular phase female rhesus monkeys, whereas dynorphin A(2-17) (0.32 mg/kg i.v.) was ineffective. The effects of dynorphin A(1-17) and U69,593 on serum prolactin were both antagonized by quadazocine (0.32 mg/kg s.c.) in a surmountable manner, consistent with opioid receptor mediation. The present studies show that serum prolactin levels are a sensitive quantitative endpoint to study the systemic effects of the endogenous opioid peptide, dynorphin A(1-17), in primates.
Asunto(s)
Conducta Animal/efectos de los fármacos , Dinorfinas/farmacología , Analgésicos Opioides/administración & dosificación , Analgésicos Opioides/farmacología , Animales , Azocinas/metabolismo , Condicionamiento Operante/efectos de los fármacos , Citocinas/metabolismo , Relación Dosis-Respuesta a Droga , Dinorfinas/administración & dosificación , Femenino , Inflamación/metabolismo , Inyecciones Intravenosas , Macaca mulatta , Masculino , Antagonistas de Narcóticos/metabolismo , Dimensión del Dolor/efectos de los fármacos , Prolactina/sangre , Esquema de RefuerzoRESUMEN
RATIONALE: E-2078 ([N-methyl-Tyr1, N-methyl-Arg7, D-Leu8] dynorphin A(1-8) ethylamide) is a dynorphin A(1-8) analog with a reduced tendency to be biotransformed, when compared to the unmodified opioid peptide. E-2078 has been found to produce kappa-opioid agonist effects in vivo in rodents. OBJECTIVE: In the present studies, we investigated whether systemically administered E-2078 could produce kappa-agonist effects in rhesus monkeys, in tests of antinociception, diuresis and ethyl-ketocyclazocine (EKC) discrimination. METHODS: E-2078 (0.32-18 mg/kg, SC, IM or IV) was tested in the warm water (50 degrees, 55 degrees C) tail withdrawal assay of thermal antinociception. The diuretic effects of E-2078 (0.056-1.8 mg/kg, SC) were also compared to those of the kappa-agonist, U69,593 (0.01-0.32 mg/kg, SC). Lastly, the effects of E-2078 (0.1-3.2 mg/kg, SC or IV) were studied in rhesus monkeys trained to discriminate EKC (0.0056 mg/kg SC) from vehicle, in a food-reinforced operant procedure. RESULTS: E-2078 did not produce thermal antinociception in rhesus monkeys following SC or IM administration, up to the largest doses presently studied (i.e., 18 and 10 mg/kg, respectively). E-2078 caused thermal antinociception by the IV route, but this effect was not apparently mediated by kappa- or mu-opioid receptors, as shown by its insensitivity to quadazocine (1 mg/kg) pretreatment. However, SC E-2078 caused diuresis, and this effect was blocked by quadazocine pretreatment, consistent with mediation by kappa-opioid receptors. E-2078 generalized in EKC-discriminating monkeys, but only after the largest dose (3.2 mg/kg), and only following IV administration. CONCLUSIONS: The present studies suggest that systemically administered E-2078 can produce some kappa-receptor mediated effects in rhesus monkeys, but its profile of action is not identical to non-peptidic kappa-agonists following all routes of administration, or across all experimental situations.
Asunto(s)
Analgésicos no Narcóticos/farmacología , Dinorfinas/farmacología , Fragmentos de Péptidos/farmacología , Analgésicos no Narcóticos/administración & dosificación , Analgésicos Opioides/farmacología , Animales , Condicionamiento Operante/efectos de los fármacos , Discriminación en Psicología/efectos de los fármacos , Diuresis/efectos de los fármacos , Dinorfinas/administración & dosificación , Etilcetociclazocina/farmacología , Femenino , Alimentos , Inyecciones Intramusculares , Inyecciones Subcutáneas , Macaca mulatta , Masculino , Dimensión del Dolor/efectos de los fármacos , Fragmentos de Péptidos/administración & dosificación , Receptores Opioides kappa/agonistas , Receptores Opioides mu/efectos de los fármacosRESUMEN
8-Methyl-N-vanillyl-6-nonenamide (capsaicin) was locally applied in the tail of rhesus monkeys to evoke a nociceptive response, thermal allodynia, which was manifested as reduced tail-withdrawal latencies in normally innocuous 46 degrees C water. Coadministration of three kappa opioid ligands, U50,488 (3.2-100 microgram), bremazocine (0.1-3.2 microgram), and dynorphin A(1-13) (3.2-100 microgram), with capsaicin in the tail dose-dependently inhibited capsaicin-induced allodynia. This local antinociception was antagonized by a small dose of an opioid antagonist, quadazocine; (0.32 mg), applied in the tail; however, this dose of quadazocine injected s.c. in the back did not antagonize local U50,488. Comparing the relative potency of either agonist or antagonist after local and systemic administration confirmed that the site of action of locally applied kappa opioid agonists is in the tail. In addition, local nor-binaltorphimine (0.32 mg) and oxilorphan (0.1-10 microgram) antagonist studies raised the possibility of kappa opioid receptor subtypes in the periphery, which indicated that U50,488 produced local antinociception by acting on kappa1 receptors, but bremazocine acted probably on non-kappa1 receptors. These results provide functional evidence that activation of peripheral kappa opioid receptors can diminish capsaicin-induced allodynia in primates. This experimental pain model is a useful tool for evaluating peripherally antinociceptive actions of kappa agonists without central side effects and suggests new approaches for opioid pain management.
Asunto(s)
Capsaicina/toxicidad , Receptores Opioides kappa/agonistas , 3,4-Dicloro-N-metil-N-(2-(1-pirrolidinil)-ciclohexil)-bencenacetamida, (trans)-Isómero/antagonistas & inhibidores , 3,4-Dicloro-N-metil-N-(2-(1-pirrolidinil)-ciclohexil)-bencenacetamida, (trans)-Isómero/farmacología , Analgésicos/antagonistas & inhibidores , Analgésicos/farmacología , Animales , Azocinas/farmacología , Benzomorfanos/antagonistas & inhibidores , Benzomorfanos/farmacología , Capsaicina/antagonistas & inhibidores , Dinorfinas/antagonistas & inhibidores , Dinorfinas/farmacología , Femenino , Calor , Ligandos , Macaca mulatta , Masculino , Naltrexona/análogos & derivados , Naltrexona/farmacología , Antagonistas de Narcóticos/farmacología , Dimensión del Dolor/efectos de los fármacos , Fragmentos de Péptidos/antagonistas & inhibidores , Fragmentos de Péptidos/farmacología , Receptores Opioides kappa/antagonistas & inhibidoresRESUMEN
The effects of i.m. injections of (+)-HA-966, a glycine-site antagonist at the N-methyl-D-aspartate (NMDA) subtype of the glutamate receptor, its enantiomer (-)-HA-966, the competitive glutamate antagonist CGS-19755, the uncompetitive glutamate antagonists phencyclidine and dizocilpine, and the micro opioid agonist morphine were evaluated in a repeated acquisition task in pigeons. All of the drugs produced dose-dependent decreases in rates of responding. The NMDA receptor and channel blockers and (+)-HA-966 appeared to have a greater effect on acquisition than did morphine at doses that did not fully suppress responding. The rate suppression and learning impairment produced by a large dose of (+)-HA-966 (100 mg/kg) were completely prevented by coadministration of the glycine-site agonist D-serine (560 mg/kg) but not by its enantiomer, L-serine (1000 mg/kg). D-Serine, however, produced incomplete antagonism of the effects of dizocilpine and phencyclidine and failed to alter those of CGS-19755. These findings provide evidence that reducing the activity of the NMDA subtype of the glutamate receptor through pharmacological action at any of three sites produces similar decrements in acquisition, and those produced through antagonism of the glycine site are differentially sensitive to the glycine-site agonist D-serine.
Asunto(s)
Condicionamiento Operante/efectos de los fármacos , Maleato de Dizocilpina/farmacología , Antagonistas de Aminoácidos Excitadores/farmacología , Fenciclidina/farmacología , Ácidos Pipecólicos/farmacología , Pirrolidinonas/farmacología , Receptores de Glicina/efectos de los fármacos , Aprendizaje Seriado/efectos de los fármacos , Animales , Sistema Nervioso Central/efectos de los fármacos , Columbidae , Agonistas de Aminoácidos Excitadores/farmacología , Receptores de Glicina/agonistas , Receptores de Glicina/antagonistas & inhibidores , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Serina/farmacologíaRESUMEN
This study characterized the antinociceptive, respiratory and heart rate effects of the cannabinoid receptor agonists Delta-9-tetrahydrocannabinol (Delta-9-THC) and WIN 55212 ((R)-(+)-2, 3-dihydro-5-methyl-3-[(4-morpholinyl)methyl]pyrol-[1,2,3-de]-1, 4-benzoxazin-6-yl)(1-naphtalenyl)methanone monomethanesulfonate), N-arachidonyl ethanolamide (anandamide) and the mu and kappa opioid receptor agonists heroin and U69593, alone and in conjunction with a cannabinoid receptor antagonist, SR 141716A [N-(piperidin-1-1-yl)-5-(4-chlorophenyl)-1(2, 4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide hydrochloride] and an opioid receptor antagonist, quadazocine, in rhesus monkeys (Macaca mulatta). Using 12 adult rhesus monkeys, latencies to remove the tail from a 50 degrees C water bath, respiration in 5% CO2 and heart rate were measured. When administered alone, SR 141716A (1.8, 5.6 mg/kg i.m.) did not alter nociception, respiration or heart rate. Delta-9-THC (0.1-10 mg/kg i.m.) and WIN 55212 (0.1-10 mg/kg i.m.) dose-dependently increased antinociception and dose-dependently decreased respiratory minute and tidal volumes and heart rate. These antinociceptive, respiratory and heart rate effects were reversed by SR 141716A but not by the opioid antagonist quadazocine (1 mg/kg i.m.). Anandamide (10 mg/kg i.m.) also produced antinociception. Heroin (0.01-10 mg/kg i.m.) and U69593 (0.01-3.2 mg/kg i.m.) also dose-dependently increased antinociception and decreased respiratory and heart rate measures; these effects were antagonized by quadazocine but not by SR 141716A. These results demonstrate selective and reversible antagonism of cannabinoid behavioral effects by SR 141716A in rhesus monkeys.
Asunto(s)
Analgésicos Opioides/farmacología , Bencenoacetamidas , Frecuencia Cardíaca/efectos de los fármacos , Piperidinas/farmacología , Pirazoles/farmacología , Receptores de Droga/agonistas , Receptores Opioides/agonistas , Mecánica Respiratoria/efectos de los fármacos , Animales , Benzoxazinas , Cannabinoides/farmacología , Relación Dosis-Respuesta a Droga , Dronabinol/antagonistas & inhibidores , Dronabinol/farmacología , Alucinógenos/antagonistas & inhibidores , Alucinógenos/farmacología , Heroína/antagonistas & inhibidores , Heroína/farmacología , Macaca mulatta , Morfolinas/antagonistas & inhibidores , Morfolinas/farmacología , Naftalenos/antagonistas & inhibidores , Naftalenos/farmacología , Dimensión del Dolor/efectos de los fármacos , Pirrolidinas/antagonistas & inhibidores , Pirrolidinas/farmacología , Receptores de Cannabinoides , Receptores de Droga/antagonistas & inhibidores , RimonabantRESUMEN
Capsaicin produces burning pain, followed by nociceptive responses, such as allodynia and hyperalgesia in humans and rodents. In the present study, when administered subcutaneously into the tail of rhesus monkeys, capsaicin (0.01-0.32 mg) dose-dependently produced thermal allodynia manifested as reduced tail-withdrawal latencies in 46 degrees C water, from a maximum value of 20 sec to approximately 2 sec. Coadministration of selective mu opioid agonists, fentanyl (0.003-0.1 mg) and (D-Ala2,N-Me-Phe4, Gly5-ol)-enkephalin (0.001-0.03 mg), dose-dependently inhibited capsaicin-induced allodynia. This local antinociception was antagonized by small doses of opioid antagonists, quadazocine (0.03 mg) and quaternary naltrexone (1 mg), applied locally in the tail. However, these doses of antagonists injected s.c. in the back did not antagonize local fentanyl. Comparing the relative potency of either agonist or antagonist after local and systemic administration confirmed that the site of action of locally applied mu opioid agonists is in the tail. These results provide evidence that activation of peripheral mu opioid receptors can diminish capsaicin-induced allodynia in primates. This experimental pain model could be a useful tool for evaluating peripherally acting antinociceptive agents without central side effects and enhance new approaches to the treatment of inflammatory pain.
Asunto(s)
Capsaicina/farmacología , Dolor/inducido químicamente , Receptores Opioides mu/fisiología , Animales , Azocinas/farmacología , Encefalina Ala(2)-MeFe(4)-Gli(5) , Encefalinas/farmacología , Femenino , Calor , Macaca mulatta , Masculino , Naltrexona/farmacología , Dolor/tratamiento farmacológicoRESUMEN
Naltrexone (NTX) exhibited approximately 3-fold higher affinity for sites labeled by [3H]U69,593 (putative kappa 1-selective ligand) than [3H]bremazocine (non-selective ligand) in the presence of mu and delta receptor blockade in monkey brain membranes. This led us to test an hypothesis that NTX could display in vivo antagonist selectivity for kappa 1-versus non-kappa 1-mediated effects. Six opioid agonists were characterized by NTX apparent pA2 analysis in a 50 degrees C water tail-withdrawal assay in rhesus monkeys. Constrained NTX pA2 values (95% confidence limits) were: alfentanil, 8.66 (8.47-8.85); ethylketocyclazocine, 7.97 (7.93-8.01); U69,593, 7.64 (7.49-7.79); U50,488, 7.55 (7.42-7.67); bremazocine, 6.92 (6.73-7.12); enadoline, 6.87 (6.69-7.05). Pretreatment with clocinnamox, an irreversible mu antagonist, confirmed that mu receptors were not involved in the antinociception produced by the kappa agonists, U69,593, U50,488, bremazocine and enadoline; however, both mu and kappa receptors mediated the antinociceptive effects of ethyl-ketocyclazocine. The apparent NTX pA2 profile of opioid agonists correlated highly with the radioligand binding studies, which indicates that U69,593 and U50,488 produced antinociception by acting on kappa-1 receptors, whereas bremazocine and enadoline probably acted via non-kappa-1 receptors. This study provides further functional evidence of kappa opioid receptor multiplicity in primates and suggests that NTX may be a useful tool to study this phenomenon in vivo.
Asunto(s)
Analgésicos Opioides/farmacología , Naltrexona/farmacología , Antagonistas de Narcóticos/farmacología , Receptores Opioides kappa/agonistas , Animales , Cinamatos/farmacología , Relación Dosis-Respuesta a Droga , Encefalina Ala(2)-MeFe(4)-Gli(5) , Encefalinas/metabolismo , Femenino , Macaca mulatta , Masculino , Derivados de la Morfina/farmacología , Receptores Opioides kappa/clasificación , Receptores Opioides kappa/metabolismoRESUMEN
The binding characteristics of the kappa opioid ligands [3H]U69,593 and [3H]bremazocine, the mu opioid ligand [3H][D-ala2,N-Me-Phe4,glycol5]enkephalin and the delta opioid ligand [3H]p-Cl-[D-pen2,5]enkephalin were studied in rhesus monkey brain membranes in saturation binding experiments and were followed by competition binding experiments with a variety of peptidic and nonpeptidic opioid ligands. The [3H]U69,593 sites appeared to be a subset of kappa opioid receptors (kappa-1 receptors: Kd, 1.2 nM; Bmax, 66 fmol/mg). [3H]Bremazocine (in the presence of mu and delta receptor-masking agents), bound to a larger population of kappa receptors (kappa-all: Kd, 0.39 nM; Bmax, 227 fmol/mg), which presumably included the aforementioned kappa-1 sites. Competition binding experiments revealed that the presently defined kappa-1 sites were similar to previously reported sites in other mammalian species, particularly in terms of the higher kappa-1 selectivity observed with arylacetamide (e.g., U50,488) vs. benzomorphan kappa agonists (e.g., ethylketocyclazocine). The kappa-selective antagonist norbinaltorphimine (nor-BNI) displayed a very small (2.3-fold) selectivity for kappa-1 vs. kappa-all sites. This led to the prediction that in rhesus monkeys (n = 3), systemically administered nor-BNI (10 mg/kg s.c.) should have a very moderate degree of antagonist selectivity for the antinociceptive effects of a putative kappa-1-agonist, the arylacetamide U50,488 (0.1-3.2 mg/kg s.c.), vs. those of the benzomorphan kappa agonist ethylketocyclazocine (0.01-056 mg/kg s.c.). This prediction was confirmed in vivo because nor-BNI (10 mg/kg) caused a robust and long lasting (up to 21 days) antagonism of the antinociceptive effects of U50,488 and a small but significant antagonism of ethylketocyclazocine. The arylacetamide congener Cl-977 (enadoline), which displayed an 11-fold kappa-1 vs. kappa-all binding selectivity, was not sensitive to nor-BNI pretreatment. This indicates that the kappa subtype-binding profile of an agonist is not necessarily predictive of its sensitivity to nor-BNI in vivo. Overall, the present results suggest that at least two functional kappa receptor populations may be present in rhesus monkey brain.
Asunto(s)
Analgésicos Opioides/farmacología , Química Encefálica , Receptores Opioides kappa/análisis , Animales , Benzofuranos/farmacología , Butorfanol/farmacología , Relación Dosis-Respuesta a Droga , Calor , Macaca mulatta , Nalbufina/farmacología , Naltrexona/análogos & derivados , Naltrexona/farmacología , Pirrolidinas/farmacología , Ensayo de Unión RadioliganteRESUMEN
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
E-2078 is a dynorphin A (1-8) analog, [N-methyl-Tyr1, N-methyl-Arg7-D-Leu8] Dyn A (1-8) ethylamide. Its biochemical stability against enzymatic degradation in vitro in human and rhesus monkey blood, and in vivo in rhesus monkey blood was studied using matrix-assisted laser desorption/ionization mass spectrometry. In vitro studies were carried out in freshly drawn human and rhesus monkey blood, incubated at 37 degrees C for various time periods. In vivo studies were conducted by E-2078 i.v. injection to rhesus monkeys, and blood samples were collected at various time points after the injection. It was found that E-2078 was stable against enzymatic degradation in vitro in freshly drawn human and rhesus monkey blood. Minor biotransformation products from E-2078, such as E (1-4), E (1-5) and E (3-6), were detected in vitro in some human and rhesus monkey blood, but they made up less than 5% of the total starting E-2078 peptide. No biotransformation products were detected in the blood samples from in vivo studies. The apparent half-life of elimination of E-2078 in vivo from the rhesus monkey blood was determined to be 44.0 min.
Asunto(s)
Analgésicos no Narcóticos/sangre , Dinorfinas/sangre , Fragmentos de Péptidos/sangre , Adulto , Analgésicos no Narcóticos/farmacocinética , Animales , Biotransformación , Dinorfinas/farmacocinética , Femenino , Humanos , Macaca mulatta , Masculino , Fragmentos de Péptidos/farmacocinética , Estándares de Referencia , Espectrometría de Masa por Láser de Matriz Asistida de Ionización DesorciónRESUMEN
Dynorphin A (1-17) [Dyn A (1-17)] is an endogenous opioid peptide. In vitro biotransformation of Dyn A (1-17) in human and rhesus monkey blood was studied by matrix-assisted laser desorption/ionization mass spectrometry. Biotransformation was observed to produce various opioid and nonopioid dynorphin A peptides. In this study, in vitro Dyn A (1-17) biotransformation at physiological temperature (37 degrees C) was found to be very similar in human and rhesus monkey blood, although Dyn A (1-17) processing occurred at a faster rate in vitro in monkey blood than in human blood. One dominant pathway in this biotransformation was the slow removal of tyrosine at position one from Dyn A (1-17) to yield the dominant product, Dyn A (2-17). Further slow biotransformation of Dyn A (2-17) also occurred. Another major pathway of Dyn A (1-17) biotransformation is cleavage of the peptide linkage between Arg(6) and Arg(7) to produce the opioid peptide, Dyn A (1-6), and the nonopioid peptide, Dyn A (7-17). These two peptides had a short lifetime in blood, undergoing rapid biotransformation. Our results indicate that the rhesus monkey may be a good model for further in vivo pharmacological and neurobiological studies.