RESUMEN
In a preclinical model of natural reward devaluation by cocaine, taste cues elicit aversive taste reactivity when they predict impending but delayed cocaine self-administration. Here, we investigated this negative affective state as a function of cocaine dose. Male, Sprague-Dawley rats were given 45 brief intraoral infusions of a 0.15% saccharin solution before 2 h cocaine self-administration for 14 days. Rats were video recorded; taste reactivity and patterns of self-administration were quantified on the first and last days. On day 14, a significant decrease in appetitive taste reactivity and increase in aversive taste reactivity was observed (compared with day 1) that did not vary as a function of cocaine dose. In contrast, patterns of cocaine self-administration (i.e. the total number of lever presses and load-up behavior) varied as a function of dose across days. Further, load-up behavior was positively correlated with aversive taste reactivity (i.e. gapes) on day 14 across all doses tested. Collectively, these findings indicate that the emergence of negative affect in this preclinical model is not dependent on cocaine dose.
Asunto(s)
Cocaína/administración & dosificación , Inhibidores de Captación de Dopamina/administración & dosificación , Recompensa , Percepción del Gusto/efectos de los fármacos , Animales , Relación Dosis-Respuesta a Droga , Comportamiento de Búsqueda de Drogas/efectos de los fármacos , Masculino , Modelos Animales , Ratas Sprague-Dawley , Sacarina/administración & dosificación , Autoadministración , Grabación en VideoRESUMEN
INTRODUCTION: Opioid withdrawal syndrome is a critical component of opioid abuse and consists of a wide array of symptoms including increases in pain sensitivity (hyperalgesia). A reliable preclinical model of hyperalgesia during opioid withdrawal is needed to evaluate possible interventions to alleviate withdrawal. The following study describes a method for assessing increases in thermal sensitivity on the hotplate in a mouse model of spontaneous morphine withdrawal. METHODS: C57BL/6J mice received 5.5days of 30, 56, or 100mg/kg morphine or saline (s.c., twice daily). In Experiment I, thermal sensitivity data were collected at baseline and at 8, 24, 32, 48h and 1week following the final injection. Thermal sensitivity was assessed by examining latency to respond on a hotplate across a range of temperatures (50, 52, 54, and 56°C). In Experiment II, 0.01mg/kg buprenorphine was administered 30min prior to each testing session during the withdrawal period. In Experiment III, jumping during a 30min period was assessed at baseline and at 0, 8, 24, 32, and 48h following the final morphine injection. RESULTS: During the withdrawal period, thermal sensitivity increased significantly in all morphine-treated mice as compared to saline-treated mice. Thermal sensitivity was greater in mice treated with 56mg/kg morphine compared to 30mg/kg and peaked earlier than in mice treated with 100mg/kg (32h v 1wk). The increase in thermal sensitivity following 56mg/kg morphine was attenuated by a dose of buprenorphine that did not produce antinociception alone (i.e., 0.01mg/kg). In general, the results of the jumping experiment paralleled those obtained in Experiment I. DISCUSSION: Response latency on the hotplate is a reliable and sensitive measure of spontaneous morphine withdrawal in mice, making it an ideal behavior for assessing the potential of medications and environmental interventions to alleviate opioid withdrawal.
Asunto(s)
Conducta Animal/efectos de los fármacos , Hiperalgesia/etiología , Hiperalgesia/fisiopatología , Morfina/toxicidad , Síndrome de Abstinencia a Sustancias/complicaciones , Síndrome de Abstinencia a Sustancias/fisiopatología , Animales , Buprenorfina/farmacología , Calor , Masculino , Ratones , Ratones Endogámicos C57BL , Antagonistas de Narcóticos/farmacología , Umbral del Dolor/fisiologíaRESUMEN
RATIONALE: There is evidence to suggest that the rewarding effects of drugs of abuse can be altered by environmental manipulations such as housing conditions and access to running wheels. There is less information about how these environmental manipulations alter withdrawal behaviors following the termination of chronic drug administration. OBJECTIVES: The objective of this study is to examine the effects of access to running wheels and group housing on spontaneous morphine withdrawal. METHODS: C57BL/6J mice were assigned to one of the three housing conditions: wheel access (singly housed), no wheels (singly housed), or group-housed (no wheels). Mice received 30 or 56 mg/kg morphine or saline (s.c.) twice daily for 5.5 days. At baseline and at 8, 24, 32, and 48 h following the final injection, latency to respond on a hot plate was determined across a range of temperatures (50, 52, 54, and 56 °C). RESULTS: Latency to respond decreased as a function of temperature. Response latencies during the withdrawal period were decreased in mice without wheel access treated with both 30 and 56 mg/kg of morphine. This increase in thermal sensitivity was significantly attenuated in singly housed mice with wheel access and in group-housed mice; however, the effects were less pronounced in the group-housed mice and depended upon the time during withdrawal. CONCLUSIONS: Both wheel access and group housing attenuate the increase in thermal sensitivity seen in morphine-treated mice during morphine withdrawal.
Asunto(s)
Vivienda para Animales , Dependencia de Morfina/fisiopatología , Carrera/fisiología , Síndrome de Abstinencia a Sustancias/rehabilitación , Animales , Relación Dosis-Respuesta a Droga , Calor , Masculino , Ratones , Ratones Endogámicos C57BL , Morfina/administración & dosificación , Morfina/efectos adversos , Recompensa , Temperatura , Factores de TiempoRESUMEN
Inhibitors of fatty acid amide hydrolase (FAAH) and anandamide (AEA) uptake, which limit the degradation of endogenous cannabinoids, have received interest as potential therapeutics for pain. There is also evidence that endogenous cannabinoids mediate the antinociceptive effects of opioids. Assays of pain-elicited and pain-suppressed behavior have been used to differentiate the effects of drugs that specifically alter nociception from drugs that alter nociception caused by nonspecific effects such as catalepsy or a general suppression of activity. Using such procedures, this study examines the effects of the direct cannabinoid type 1 (CB1) agonist (-)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(3-hydroxypropyl)cyclohexanol (CP55940), the FAAH inhibitor cyclohexylcarbamic acid 3'-carbamoylbiphenyl-3-yl ester (URB597), and the AEA uptake inhibitor N-(4-hydroxyphenyl) arachidonylamide (AM404). Additional experiments examined these compounds in combination with morphine. CP55940 produced antinociception in assays of pain-elicited, but not pain-suppressed, behavior and disrupted responding in an assay of schedule-controlled behavior. URB597 and AM404 produced antinociception in assays of pain-elicited and pain-suppressed behavior in which acetic acid was the noxious stimulus, but had no effect on the hotplate and schedule-controlled responding. CP55940 in combination with morphine resulted in effects greater than those of morphine alone in assays of pain-elicited and scheduled-controlled behavior but not pain-suppressed behavior. URB597 in combination with morphine resulted in enhanced morphine effects in assays of pain-elicited and pain-suppressed behavior in which diluted acetic acid was the noxious stimulus, but did not alter morphine's effects on the hotplate or schedule-controlled responding. These studies suggest that, compared with direct CB1 agonists, manipulations of endogenous cannabinoid signaling have enhanced clinical potential; however, their effects depend on the type of noxious stimulus.
Asunto(s)
Moduladores de Receptores de Cannabinoides/metabolismo , Morfina/farmacología , Dolor/tratamiento farmacológico , Dolor/metabolismo , Amidohidrolasas/antagonistas & inhibidores , Analgésicos/farmacología , Animales , Ácidos Araquidónicos/antagonistas & inhibidores , Ácidos Araquidónicos/farmacología , Benzamidas/farmacología , Carbamatos/farmacología , Ciclohexanoles/farmacología , Endocannabinoides/antagonistas & inhibidores , Masculino , Ratones , Ratones Endogámicos C57BL , Nocicepción/efectos de los fármacos , Alcamidas Poliinsaturadas/antagonistas & inhibidores , Receptor Cannabinoide CB1/antagonistas & inhibidores , Receptor Cannabinoide CB1/metabolismoRESUMEN
The present study examined the effects of the mGluR1 antagonist JNJ16259685 (JNJ) and the mGluR5 antagonist 2-methyl-6-phenylethynylpyridine (MPEP) alone and in combination with morphine in two acute pain models (hotplate, warm water tail-withdrawal), and a persistent, inflammatory pain model (capsaicin). In the hotplate and warm water tail-withdrawal procedures, JNJ and MPEP were ineffective when administered alone. In both procedures, JNJ potentiated morphine antinociception. In the hotplate procedure, MPEP potentiated morphine antinociception at the highest dose examined, whereas in the warm water tail-withdrawal procedure MPEP attenuated morphine antinociception at a moderate dose and potentiated morphine antinociception at a high dose. For both JNJ and MPEP, the magnitude of this morphine potentiation was considerably greater in the hotplate procedure. In the capsaicin procedure, the highest dose of MPEP produced intermediate levels of antihyperalgesia and also attenuated the effects of a dose of morphine that produced intermediate levels of antihyperalgesia. In contrast, JNJ had no effect when administered alone in the capsaicin procedure and did not alter morphine-induced antihyperalgesia. The present findings suggest that the effects produced by mGluR1 and mGluR5 antagonists alone and in combination with morphine can be differentiated in models of both acute and persistent pain.
Asunto(s)
Antagonistas de Aminoácidos Excitadores/uso terapéutico , Morfina/uso terapéutico , Narcóticos/uso terapéutico , Dolor/tratamiento farmacológico , Piridinas/uso terapéutico , Quinolinas/uso terapéutico , Receptores de Glutamato Metabotrópico/antagonistas & inhibidores , Animales , Conducta Animal/efectos de los fármacos , Capsaicina , Modelos Animales de Enfermedad , Quimioterapia Combinada , Antagonistas de Aminoácidos Excitadores/farmacología , Inflamación/tratamiento farmacológico , Masculino , Morfina/farmacología , Dolor/inducido químicamente , Dimensión del Dolor/efectos de los fármacos , Piridinas/farmacología , Quinolinas/farmacología , Ratas , Ratas Endogámicas F344RESUMEN
This study explored the involvement of N-methyl-D-aspartate (NMDA) in the effects of µ-opioid agonists. A hot-plate procedure was used to assess antinociception and tolerance in mice in which the NR1 subunit of the NMDA receptor was reduced [knockdown (KD)] to approximately 10%, and in mice treated with the NMDA antagonist, (-)-6-phosphonomethyl-deca-hydroisoquinoline-3-carboxylic acid (LY235959). The µ opioid agonists, morphine, l-methadone and fentanyl, were approximately three-fold less potent in the NR1 KD mice than in wild-type (WT) controls; however, the development of morphine tolerance and dependence did not differ markedly in the NR1 KD and the WT mice. Acute administration of the NMDA antagonist, LY235959, produced dose-dependent, leftward shifts in the morphine dose-effect curve in the WT mice, but not in the NR1 KD mice. Chronic administration of LY235959 during the morphine tolerance regimen did not attenuate the development of tolerance in the NR1 KD or the WT mice. These results indicate that the NR1 subunit of the NMDA receptor does not play a prominent role in µ opioid tolerance.
Asunto(s)
Analgésicos Opioides/farmacología , Morfina/farmacología , Dolor/tratamiento farmacológico , Receptores de N-Metil-D-Aspartato/metabolismo , Analgésicos Opioides/administración & dosificación , Animales , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Tolerancia a Medicamentos , Antagonistas de Aminoácidos Excitadores/administración & dosificación , Antagonistas de Aminoácidos Excitadores/farmacología , Técnicas de Silenciamiento del Gen , Isoquinolinas/administración & dosificación , Isoquinolinas/farmacología , Masculino , Ratones , Morfina/administración & dosificación , Dependencia de Morfina/metabolismo , Receptores de N-Metil-D-Aspartato/efectos de los fármacos , Receptores de N-Metil-D-Aspartato/genética , Receptores Opioides mu/agonistasRESUMEN
RATIONALE: Pharmacological manipulations of the type 1 cannabinoid receptor (CB1) suggest a role for CB1 in morphine-induced antinociception, but studies utilizing CB1 knockout (KO) mice do not support this conclusion. Since studies using CB1 KO mice to study morphine's antinociceptive effects have only examined thermal nociception, this study examines these interactions in models that employ a chemical stimulus. OBJECTIVES: To determine whether the findings obtained with thermal pain models extend to other models, the effects of morphine on acetic acid-induced writhing were examined in CB1 KO and wildtype (WT) mice. Behaviors that decrease in response to acid injection, feeding and wheel running, were also examined, and investigations were carried out in the thermal hotplate assay. The CB1 antagonist SR141716A was also examined in these assays. RESULTS: Morphine completely blocked acid-induced writhing (1.0-10.0 mg/kg) and increased response latencies in the hotplate (10.0-32.0 mg/kg) in both genotypes. Morphine (3.2 mg/kg) significantly attenuated the suppression of wheel running but did not completely prevent this effect in either genotype. Morphine did not alter pain-suppressed feeding. In each of these assays, morphine's effects were not altered in CB1 KO mice compared with WT mice; however, SR141716A attenuated morphine's effects in C57BL/6 mice. CONCLUSIONS: The effects of morphine do not differ in CB1 KO and WT mice in preclinical pain models using thermal and chemical stimuli. Since SR141716A did attenuate the effects of morphine, it is possible that CB1 KO mice undergo developmental changes that mask the role of CB1 receptors in morphine's antinociceptive effects.
Asunto(s)
Analgésicos Opioides/farmacología , Morfina/farmacología , Dolor/tratamiento farmacológico , Receptor Cannabinoide CB1/genética , Analgésicos Opioides/administración & dosificación , Animales , Conducta Animal/efectos de los fármacos , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Femenino , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Morfina/administración & dosificación , Dolor/fisiopatología , Dimensión del Dolor , Piperidinas/farmacología , Pirazoles/farmacología , RimonabantRESUMEN
CB(1) cannabinoid (CB(1)) receptor agonists and N-Methyl-d-Aspartate (NMDA) receptor antagonists attenuate the development of morphine antinociceptive tolerance. The present study used dose-addition analysis to evaluate CB(1)/NMDA receptor interactions on this endpoint. Chronic morphine administration (5 days, 100 mg/kg, twice daily) resulted in a 2.8-fold rightward shift in the morphine dose-effect curve. Co-administration of either the CB(1) receptor agonist CP-55940 (5-(1,1-Dimethylheptyl)-2-[5-hydroxy-2-(3-hydroxypropyl)cyclohexyl]phenol; 0.32-1.0 mg/kg) or the NMDA receptor antagonist (-)-6-phosphonomethyl-deca-hydroisoquinoline-3-carboxylic acid (LY235959; 1.0-3.2 mg/kg) with morphine dose-dependently attenuated morphine tolerance. The relative potency of each drug alone was quantified using a defined level of effect (one-quarter log shift in the morphine dose-effect curve), resulting in equieffective doses of 0.42 mg/kg and 1.1 mg/kg for CP-55940 and LY235959, respectively. Subsequent experiments assessed CP-55940/LY235959 interactions using a fixed-proportion design. Co-administration of CP-55940/LY235959 mixtures (1:1, 1:3.2, or 1:10 CP-55940/LY235959) with morphine dose-dependently attenuated morphine tolerance. Isobolographic and dose-addition analysis were used to statistically compare the experimentally determined potency for each mixture (z(mix)) with predicted additive potency (z(add)). Mixtures of 1:1 and 1:3.2 CP-55940/LY235959 produced additive effects (z(add) = z(mix)), while the mixture of 1:10 CP-55940/LY235959 produced a supra-additive effect (z(add) > z(mix)). These results suggest that CP-55940 and LY235959 produce additive or supra-additive attenuation of morphine antinociceptive tolerance after repeated morphine administration, depending on their relative concentrations.
Asunto(s)
Analgésicos Opioides/farmacología , Tolerancia a Medicamentos , Morfina/farmacología , Dolor/tratamiento farmacológico , Receptor Cannabinoide CB1/agonistas , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Analgésicos/administración & dosificación , Analgésicos/farmacología , Analgésicos Opioides/administración & dosificación , Animales , Ciclohexanoles/administración & dosificación , Ciclohexanoles/farmacología , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Quimioterapia Combinada , Antagonistas de Aminoácidos Excitadores/administración & dosificación , Antagonistas de Aminoácidos Excitadores/farmacología , Calor , Isoquinolinas/administración & dosificación , Isoquinolinas/farmacología , Masculino , Ratones , Ratones Endogámicos C57BL , Morfina/administración & dosificación , Dolor/metabolismo , Dimensión del Dolor , Receptor Cannabinoide CB1/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismoRESUMEN
Cannabinoid CB1 antagonists decrease self-administration of palatable food and several abused drugs in animals and modulate extinction of conditioned fear responses. Less is known, however, about whether and how CB1 antagonists might modulate the extinction of appetitive behavior. Therefore, this study examined the effects of the CB1 receptor antagonist rimonabant (SR141716) during extinction of responding maintained either by cocaine or by palatable foods (corn oil or Ensure), as well as responding elicited by stimulus cues that had been paired with the presentation of cocaine (i.e., cue-induced reinstatement) or a prime (presentation of cocaine or food). The effect of rimonabant on high rate responding in water-deprived mice trained to self-administer water was also examined. In mice self-administering cocaine, rimonabant attenuated cue-induced reinstatement of cocaine self-administration, the initial burst of responding during cocaine extinction and responding during spontaneous recovery. In mice self-administering corn oil, rimonabant decreased responding during extinction and also attenuated responding that had been reinstated by a priming presentation of corn oil. Moreover, mice treated with rimonabant required fewer daily sessions to reach criterion for extinction of cocaine-maintained responding than vehicle treated mice. Also, rimonabant had no effect on the rate of operant responding in mice trained to respond for water under an FR5 schedule of reinforcement. Taken together, these data suggest that in addition to attenuating the primary reinforcing effects of both palatable foods and drugs of abuse, CB1 receptor antagonism can attenuate context and cue reactivity during extinction learning and potentially enhance extinction learning in this way.
Asunto(s)
Trastornos Relacionados con Cocaína/prevención & control , Cocaína/administración & dosificación , Extinción Psicológica/efectos de los fármacos , Piperidinas/farmacología , Pirazoles/farmacología , Receptor Cannabinoide CB1/antagonistas & inhibidores , Autoadministración/psicología , Animales , Conducta Adictiva/tratamiento farmacológico , Trastornos Relacionados con Cocaína/tratamiento farmacológico , Condicionamiento Operante/efectos de los fármacos , Aceite de Maíz/administración & dosificación , Señales (Psicología) , Sacarosa en la Dieta/administración & dosificación , Modelos Animales de Enfermedad , Alimentos Formulados , Masculino , Ratones , Ratones Endogámicos C57BL , Piperidinas/uso terapéutico , Pirazoles/uso terapéutico , Recurrencia , Esquema de Refuerzo , Rimonabant , Agua/administración & dosificaciónRESUMEN
Cannabinoid signaling via the type 1 cannabinoid (CB1) receptor modulates the effects of drugs of abuse and the response to exposure to stressors. In addition, exposure to stressors can alter the effects of drugs of abuse. This study examined the effects of exposure to chronic unpredictable stress (CUS) in CB1 receptor knockout (CB1 KO) mice and their wild-type (WT) littermates, using cocaine-conditioned place preference (CPP) to compare their response to cocaine. Mice were untreated or exposed to 2 weeks of CUS. After this period, the acquisition of a cocaine CPP was examined with one of three doses (3.2, 10.0, or 17.0 mg/kg) of cocaine. Untreated CB1 KO and WT mice both acquired the cocaine CPP; however, exposure to CUS enhanced the acquisition of the cocaine CPP in CB1 KO mice, but did not significantly alter the effects of cocaine in WT mice. Taken together, these findings support earlier evidence suggesting a role for the CB1 receptor in the response to stress as well as in the effects of cocaine.
Asunto(s)
Trastornos Relacionados con Cocaína/genética , Condicionamiento Clásico/fisiología , Receptor Cannabinoide CB1/genética , Medio Social , Estrés Psicológico/complicaciones , Animales , Nivel de Alerta/efectos de los fármacos , Nivel de Alerta/genética , Encéfalo/efectos de los fármacos , Encéfalo/fisiopatología , Cocaína/farmacología , Trastornos Relacionados con Cocaína/fisiopatología , Relación Dosis-Respuesta a Droga , Genotipo , Ratones , Ratones Endogámicos BALB C , Ratones Noqueados , Actividad Motora/efectos de los fármacos , Actividad Motora/genética , Receptor Cannabinoide CB1/fisiología , Transducción de Señal/genética , Transducción de Señal/fisiologíaRESUMEN
RATIONALE: Recent experimental data suggest that metabotropic glutamate receptor (mGluR) antagonists with selectivity for mGluR1 and mGluR2/3 enhance morphine-induced antinociception. OBJECTIVES: The present study addressed the hypothesis that mGluR antagonists enhance opioid antinociception by increasing opioid efficacy. MATERIALS AND METHODS: The antinociceptive effects of the partial mu-opioid receptor agonists buprenorphine and dezocine were first assessed in a hot-plate procedure under conditions of low (53 degrees C) and high (56 degrees C) stimulus intensity. Under conditions in which buprenorphine and dezocine produced submaximal antinociceptive effects, these drugs were assessed after pretreatment with the mGluR1 antagonist JNJ16259685, the mGluR5 antagonist MPEP, the mGluR2/3 antagonist LY341495, and for comparison, the N-methyl-D-aspartate (NMDA) receptor antagonist LY235959. RESULTS: Buprenorphine (0.032-3.2 mg/kg) and dezocine (0.1-10 mg/kg) were fully efficacious at 53 degrees C and produced submaximal antinociceptive effects at 56 degrees C (i.e., their effects did not exceed 50% of the maximum possible effect). Pretreatment with JNJ16259685 (1.0-3.2 mg/kg), LY341495 (1.0-3.2 mg/kg), and LY235959 (0.32-1.0 mg/kg) enhanced the antinociceptive effects of buprenorphine and dezocine at 56 degrees C, as revealed by significant increases in the peak effects of both drugs to approximately 100% maximum possible effect. In contrast, pretreatment with MPEP (1.0-3.2 mg/kg) did not modulate the antinociceptive effects of buprenorphine and dezocine. CONCLUSIONS: These results suggest that, similar to the NMDA receptor antagonist LY235959, the mGluR1 antagonist JNJ16259685 and the mGluR2/3 antagonist LY341495 increase the antinociceptive efficacy of buprenorphine and dezocine.
Asunto(s)
Analgésicos Opioides/farmacología , Antagonistas de Aminoácidos Excitadores/farmacología , Isoquinolinas/farmacología , Receptores de Glutamato Metabotrópico/antagonistas & inhibidores , Receptores Opioides mu/agonistas , Animales , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Buprenorfina/farmacología , Relación Dosis-Respuesta a Droga , Calor , Masculino , Ratones , Ratones Endogámicos C57BL , Morfina/farmacología , Antagonistas de Narcóticos/farmacología , Dimensión del Dolor/efectos de los fármacos , Tetrahidronaftalenos/farmacologíaRESUMEN
NMDA receptor-mediated glutamate transmission is required for several forms of neuronal plasticity. Its role in the neuronal responses to addictive drugs is an ongoing subject of investigation. We report here that the acute locomotor-stimulating effect of cocaine is absent in NMDA receptor-deficient mice (NR1-KD). In contrast, their acute responses to amphetamine and to direct dopamine receptor agonists are not significantly altered. The striking attenuation of cocaine's acute effects is not likely explained by alterations in the dopaminergic system of NR1-KD mice, since most parameters of pre- and postsynaptic dopamine function are unchanged. Consistent with the behavioral findings, cocaine induces less c-Fos expression in the striatum of these mice, while amphetamine-induced c-Fos expression is intact. Furthermore, chronic cocaine-induced sensitization and conditioned place preference are attenuated and develop more slowly in mutant animals, but amphetamine's effects are not altered significantly. Our results highlight the importance of NMDA receptor-mediated glutamatergic transmission specifically in cocaine actions, and support a hypothesis that cocaine and amphetamine elicit their effects through differential actions on signaling pathways.
Asunto(s)
Anfetamina/administración & dosificación , Cocaína/administración & dosificación , Receptores de N-Metil-D-Aspartato/deficiencia , Receptores de N-Metil-D-Aspartato/genética , Animales , Condicionamiento Psicológico/efectos de los fármacos , Condicionamiento Psicológico/fisiología , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos DBA , Actividad Motora/efectos de los fármacos , Actividad Motora/fisiologíaRESUMEN
The present study examined the interactive effects of morphine in combination with metabotropic glutamate (mGlu) receptor antagonists on schedule-controlled responding and thermal nociception. Drug interaction data were examined with isobolographic and dose-addition analysis. Morphine, the mGlu1 receptor antagonist JNJ16259685 [(3,4-dihydro-2H-pyrano-[2,3-b]quinolin-7-yl)-(cis-4-methoxycyclohexyl)-methanone], the mGlu5 receptor antagonist MPEP [2-methyl-6-(phenylethynyl)pyridine hydrochloride], and the mGlu2/3 receptor antagonist LY341495 [(2S)-2-amino-2-[(1S,2S-2-carboxycycloprop-1-yl]-3-(xanth-9-yl) propanoic acid] all decreased rates of schedule-controlled responding. JNJ16259685/morphine, MPEP/morphine, and LY341495/morphine mixtures produced additive effects on this endpoint. Morphine also produced dose-dependent antinociception in the assay of thermal nociception, whereas JNJ16259685, MPEP, and LY341495 failed to produce an effect. In this assay, JNJ16259685 and LY341495 potentiated the antinociceptive effects of morphine, whereas MPEP/morphine mixtures produced additive effects. These results suggest that an mGlu1 and an mGlu2/3 receptor antagonist, but not an mGlu5 receptor antagonist, selectively enhance the antinociceptive effects of morphine. In addition, these data confirm that the behavioral effects of drug mixtures depend on the endpoint under study.
Asunto(s)
Antagonistas de Aminoácidos Excitadores/administración & dosificación , Calor/efectos adversos , Morfina/administración & dosificación , Dimensión del Dolor/efectos de los fármacos , Receptores de Glutamato Metabotrópico/antagonistas & inhibidores , Esquema de Refuerzo , Animales , Condicionamiento Operante/efectos de los fármacos , Condicionamiento Operante/fisiología , Relación Dosis-Respuesta a Droga , Quimioterapia Combinada , Masculino , Ratones , Ratones Endogámicos C57BL , Dolor/tratamiento farmacológico , Dolor/psicología , Dimensión del Dolor/métodos , Receptores de Glutamato Metabotrópico/fisiologíaRESUMEN
The cannabinoid CB1 receptor antagonist SR141716A decreases cue-induced reinstatement of sucrose and drug seeking in rats. Reinstatement behavior is not well characterized in C57Bl/6 mice, including CB1 receptor knockout mice generated on a C57Bl/6 background. In the present study, male C57Bl/6, CB1 knockout (CB1 KO), and wild-type littermate (WT) mice were trained to respond for the sweet reinforcer Ensure or corn oil. Responding was maintained on a fixed ratio 1 (FR1) schedule of reinforcement for 10 days, and then extinguished by the removal of the reinforcer and associated cues. Subsequently, the effect of either pretreatment with SR141716A or CB1 receptor knockout on cue-induced reinstatement of Ensure or corn-oil seeking was assessed. Both 1.0 and 3.0 mg/kg SR141716A decreased reinstatement of Ensure seeking in C57Bl/6 mice. A tenfold higher dose of SR141716A (10.0 mg/kg) was required to attenuate reinstatement behavior in C57Bl/6 mice responding for corn oil, suggesting that CB1 receptors may be selectively involved in the neurobiology underlying reinstatement of responding for some food reinforcers but not others. Whereas CB1 receptor antagonism selectively attenuated reinstatement of responding for Ensure, genetic deletion of the CB1 receptor produced only a trend in decreasing reinstatement of Ensure seeking, and did not attenuate reinstatement of corn-oil seeking. Baseline differences in levels of operant responding were also observed in WT vs CB1 KO mice maintained by Ensure and corn oil. This and other possible reasons for the observed discrepancy between pharmacological blockade vs genetic invalidation of the CB1 receptor on reinstatement of Ensure seeking are discussed.
Asunto(s)
Condicionamiento Operante/efectos de los fármacos , Señales (Psicología) , Sacarosa en la Dieta/administración & dosificación , Conducta Alimentaria/efectos de los fármacos , Piperidinas/farmacología , Pirazoles/farmacología , Receptor Cannabinoide CB1/deficiencia , Animales , Conducta Animal , Aceite de Maíz/administración & dosificación , Alimentos Formulados , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Receptor Cannabinoide CB1/antagonistas & inhibidores , Esquema de Refuerzo , Rimonabant , Autoadministración/métodosRESUMEN
RATIONALE: Muscarinic acetylcholine receptors (M1-M5) modulate the activity of the central nervous system and an array of physiological functions. Recent evidence has also implicated muscarinic receptors in behavioral effects of drugs of abuse such as morphine and cocaine. However, the genetic similarity between muscarinic receptors and the coexpression of multiple subtypes in most cells has impeded the development of selective antagonists and the determination of the role of each muscarinic receptor subtype in morphine's and cocaine's behavioral effects. OBJECTIVE: The present studies employ mice deficient in the M1 receptor subtype (M1 KO) to assess morphine antinociception (2.5, 5.0, 10, or 20 mg/kg) and the conditioned rewarding effects of morphine and cocaine (2.5, 5.0, or 10 mg/kg). METHODS: M1 KO and their wild-type (WT) littermates were tested using a 56 degrees C hotplate assay and a conditioned place preference procedure. Parallel studies using the M1 receptor antagonist, pirenzepine, were also conducted in the background strain C57BL6 mice. RESULTS: The results demonstrate that M1 KO mice display a greater antinociceptive effect of morphine in the hotplate assay; however, the effects of morphine as well as cocaine were attenuated in the conditioned place preference procedure. Comparable results were obtained with the pharmacological antagonism of the M1 receptor by pirenzepine. CONCLUSIONS: These results suggest a modulatory role of the M1 muscarinic receptor in opioid antinociception and conditioned drug reward, and demonstrate the utility of M1 receptor knockout models for the determination of the role of the M1 subtype in the behavioral effects of morphine and cocaine.
Asunto(s)
Analgésicos Opioides/farmacología , Conducta Animal/efectos de los fármacos , Estimulantes del Sistema Nervioso Central/farmacología , Cocaína/farmacología , Morfina/farmacología , Receptor Muscarínico M1/metabolismo , Animales , Condicionamiento Psicológico/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Locomoción/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Antagonistas Muscarínicos/farmacología , Dimensión del Dolor , Umbral del Dolor/efectos de los fármacos , Pirenzepina/farmacología , Receptor Muscarínico M1/antagonistas & inhibidores , Receptor Muscarínico M1/deficiencia , Receptor Muscarínico M1/genética , RecompensaRESUMEN
RATIONALE: Chronic high dose consumption of cocaine is associated with significant negative effects to individual users and society. Nevertheless, the precise mechanisms that mediate increases in cocaine consumption in a drug-using individual are not fully understood. OBJECTIVES: This study used a long access version of the drug self-administration procedure to determine whether escalation of cocaine consumption is mediated by increased activity through N-methyl-D: -aspartate (NMDA) receptors. MATERIALS AND METHODS: Male Sprague-Dawley rats (n = 63) were first trained to self-administer cocaine (0.33 mg/infusion, i.v.) under a fixed-ratio 1 schedule of reinforcement. After training, some rats were implanted with subcutaneous osmotic minipumps filled with vehicle or the competitive NMDA receptor antagonist, LY235959, and subsequently allowed to self-administer cocaine in short (2 h) or long (6 h) access self-administration sessions. RESULTS: Vehicle-treated rats escalated cocaine self-administration across 14 long-access self-administration sessions. Rats treated with LY235959 via osmotic minipump, but not twice daily injections, escalated cocaine self-administration at a greater rate and to a greater degree than vehicle-treated rats. In post-escalation cocaine dose-infusion tests, rats treated continuously with LY235959 self-administered more cocaine (0.08-1.32 mg/infusion) than vehicle-treated rats, regardless of access condition, shifting the dose-infusion curves upward. During extinction sessions, which were conducted after the escalation phase of the study, rats that had long (6 h) access to cocaine stopped responding sooner than rats that had short (2 h) access to cocaine, independent of LY235959 treatment. CONCLUSIONS: These data are consistent with hypo-glutamatergic consequences of repeated cocaine exposure.
Asunto(s)
Cocaína/farmacología , Inhibidores de Captación de Dopamina/farmacología , Isoquinolinas/farmacología , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Esquema de Refuerzo , Análisis de Varianza , Animales , Conducta Adictiva , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Extinción Psicológica/efectos de los fármacos , Ácido Glutámico/metabolismo , Isoquinolinas/administración & dosificación , Masculino , Neurotransmisores , Ratas , Ratas Sprague-Dawley , Receptores de N-Metil-D-Aspartato/efectos de los fármacos , Receptores de N-Metil-D-Aspartato/fisiología , AutoadministraciónRESUMEN
A growing body of literature has implicated N-methyl-d-aspartate (NMDA) receptor mechanisms in the acute antinociceptive effects of morphine; however, the nature of this interaction has not been thoroughly quantified. Moreover, it is not clear whether NMDA/morphine interactions extend to less efficacious opioids. Therefore, the present study examined the effects of morphine and various low-efficacy opioid agonists in combination with the NMDA antagonist (-)-6-phosphonomethyl-deca-hydroisoquinoline-3-carboxylic acid (LY235959) in two different assays: schedule-controlled responding and thermal nociception. Data were examined with dose-addition analysis to provide a quantitative assessment of the drug interactions. LY235959 and the opioid agonists morphine, buprenorphine, butorphanol, and nalbuphine all decreased rates of schedule-controlled responding. LY235959/morphine and LY235959/buprenorphine mixtures produced additive or subadditive effects in this assay, whereas LY235959/butorphanol and LY235959/nalbuphine mixtures produced additive or supra-additive effects, depending on the relative proportions of each drug in mixture. Morphine, buprenorphine, butorphanol, and nalbuphine also produced dose-dependent antinociception in the assay of thermal nociception, whereas LY235959 failed to produce an effect. In this assay, LY235959 potentiated the antinociceptive effects of morphine and each of the low-efficacy opioids tested. These results suggest that LY235959 may selectively increase the antinociceptive effects of morphine and some low-efficacy opioid receptor agonists without increasing their rate-altering effects. In addition, these data confirm that the behavioral effects of drug mixtures depend on the relative concentrations of the drugs in the mixture and on the endpoint under study.
Asunto(s)
Analgésicos Opioides/farmacología , Condicionamiento Psicológico/efectos de los fármacos , N-Metilaspartato/antagonistas & inhibidores , Receptores Opioides/agonistas , Animales , Buprenorfina/farmacología , Butorfanol/farmacología , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Calor , Isoquinolinas/farmacología , Masculino , Ratones , Ratones Endogámicos BALB C , Morfina/farmacología , Nalbufina/farmacologíaRESUMEN
UNLABELLED: Although N-methyl-D-aspartate (NMDA) receptor antagonists clearly attenuate the development of tolerance to the antinociceptive effects of opioids, it is not clear whether they also alter acute opioid-induced antinociception. The present study was designed to assess NMDA/opioid interactions in C57BL/6 mice by examining various NMDA receptor antagonists of different selectivity in combination with the mu opioid receptor agonists morphine and l-methadone. A mouse hot plate procedure was used to assess the effects of morphine (0.1 to 10.0 mg/kg) and l-methadone (0.1 to 5.6 mg/kg) alone and after pretreatment with the competitive NMDA receptor antagonist LY235959 (0.1 to 1.0 mg/kg), the glycine site NMDA receptor antagonist R(+)-HA-966 (10.0 to 56.0 mg/kg), or the polyamine site and NR2B selective NMDA receptor antagonist ifenprodil (3.2 to 10.0 mg/kg). Morphine and l-methadone produced dose- and time-dependent increases in 56 degrees C hot plate latencies. At the doses tested, the NMDA receptor antagonists produced no effect on hot plate latencies. However, when these drugs were combined with morphine, latency to respond to the hot plate was significantly increased from morphine alone. Combinations of the NMDA receptor antagonist LY235959 and l-methadone produced similar increases in hot plate latencies; however, combinations of l-methadone with R(+)-HA-966 or ifenprodil did not increase hot plate latencies compared with l-methadone alone. These results suggest that a range of NMDA receptor antagonists potentiate morphine-induced antinociception, although the potentiation of l-methadone might be specific to the antagonist examined. PERSPECTIVE: The inclusion of low-dose NMDA receptor antagonists to opioids might be beneficial for the treatment of acute pain by enhancing the antinociceptive effects of the opioid.
Asunto(s)
Analgésicos Opioides/farmacología , Sistema Nervioso Central/efectos de los fármacos , Antagonistas de Aminoácidos Excitadores/farmacología , Nociceptores/efectos de los fármacos , Dolor/tratamiento farmacológico , Receptores de N-Metil-D-Aspartato/efectos de los fármacos , Analgesia , Animales , Sistema Nervioso Central/fisiología , Relación Dosis-Respuesta a Droga , Sinergismo Farmacológico , Isoquinolinas/farmacología , Masculino , Metadona/farmacología , Ratones , Ratones Endogámicos C57BL , Morfina/farmacología , Nociceptores/fisiología , Dolor/metabolismo , Dolor/fisiopatología , Dimensión del Dolor/efectos de los fármacos , Umbral del Dolor/efectos de los fármacos , Umbral del Dolor/fisiología , Piperidinas/farmacología , Pirrolidinonas/farmacología , Tiempo de Reacción/efectos de los fármacos , Tiempo de Reacción/fisiología , Receptores de Glicina/efectos de los fármacos , Receptores de Glicina/fisiología , Receptores de N-Metil-D-Aspartato/fisiologíaRESUMEN
Key pecking by 3 pigeons was maintained by a multiple fixed-ratio 10, fixed-ratio 30, fixed-ratio 90 schedule of food presentation. Components differed with respect to amount of reinforcement, such that the unit price was 10 responses per 1-s access to food. Acute administration of morphine, l-methadone, and cocaine dose-dependently decreased overall response rates in each of the components. When a rate decreasing dose of morphine was administered daily, tolerance, as measured by an increase in the dose that reduced response rates to 50% of control (i.e., the ED50 value), developed in each of the components; however, the degree of tolerance was smallest in the fixed-ratio 90 component (i.e., the ED50 value increased the least). When the l-methadone dose-effect curve was redetermined during the chronic morphine phase, the degree of cross-tolerance conferred to l-methadone was similar across components, suggesting that behavioral variables may not influence the degree of cross-tolerance between opioids. During the chronic phase, the cocaine dose-effect curve shifted to the right for 2 pigeons and to the left for 1 pigeon, which is consistent with predictions based on the lack of pharmacological similarity between morphine and cocaine. When the morphine, l-methadone, and cocaine dose-effect curves were redetermined after chronic morphine administration ended, the morphine and l-methadone ED50s replicated those obtained prior to chronic morphine administration. The morphine data suggest that the fixed-ratio value (i.e., the absolute output) determines the degree of tolerance and not the unit price.
Asunto(s)
Tolerancia a Medicamentos , Morfina/farmacología , Narcóticos/farmacología , Refuerzo en Psicología , Animales , Conducta Animal , Cocaína/administración & dosificación , Cocaína/farmacología , Columbidae , Inhibidores de Captación de Dopamina/administración & dosificación , Inhibidores de Captación de Dopamina/farmacología , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Femenino , Metadona/administración & dosificación , Metadona/farmacología , Morfina/administración & dosificación , Narcóticos/administración & dosificación , Esquema de RefuerzoRESUMEN
It is difficult to determine the precise role of the N-methyl-D-aspartate (NMDA) receptor system in the reinforcing effects of cocaine since uncompetitive NMDA receptor antagonists alter cocaine self-administration in different ways, depending on the antagonist examined and the behavior being measured. To increase understanding of the role of the NMDA system in cocaine's reinforcing effects, this study measured the effects of the competitive NMDA receptor antagonist, LY235959 [(-)-6-phosphonomethyl-deca-hydroisoquinoline-3-carboxylic acid], in rats that self-administered cocaine under both fixed ratio (FR) 1 and progressive ratio (PR) schedules of reinforcement. Rats were trained to self-administer cocaine (0.33 mg/infusion) under an FR1 schedule of reinforcement. Thereafter, the effects of pretreatment with LY235959, or the uncompetitive antagonists dextromethorphan and dizocilpine, were examined. The number of infusions earned during the first 10 min of responding under the FR1 schedule was analyzed separately. When rats responded for 0.33 mg/infusion cocaine under an FR1 schedule of reinforcement, 3 mg/kg LY235959 decreased cocaine self-administration only during the first 10 min of the responding. This effect was dose and time dependent and blocked by the competitive NMDA receptor agonist, NMDA. LY235959 (3 mg/kg) decreased total responding for cocaine only when the self-administered dose of cocaine was small (0.02-0.04 mg/infusion) or when responding was reinforced under the PR schedule. In contrast, dizocilpine decreased responding under the FR1 schedule but increased responding under the PR schedule. These data suggest that LY235959 decreased the reinforcing effectiveness of cocaine, a finding reported with systemically administered NMDA receptor antagonists other than dizocilpine.