RESUMEN
Naltrexone is used to antagonise etorphine immobilisation, but a safe and effective dose for this purpose has not been objectively determined. Eight domestic goats were immobilised with etorphine (0.07 mg/kg) eight times at ≥13 day intervals. Naltrexone at doses of 0.5, 1, 2, 5, 10, 20 and 40 mg/mg etorphine were administered intravenously 17 minutes after etorphine injection. Effectiveness of antagonism was recorded based on recovery and renarcotisation scores and clinical observations. All doses produced rapid recovery to the point of standing (median 59 seconds, range 33-157 seconds), with no significant differences in recovery times (P=0.44). The lower naltrexone doses resulted in renarcotisation in some goats: 4/8 in the 10-mg dose trial, 7/8 in the 5-mg dose trial, and 8/8 in the 2-mg, 1-mg and 0.5-mg dose trials. Lower doses resulted in more severe signs of renarcotisation. Complications of renarcotisation included increased body temperature; this occurred just before signs of renarcotisation and was greater in animals with high renarcotisation scores (P<0.01). The lowest, safest effective naltrexone dose that we used to antagonise etorphine immobilisation was 20 mg/mg etorphine, which produced rapid recovery to standing with no renarcotisation.
Asunto(s)
Etorfina/antagonistas & inhibidores , Inmovilización/veterinaria , Naltrexona/administración & dosificación , Antagonistas de Narcóticos/administración & dosificación , Animales , Estudios Cruzados , Relación Dosis-Respuesta a Droga , Femenino , Cabras , MasculinoRESUMEN
RATIONALE: Although dihydroetorphine has micro opioid agonist activity there is evidence to suggest that it is not identical to that of morphine. OBJECTIVE: This study compared dihydroetorphine to other opioids under behavioral conditions that are sensitive to micro opioid agonism. METHODS: The acute effects of dihydroetorphine, etorphine and morphine were evaluated using two procedures. In one procedure, monkeys received 3.2 mg/kg per day of morphine and discriminated naltrexone from saline while responding under a fixed-ratio 5 schedule of stimulus shock termination. In addition, a warm-water, tail-withdrawal procedure was used in untreated monkeys. RESULTS: When acutely deprived of morphine, monkeys responded on the naltrexone lever, and this effect was reversed by dihydroetorphine, etorphine and morphine. Each agonist produced the maximum (20-s latency) antinociceptive effect in 50 degrees C water. Naltrexone antagonized the discriminative stimulus and antinociceptive effects of dihydroetorphine and etorphine, although Schild analyses yielded large variability in slopes and pA(2) values. Naltrexone reversed established effects of dihydroetorphine and morphine in both procedures and pretreatment with dihydroetorphine (2, 6 or 24 h) did not alter the discriminative stimulus effects of morphine. CONCLUSIONS: Taken together, these data support the notion that dihydroetorphine is a micro agonist with a short duration of action; however, variability in antagonism of dihydroetorphine and morphine might be a manifestation of differences that have been reported for these drugs at the cellular level.
Asunto(s)
Analgésicos Opioides/farmacología , Aprendizaje Discriminativo/efectos de los fármacos , Etorfina/análogos & derivados , Etorfina/farmacología , Morfina/farmacología , Naltrexona/farmacología , Analgésicos Opioides/antagonistas & inhibidores , Animales , Etorfina/antagonistas & inhibidores , Femenino , Macaca mulatta , Masculino , Morfina/antagonistas & inhibidoresRESUMEN
D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2 (CTAP) is a peptide antagonist that demonstrates potent and selective affinity for micro-opioid receptors in radioligand binding assays and in vitro bioassays. However, previous studies indicate that CTAP may possess unusual pharmacology under certain conditions. Therefore, CTAP was evaluated as an antagonist of the antinociceptive effects of a range of structurally diverse high- and low-efficacy peptide and alkaloid opioid agonists and compared with the traditional antagonist naltrexone. Male Sprague-Dawley rats (N = 227) were loosely restrained and the latency for tail withdrawal from 55 degrees C water was measured. Morphine s.c. and i.c.v., buprenorphine s.c., etorphine s.c. and i.c.v., [N-Me-Phe3,D-Pro4]-morphiceptin and [D-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin produced antinociceptive effects. CTAP was at least 10-fold more potent than naltrexone as an antagonist of the antinociceptive effects of all five agonists. High doses of CTAP produced a noncompetitive antagonism of etorphine s.c. and morphine s.c. suggesting that CTAP may interact with additional opioid receptors in vivo or produce insurmountable antagonism at these doses. CTAP was approximately 300-fold more potent as an antagonist of DAMGO than the other agonists, indicating that CTAP may distinguish some peptide agonists such as DAMGO from other agonists based on binding interactions within the micro-opioid receptor or pharmacodynamic properties of these peptides. Naltrexone, however, administered by either s.c. or i.c.v. routes of administration was approximately equipotent as an antagonist of the antinociceptive effects of most agonists. Taken together, these data indicate that the peptide antagonist CTAP possesses a unique pharmacology unlike traditional opioid antagonists such as naltrexone
Asunto(s)
Alcaloides/antagonistas & inhibidores , Antagonistas de Narcóticos/farmacología , Péptidos Opioides/antagonistas & inhibidores , Dimensión del Dolor/efectos de los fármacos , Péptidos/farmacología , Receptores Opioides mu/agonistas , Analgésicos Opioides/antagonistas & inhibidores , Analgésicos Opioides/farmacología , Animales , Unión Competitiva/efectos de los fármacos , Buprenorfina/antagonistas & inhibidores , Buprenorfina/farmacología , Relación Dosis-Respuesta a Droga , Encefalina Ala(2)-MeFe(4)-Gli(5)/antagonistas & inhibidores , Encefalina Ala(2)-MeFe(4)-Gli(5)/farmacología , Etorfina/antagonistas & inhibidores , Etorfina/farmacología , Inyecciones Intraventriculares , Inyecciones Subcutáneas , Masculino , Morfina/antagonistas & inhibidores , Morfina/farmacología , Naltrexona/farmacología , Fragmentos de Péptidos , Ratas , Ratas Sprague-Dawley , Tiempo de Reacción/efectos de los fármacos , SomatostatinaRESUMEN
An adult, 23 yr-old, male greater one-horned rhinoceros (Rhinoceros unicornis) was repeatedly immobilized with combinations of etorphine, detomidine, and ketamine to provide medical and surgical care to chronic, bilateral, soft tissue lesions on the hind feet and to collect semen by electroejaculation. The rhinoceros was successfully immobilized on 24 occasions over a 55 mo period at approximately 8-10 wk intervals, 17 times with a combination of etorphine and detomidine (M99-D, i.m.) by projectile dart and seven times with a combination of etorphine, ketamine, and detomidine (M99-K-D, i.m.) by pole syringe. The combination of etorphine, detomidine, and ketamine repeatedly and safely induced prolonged anesthesia, and a suitable drug combination includes 3.5-3.8 mg etorphine, 14 mg detomidine, and 400 mg ketamine (M99-K-D) administered i.m. into the neck.
Asunto(s)
Anestésicos Disociativos , Etorfina , Hipnóticos y Sedantes , Imidazoles , Inmovilización , Ketamina , Perisodáctilos/fisiología , Animales , Temperatura Corporal/efectos de los fármacos , Combinación de Medicamentos , Etorfina/antagonistas & inhibidores , Frecuencia Cardíaca/efectos de los fármacos , Hipnóticos y Sedantes/antagonistas & inhibidores , Masculino , Naltrexona/farmacología , Antagonistas de Narcóticos/farmacología , Oximetría/veterinaria , Respiración/efectos de los fármacos , Factores de TiempoRESUMEN
The physiological effects on respiratory function of etorphine (M99, Logos Agvet) (30 microg/kg) administered intramuscularly were determined in boer goats. The goats were habituated to the experimental procedures so that respiratory function could be determined while the animals stood quietly at rest. This enabled the physiological changes induced by etorphine to be measured and compared with those obtained before administration of the immobilising drug. The effectiveness of diprenorphine (M5050, Logos Agvet) (3 mg/l mg etorphine) as an antagonist of the physiological changes induced by the etorphine treatment was also determined. Etorphine depressed respiratory function, which resulted in a decrease in PaO2 and an increase in PaCO2. These changes were limited and occurred as a result of decreases in respiratory minute volume and alveolar minute ventilation caused by a decrease in respiratory rate. The physiological shunt fraction did not change significantly but there was a significant decrease in percentage physiological dead space ventilation. It was not possible to determine how effectively diprenorphine reversed the respiratory effects due to etorphine.
Asunto(s)
Etorfina/farmacología , Cabras/fisiología , Narcóticos/farmacología , Respiración/efectos de los fármacos , Animales , Análisis de los Gases de la Sangre/veterinaria , Dióxido de Carbono/sangre , Diprenorfina/administración & dosificación , Diprenorfina/farmacología , Etorfina/administración & dosificación , Etorfina/antagonistas & inhibidores , Femenino , Inmovilización , Inyecciones Intramusculares/veterinaria , Antagonistas de Narcóticos/administración & dosificación , Antagonistas de Narcóticos/farmacología , Narcóticos/administración & dosificación , Narcóticos/efectos adversos , Consumo de Oxígeno/efectos de los fármacos , Presión Parcial , Espacio Muerto Respiratorio , Pruebas de Función Respiratoria/veterinaria , Volumen de Ventilación Pulmonar/efectos de los fármacos , Factores de TiempoRESUMEN
The locus coeruleus (LC) is a major noradrenergic nucleus in the brain. The activity of the LC neurons is chronically regulated by opioids. So far, very little is known about the morphological changes induced by chronic treatment with opioids. In the present study, the effects of chronic treatment with morphine and dihydroetorphine, a new narcotic analgesic with lower physical dependence potential than morphine, were investigated on the ultrastructure of the rat LC. Rats received saline or increasing doses of morphine or dihydroetorphine for 5 days by twice daily subcutaneous injections. Withdrawal was precipitated in half of the opioid-treated rats by a single intraperitoneal injection of naloxone 4 h after the last injections of opioids. The ultrastructure of the LC was examined by electron microscopy. Results showed that chronic morphine treatment induced a marked injury to the LC neurons. The primary changes in the cell body were the indentation of nuclei, the fragmentation and degranulation of rough endoplasmic reticulum, as well as the disaggregation of polyribosomes. Myelinoid bodies were seen in the processes. An accumulation of presynaptic vesicles was observed in some of the terminals which formed synaptic junctions with the LC neurons as compared to the normal controls. Naloxone-precipitated withdrawal from morphine did not stop the morphine-induced injury on the LC neurons except that less accumulation of presynaptic vesicles occurred. Chronic dihydroetorphine treatment only induced a slight change in the ultrastructure of the LC neurons. These results indicate that the LC neurons are more vulnerable to chronic treatment with morphine than to that with dihydroetorphine.
Asunto(s)
Analgésicos/farmacología , Locus Coeruleus/efectos de los fármacos , Locus Coeruleus/ultraestructura , Narcóticos/farmacología , Animales , Retículo Endoplásmico Rugoso/efectos de los fármacos , Retículo Endoplásmico Rugoso/ultraestructura , Etorfina/análogos & derivados , Etorfina/antagonistas & inhibidores , Etorfina/farmacología , Masculino , Morfina/antagonistas & inhibidores , Morfina/farmacología , Vaina de Mielina/efectos de los fármacos , Vaina de Mielina/ultraestructura , Naloxona/farmacología , Antagonistas de Narcóticos/farmacología , Neuronas/efectos de los fármacos , Neuronas/ultraestructura , Polirribosomas/efectos de los fármacos , Polirribosomas/ultraestructura , Ratas , Ratas Wistar , Vesículas Sinápticas/efectos de los fármacos , Vesículas Sinápticas/ultraestructuraRESUMEN
Etorphine is an non-selective opioid receptor agonist with very potent analgesic effect. Low concentrations (< nM) of most opioid receptor agonists decrease the K+ conductance (gK) in cultures of dissociated mouse dorsal root ganglion neurons regardless of the presence of Ba2+ However, low concentrations of etorphine, in contrast to all other opioids tested, decreased gK only in the absence of Ba2+. In the presence of Ba2+, pM-nM etorphine elicited dose-dependent increases, instead of decreases in gK. Higher concentrations of etorphine (> nM) not only increased gK but, in addition, appreciably increased a delayed-onset inward Ca2+ current during pulsed depolarization regardless of the presence of Ba2+.
Asunto(s)
Bario/farmacología , Canales de Calcio/fisiología , Etorfina/farmacología , Ganglios Espinales/fisiología , Neuronas/fisiología , Canales de Potasio/fisiología , Animales , Canales de Calcio/efectos de los fármacos , Células Cultivadas , Etorfina/antagonistas & inhibidores , Feto , Cinética , Ratones , Neuronas/efectos de los fármacos , Potasio/metabolismo , Canales de Potasio/efectos de los fármacosRESUMEN
Reversal of opioid-related respiratory depression is often accompanied by an "acute abstinence like syndrome" with hypertension, tachycardia, and pain. This overshoot was used to investigate the extent at which opioids of high potency but different structure are involved in naloxone-induced abstinence. In 10 awake and trained mongrel dogs two highly mu-selective compounds, alfentanil and fentanyl, were given in cumulative doses and at different occasions (30-60-120-240 micrograms/kg, and 6-12-24-48 micrograms/kg, respectively). Subsequently, a high dose of naloxone (100 micrograms/kg) was given at 5 min intervals while arterial blood gases, blood pressure, heart rate and the somatosensory evoked potential (SEP) were measured continuously. Following a wash-out period, the 19-isoamyl derivative of etorphine (M-140; 10,000 times more potent than normorphine and a 4.5 fold potency of ethylketocyclazocine in a bioessay preparation) was also given in increasing doses (0.2-0.4-0.8-3.2 micrograms/kg). Again, naloxone was given (100 micrograms/kg) at 5 min interval, while cardiovascular parameters, blood gases and SEPs were measured continuously. All three opioids induced a dose-related respiratory depression with hypercarbia and hypoxia, a dose-related bradycardia, and a modest hypotension. This was accompanied by a dose-related depression of the amplitude of the SEP, reflecting the degree of blockade of nociceptive afferents. Naloxone was sufficient to reverse respiratory impairment after fentanyl, alfentanil and M-140. However, in contrast to fentanyl and alfentanil, there was no cardiovascular or evoked potential overshoot following naloxone reversal of M-140. After alfentanil naloxone increased blood pressure, heart rate and amplitude of the SEP by 7%, 41% and 38%, respectively. After fentanyl this increase in blood pressure, heart rate and amplitude of the SEP was 17%, 43% and 96%, respectively. The study indicates that the more potent the opiate mu ligands are the more is naloxone liable to induce a hyperexcitatory state of the cardiovascular system and an increase of nociceptive stimuli to pain modulating centres. After M-140 reversal of mu-related respiratory depression by naloxone was possible. However, no precipitation on an acute abstinence-like syndrome affecting antinociception or inducing cardiovascular overshoot was observed. This may stem from an intense binding and slow dissociation of the ligand from the receptor site or may be due to high binding affinity to both the mu and the kappa receptor site. Opioids which interact with various receptor sites may be of clinical interest for substitution therapy in opioid dependent addicts.
Asunto(s)
Analgésicos Opioides/antagonistas & inhibidores , Etorfina/análogos & derivados , Naloxona/farmacología , Antagonistas de Narcóticos/farmacología , Síndrome de Abstinencia a Sustancias/fisiopatología , Alfentanilo/farmacología , Analgésicos Opioides/farmacología , Animales , Análisis de los Gases de la Sangre , Presión Sanguínea/efectos de los fármacos , Perros , Relación Dosis-Respuesta a Droga , Etorfina/antagonistas & inhibidores , Etorfina/farmacología , Fentanilo/farmacología , Frecuencia Cardíaca/efectos de los fármacos , Receptores Opioides mu/efectos de los fármacos , Receptores Opioides mu/metabolismoRESUMEN
The antinociceptive potency of dihydroetorphine in diabetic mice was examined. Subcutaneous administration of dihydroetorphine produced a dose-dependent antinociception in both non-diabetic and diabetic mice. The antinociceptive potency of s.c. dihydroetorphine was less in diabetic mice than in non-diabetic mice. The antinociception induced by i.c.v. dihydroetorphine (0.02 microgram) was also significantly less in diabetic mice than in non-diabetic mice. The antinociceptive effects of dihydroetorphine (10 micrograms/kg i.p.) in both diabetic and non-diabetic mice were significantly antagonized by s.c. administration of beta-funaltrexamine, a selective mu-opioid receptor antagonist. Furthermore, the antinociceptive effect of dihydroetorphine (10 micrograms/kg i.p.) in non-diabetic mice, but not in diabetic mice, was also significantly antagonized by naloxonazine, a selective mu 1-opioid receptor antagonist. The time course and the potency of the antinociceptive effect of dihydroetorphine (10 micrograms/kg i.p.) in diabetic mice were similar to those in naloxonazine-treated non-diabetic mice. Naltrindole, a selective delta-opioid receptor antagonist, or nor-binaltorphimine, a selective kappa-opioid receptor antagonist, had no significant effect on the antinociceptive effect of dihydroetorphine (10 micrograms/kg i.p.) in both diabetic and non-diabetic mice. These results suggest that dihydroetorphine produces an antinociceptive effect through the activation of both mu 1- and mu 2-opioid receptors in mice. Furthermore, the reduction in dihydroetorphine-induced antinociception in diabetic mice, as compared with non-diabetic mice, may be due to the hyporesponsive to supraspinal mu 1-opioid receptor-mediated antinociception in diabetic mice.
Asunto(s)
Analgésicos Opioides/farmacología , Diabetes Mellitus Experimental/fisiopatología , Etorfina/análogos & derivados , Analgesia , Analgésicos Opioides/administración & dosificación , Analgésicos Opioides/metabolismo , Animales , Unión Competitiva , Relación Dosis-Respuesta a Droga , Etorfina/administración & dosificación , Etorfina/antagonistas & inhibidores , Etorfina/farmacología , Inyecciones Intraperitoneales , Inyecciones Intraventriculares , Inyecciones Subcutáneas , Masculino , Ratones , Ratones Endogámicos ICR , Naloxona/administración & dosificación , Naloxona/análogos & derivados , Naloxona/metabolismo , Naloxona/farmacología , Naltrexona/administración & dosificación , Naltrexona/análogos & derivados , Naltrexona/metabolismo , Naltrexona/farmacología , Antagonistas de Narcóticos/metabolismo , Antagonistas de Narcóticos/farmacología , Dimensión del Dolor , Receptores Opioides delta/antagonistas & inhibidores , Receptores Opioides mu/agonistasRESUMEN
The effects of in vivo pertussis toxin (PTX) treatment on the functional effects of opioid agonists were examined in the mouse. Mice were injected intracerebroventricularly (ICV), or intrathecally (IT), or IT and ICV with PTX, and dose-response studies of the antinociceptive action of systemic (SC) morphine, fentanyl, and etorphine were conducted 10 days later. IT PTX decreased the potency (approximately 4.5-fold) of morphine more than ICV administration (approximately 1.5-fold), whereas the combination of IT and ICV administration produced an additive effect. When PTX was administered spinally and supraspinally, the potency of morphine, fentanyl, and etorphine was reduced similarly (approximately 5-7-fold), indicating that the effect of PTX does does not vary considerably among agonists of different intrinsic efficacies. These studies indicate that in vivo PTX can reduce the potency of opioid agonists with different intrinsic efficacies, and that spinal mechanisms appear to be more sensitive to PTX treatment.
Asunto(s)
Analgésicos/antagonistas & inhibidores , Antagonistas de Narcóticos/farmacología , Narcóticos/farmacología , Toxina del Pertussis , Médula Espinal/efectos de los fármacos , Factores de Virulencia de Bordetella/farmacología , Analgésicos/farmacología , Animales , Relación Dosis-Respuesta a Droga , Etorfina/antagonistas & inhibidores , Etorfina/farmacología , Fentanilo/antagonistas & inhibidores , Fentanilo/farmacología , Inyecciones Intraventriculares , Inyecciones Espinales , Masculino , Ratones , Morfina/antagonistas & inhibidores , Morfina/farmacología , Dimensión del Dolor/efectos de los fármacos , Factores de Virulencia de Bordetella/administración & dosificaciónRESUMEN
White-tailed deer (Odocoileus virginianus) were immobilized with either 4.0 mg etorphine hydrochloride (ETOR) or 3.5 mg ETOR and 50.0 mg xylazine (XYL). Deer immobilized with ETOR only were given 4.0 mg nalmefene hydrochloride (NAL), a new opioid antagonist, 20 min after induction. Deer immobilized with ETOR and XYL received 3.5 mg NAL and 0.125 mg/kg yohimbine hydrochloride (YOH). The dose of 4.0 mg ETOR did not provide acceptable immobilization and was discontinued. A NAL:ETOR ratio of 1:1 was insufficient for complete and sustained antagonism of ETOR. Subsequently, deer were immobilized with ETOR and XYL as before which was then antagonized with 35.0 mg NAL and 0.125 mg/kg YOH. The 10:1 ratio of NAL:ETOR appeared to provide complete antagonism with no evidence of renarcotization. Although more study is required, NAL could become a useful antagonist for opioid-induced immobilizations.
Asunto(s)
Anestesia General/veterinaria , Ciervos , Etorfina , Inmovilización , Morfinanos , Naltrexona/análogos & derivados , Tiazinas , Xilazina , Yohimbina , Anestesia Intravenosa/veterinaria , Animales , Etorfina/administración & dosificación , Etorfina/antagonistas & inhibidores , Femenino , Inyecciones Intramusculares , Masculino , Morfinanos/administración & dosificación , Morfinanos/antagonistas & inhibidores , Naltrexona/administración & dosificación , Naltrexona/antagonistas & inhibidores , Tiazinas/administración & dosificación , Tiazinas/antagonistas & inhibidores , Xilazina/administración & dosificación , Xilazina/antagonistas & inhibidores , Yohimbina/administración & dosificación , Yohimbina/antagonistas & inhibidoresRESUMEN
Forty-eight newly captured free-ranging feral stallions (Equus caballus) from two different locations and six captive stallions were immobilized using combinations of etorphine hydrochloride, xylazine hydrochloride and atropine sulfate with or without acepromazine. Six animals were immobilized twice, 1 mo apart. The drugs were administered either intramuscularly (n = 13) or intravenously (n = 44). Mean immobilization time (+/- SE) after intravenous (i.v.) injection of etorphine, xylazine and atropine was 55 +/- 4 sec (range 20 to 185 sec) compared to 708 +/- 131 sec (range 390 to 1,140 sec) for intramuscular (i.m.) injection. Immobilization was reversed with i.v. administration of 3 to 11 mg diprenorphine hydrochloride and 16 to 24 mg yohimbine hydrochloride. Average time from administration to standing and walking was 86 +/- 7 sec (n = 55). Reversal of etorphine-induced immobilization with an amount of diprenorphine equal to the etorphine and administered i.v. was as effective as a 2:1 ratio of diprenorphine to etorphine. Acepromazine had no effect on induction time, but decreased relaxation after immobilization and prolonged ataxia after reversal of the etorphine and xylazine. Eight free-ranging horses were immobilized in 708 +/- 132 sec by darting with 5.5 mg etorphine, 1,300 mg xylazine and 15 mg atropine from a helicopter. Three animals died during the study: one immediately after reversal of an i.v. administration, one from a broken neck during induction from darting, and one was found a week later at the site of darting.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Animales Salvajes/fisiología , Atropina/farmacología , Etorfina/farmacología , Caballos/fisiología , Inmovilización , Morfinanos/farmacología , Tiazinas/farmacología , Xilazina/farmacología , Acepromazina/farmacología , Animales , Atropina/antagonistas & inhibidores , Diprenorfina/farmacología , Etorfina/antagonistas & inhibidores , Masculino , Xilazina/antagonistas & inhibidores , Yohimbina/farmacologíaRESUMEN
The potent opioid peptide beta-endorphin is found in the brain and pituitary with two related fragments, beta-endorphin-(1-27) and beta-endorphin-(1-26). The fragments retain substantial opioid-receptor binding activity but are virtually inactive analgesically. beta-Endorphin-(1-27) inhibits beta-endorphin-induced and etorphine-induced analgesia when coinjected intracerebroventricularly into mice. Antagonism by competition at the same site(s) is suggested from parallel shifts of the dose-response curves of etorphine or beta-endorphin in the presence of beta-endorphin-(1-27). Its potency is 4-5 times greater than that of the opiate antagonist naloxone. beta-Endorphin-(1-26) does not antagonize the antinociceptive action of etorphine or beta-endorphin in doses up to 500 pmol per animal.
Asunto(s)
Endorfinas/farmacología , Etorfina/antagonistas & inhibidores , Morfinanos/antagonistas & inhibidores , Dolor/fisiopatología , Fragmentos de Péptidos/farmacología , betaendorfina , Animales , Unión Competitiva , Relación Dosis-Respuesta a Droga , Endorfinas/metabolismo , Etorfina/metabolismo , Masculino , Ratones , Naloxona/farmacología , Fragmentos de Péptidos/metabolismo , Receptores Opioides/metabolismoRESUMEN
Human beta-endorphin (beta h-EP) analogs of variable chain lengths have been investigated for their potency in inhibiting analgesia induced by beta h-EP or by the potent opiate etorphine. It was found that beta h-EP-(1-28) inhibits the analgesic effect of beta h-EP and etorphine when co-injected intracerebroventricularly into mice. Antagonism by competition at same opioid receptor subtypes is suggested from parallel shifts of the dose-response curve of etorphine or beta h-EP in the presence of increasing doses of beta h-EP-(1-28). On a molar basis, beta h-EP-(1-28) is nearly 10 times more potent than naloxone. The reduction of the chain length from residues 1-28 to 1-27 lowered the antagonist potency while further reduction of the peptide chain led to a complete loss of inhibitory activity. From comparison of the opioid-receptor binding affinity, analgesic activity and antagonist potency, it is concluded that the C-terminus of beta-EP is critical to the biological efficacy of the molecule and that the antagonist activity of C-terminal deletion analogs is probably mediated through residues 27 and 28.
Asunto(s)
Analgésicos/antagonistas & inhibidores , Endorfinas/antagonistas & inhibidores , Endorfinas/farmacología , Fragmentos de Péptidos/farmacología , Animales , Endorfinas/metabolismo , Etorfina/antagonistas & inhibidores , Técnicas In Vitro , Ratones , Naloxona/farmacología , Fragmentos de Péptidos/metabolismo , Ratas , Receptores Opioides/metabolismo , betaendorfinaRESUMEN
Intravenous injection of opiates in rats is known to produce a rapid fall in heart rate, blood pressure, and respiratory frequency. Etorphine, a potent opiate agonist which reaches central and peripheral receptors, administered at 1.1 nmol/kg i.v., evoked these characteristic effects in the urethane-anaesthetized rat. Three opiate antagonists, with somewhat different properties, have been used to assess the site of action of etorphine-induced bradycardia, hypotension, and inhibition of respiration. The antagonists used were naloxone hydrochloride, N-methylnaloxone bromide, and SMS 201-995. Low doses of naloxone blocked the cardiovascular and respiratory effects of etorphine. N-Methylnaloxone blocked the bradycardia, hypotension and the initial phase of apnea produced by etorphine but not the subsequent slowing of respiration. SMS 201-995 blocked the bradycardia and partially antagonized the hypotension and inhibition of respiratory rate produced by etorphine. These results indicate that N-methylnaloxone and SMS 201-995 can block the peripheral receptors which mediate opiate-induced bradycardia. Naloxone blocks both the central and peripheral actions of etorphine and so more completely antagonizes the cardiovascular and respiratory effects of etorphine.
Asunto(s)
Etorfina/antagonistas & inhibidores , Hidromorfona/análogos & derivados , Morfinanos/antagonistas & inhibidores , Naloxona/farmacología , Oximorfona/farmacología , Reflejo/efectos de los fármacos , Somatostatina/análogos & derivados , Nervio Vago/fisiología , Animales , Presión Sanguínea/efectos de los fármacos , Frecuencia Cardíaca/efectos de los fármacos , Masculino , Octreótido , Ratas , Ratas Endogámicas , Respiración/efectos de los fármacos , Somatostatina/farmacologíaRESUMEN
The death rate due to neuroleptanalgesia (0.35%) was significantly lower than for barbiturate anaesthesia (1.59%). Complications were few even when animals received multiple, repeated, anaesthesia, and depth of anaesthesia could be adjusted easily. Further, it could be reversed within minutes by the specific antagonist diprenorphine.
Asunto(s)
Acepromazina , Diprenorfina , Etorfina , Morfinanos , Neuroleptanalgesia/veterinaria , Ratas/fisiología , Acepromazina/antagonistas & inhibidores , Animales , Conducta Animal/efectos de los fármacos , Diprenorfina/farmacología , Evaluación de Medicamentos/veterinaria , Etorfina/antagonistas & inhibidores , Femenino , Masculino , Morfinanos/antagonistas & inhibidores , Morfinanos/farmacología , Neuroleptanalgesia/mortalidad , Ratas Endogámicas/fisiología , Respiración/efectos de los fármacosAsunto(s)
Encéfalo/efectos de los fármacos , Discriminación en Psicología/efectos de los fármacos , Naloxona/análogos & derivados , Naltrexona/análogos & derivados , Antagonistas de Narcóticos/farmacología , Narcóticos/farmacología , Animales , Columbidae , Etorfina/antagonistas & inhibidores , Macaca mulatta , Masculino , Morfina/antagonistas & inhibidores , Contracción Muscular/efectos de los fármacos , Músculo Liso/efectos de los fármacos , Naltrexona/farmacología , Receptores Opioides/metabolismoRESUMEN
Studies on the mechanism of post-etorphine catalepsy. Modyfying of amphetamine, apomorphine and dihydroxyphenyl-alanine (L-DOPA) on etorphine-induced concentrations of dopamine and noradrenaline in the rat central nervous system. Acta Physiol. Pol., 1979, 30 (2): 279--287. During stereotypy induced with amphetamine, apomorphine and 1-dihydroxyphenylalanine (L-DOPA) increased concentrations of dopamine (DA) and noradrenaline (NA) were found in the motor centres of the central nervous system (CNS). In post-etorphine catalepsy the concentrations of DA and NA were also increased in the frontal cortex, striopallidum, pons and cerebellum and in the lumbosacral spinal cord. However, these stereotypy-inducing agents used in premedication of post-etorphine catalepsy delayed significantly its onset and reduced its duration.
Asunto(s)
Anfetamina/farmacología , Apomorfina/farmacología , Química Encefálica , Catalepsia/fisiopatología , Dopamina/análisis , Etorfina/antagonistas & inhibidores , Levodopa/farmacología , Morfinanos/antagonistas & inhibidores , Norepinefrina/análisis , Animales , Etorfina/farmacología , Humanos , Masculino , RatasRESUMEN
The effectiveness of naloxone hydrochloride in reversing Immobilon anaesthesia was evaluated in 14 dogs. Although a dose rate of 0.02 mg per kg body-weight briefly reversed the respiratory and cardiovascular depression, a dose of at least 0.6 mg per kg body-weight was required before full recovery of consciousness occurred. The action of naloxone was found to be relatively short lived and relapse tended to occur after 10 to 15 minutes. The implications of these findings are discussed in relation to the use of naloxone in the event of accidental self-administration of Immobilon in man.