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The synthesis and the biological and pharmacological evaluation of several 14-phenylpropoxy analogues of 14-methoxymetopon are described. Most of the new compounds were nonselective and exhibited binding affinities in the subnanomolar or low nanomolar range at opioid receptors mu, kappa, delta), with 14-phenylpropoxymetopon (PPOM; 7) displaying the highest affinity for all three opioid receptor types. The most striking finding of this study is that the derivatives from the novel series of N-methyl-14-phenylpropoxymorphinans acted as extremely powerful antinociceptives with potencies higher than that of 14-methoxymetopon (1) and even etorphine. 14-Phenylpropoxymetopon (PPOM; 7) showed considerably increased potency in the in vivo assays in mice (25-fold in the tail-flick assay, 10-fold in the hot-plate assay, and 2.5-fold in the paraphenylquinone writhing test) when compared to etorphine, while it was equipotent to dihydroetorphine in the hot-plate assay and the paraphenylquinone writhing test and ca. twice as potent in the tail-flick assay than this reference compound. The 3-O-alkyl ethers of PPOM, compounds 6 and 8, showed less potency in in vivo assays, but partly surpassed the potency of the 3-OH analogue 14-methoxymetopon (1).

Previous reports have shown that [Leu5]enkephalin or [Met5] enkephalin, endogenous delta receptor agonists, or synthetic analogues of these substances, can respectively produce a positive (i.e., increase) or negative (i.e., decrease) modulation of the antinociceptive potency of mu agonists such as morphine; such modulation is believed to be the result of interactions between delta and mu receptors. In spite of these studies showing modulation of mu agonist potency, it is unclear whether delta agonists can similarly modulate the antinociceptive efficacy of mu agonists. This question was addressed by using several levels of nociceptive stimulus intensity in mice. As the nociceptive stimulus intensity increased, the i.c.v. morphine dose-response line was shown to be displaced progressively to the right with decreasing maximal effect (i.e., decreased efficacy) a pattern typical of partial agonists. In contrast, the antinociceptive potency and efficacy of i.c.v. etorphine was unaffected by increasing the stimulus intensity, suggesting that this compound has higher efficacy than morphine in this nociceptive assay. Coadministration of delta opioid agonists produced leftward ([D-Pen2, D-Pen5] enkephalin) or rightward ([Met5]enkephalin) displacement of the morphine dose-response line (i.e., changes in potency). When the delta agonists were coadministered with morphine under conditions of high stimulus intensity, the maximal antinociceptive effects of i.c.v. morphine were increased or decreased from studies with morphine alone (i.e., change in efficacy). Both changes in potency and efficacy produced by the delta agonists, but not the direct antinociceptive effects of morphine, were blocked by the delta antagonist, ICI 174,864, suggesting that modulation occurred via the delta receptor.(ABSTRACT TRUNCATED AT 250 WORDS)

We have investigated the expression and regulation of kappa opiate receptors in rat spinal cord-dorsal root ganglion primary cocultures. The density of opiate receptors increased markedly during the differentiation of the cultures; after 10 days in vitro the number of [3H]diprenorphine binding sites reached 244 +/- 47 fmol/mg protein. Most of the binding sites were of the kappa type, representing about 65-80% of total opiate receptors, while mu sites were expressed at a lower density (ca. 20% of total opiate sites). Following this period of development, the number of kappa and mu receptors did not change significantly. No detectable delta sites were observed at any time of culture (up to 4 weeks in vitro). Chronic opiate agonist treatment (24 h) of the cultured cells with either 10 microM U50488 (a selective kappa agonist), or 1 microM etorphine (a nonselective opiate agonist), did not change the number of kappa receptors and their binding affinity to [3H]diprenorphine. On the other hand, 50% of the mu receptor sites down-regulated following 24 h treatment with 1 microM etorphine. Chronic antagonist exposure (5 days) with 10 microM naloxone, markedly up-regulated the mu receptors (261% of control), whereas kappa sites exhibited a much weaker upregulation (164% of control). These data demonstrate that kappa opiate receptors are expressed at high concentration in spinal cord-dorsal root ganglion cocultures and that contrary to mu sites, kappa receptor density is less susceptible to modulation by chronic opiate treatment. The results also suggest that postreceptor components are important in regulating the kappa receptor function following prolonged opiate exposure.

The effect of etorphine on nicotine and muscarine-mediated catecholamine (CA) release from isolated perfused rat adrenal glands was investigated. Nicotine increased CA secretion at the low concentration of 0.5 micrograms while higher concentrations of muscarine (5 micrograms) were required. Moreover, muscarine released primarily epinephrine (EP) from rat adrenal glands while nicotine released norepinephrine (NE) and Ep. Etorphine inhibited NE and EP release evoked by nicotine to the same extent, whereas, muscarine-mediated release of NE and EP was not affected. Mecamylamine and verapamil inhibited nicotine but not muscarine-induced CA secretion. Our results suggest that etorphine preferentially interacts with nicotinic receptors on rat adrenal chromaffin cell membranes.

One hundred forty-two rats given intracerebral microinjections of 1 microgram of etorphine hydrochloride were observed for subsequent analgesia (flinch-jump technique) and catatonia (bar test). Neuroanatomical specificity of effect was demonstrated to the extent that behavioral effects did not result from injections into areas of low opiate receptor binding affinity, such as medial cerebral cortex and hippocampus, nor were positive results obtained from injections into fiber bundles, such as the corpus callosum and internal capsule. Positive results were obtained in a large number of areas, ranging from brain stem to telencephalon. Injections eliciting analgesia without catatonia were limited in number (9 animals) and were widely scattered throughout neuroanatomical loci. Microinjection more frequently elicited catatonia only (29 animals), and site of injection was limited to posterior cerebral cortex, posterior amygdala, dorsal reticular formation, and cerebral aqueduct. Dual behavioral effects were elicited in 28 of the animals and occurred most frequently upon injection into the periaqueductal gray, inferior colliculus, and cerebral aqueduct. (Injection into cerebral aqueduct produced 50% catatonia only and 50% dual effects). The study suggests that opiate-elicited analgesia and catatonia may be neuroanatomically distinct phenomena.

The effects of etorphine, fentanyl and morphine on noradrenaline and dopamine concentrations in the striatum of rat. Acta Physiol. Pol. 1977, 28 (2): 107--112. Dopamine (DA) concentrations were determined after administration of etorphine (M 99--0.008 mg/kg), fentanyl (0.006 mg/kg) and very high doses of morphine (20.0 mg/kg). DA was chosen as a striatal neurotransmitter playing the main role in the extrapyramidal system. The concentrations of noradrenaline (NA) were determined for comparison. Etorphine in therapeutic doses and morphine in subtoxic doses increased the concentration of DA in striatal neurons. Since, under these conditions, the behavior of animals resembles the symptom complex characteristic of the so-called parkinsonian or postneuroleptic syndrome in which a deficiency of absence of DA has been found in striatum, it might be supposed that the cataleptic action of etorphine and morphine may be due to inhibition of presynaptic striatal structures, with consequent disturbances in DA release from its stores.

Basic haematological values in 32 animals of five species were estimated after administration of sedating agents. In all species under investigation, a time-dependent decrease of erythrocyte counts, haematocrit values and haemoglobin content was noted during the first 30 min after sedation, for the following 30 min the lowered values remained essentially without any change in zebras. Derived parameters, mean corpuscular haemoglobin, mean corpuscular Hb concentration and mean corpuscular volume did not change during the period of observation. Only insignificant changes in leukocyte count and in the proportion of lymphocytes and neutrophiles were registered. The shortest possible time between sedation and blood sampling is recommended to minimalize a distortion especially in the red blood picture.

The effects of various opiate compounds have been studied on the electrocorticogram (ECoG) of the rat following local injection into various brain areas. Injections of all compounds studied into both the caudate-putamen and the basal forebrain, in particular the olfactory tubercles, induced changes in the ECoG. Injections of saline vehicle into these areas were ineffective as were injections of morphine into the corpus callosum. Potency was etorphine greater than morphine = codeine greater than thebaine. Naloxone alone was inactive following injection but if combined with morphine markedly attenuated the normal morphine response and reversed the morphine response if injected following morphine. The endogenous opiate compound enkephalin and the synthetic analogue D-ala2-met5-encamide also induced electrocortical changes which were naloxone sensitive. The results are similar to those following systemic administration of opiates. It is possible that the areas studied represent the site of action of systemically applied opiates. It is suggested that the opiates and enkephalins produce their actions by acting at the same site. Since the areas studied are rich in dopaminergic terminals an interaction may exist between dopaminergic and opiate mechanism to bring about the observed changes.

Clinical and pharmacological analyses showed a full immobilizing action of etorphine in adult sheep +/- 7 min. after a deep i.m. injection of the drug at a dosage rate of 20 micrograms/kg. Neurochemical analyses of motoric CNS-structures done within 30 min. after i.m. injection of etorphine in an immobilizing dose, showed the following: A significant decrease of dopamine (DA) and homovanilic acid (HVA) concentrations in the corpus striatum, the frontal motor cortex, cerebellum and in the lumbo-sacral portion of the spinal cord. A decrease of DA-concentration with a simultaneous increase of HVA-concentration in the pons. A significant decrease of noradrenaline (NA) concentration in the cerebellum and lumbo-sacral portion of the spinal cord and an insignificant decrease of amine concentration in the pons. A significant increase of adrenaline (A) concentration in the frontal motor cortex. A significant decrease of 5-hydroxytryptamine (5-HT) concentration in the frontal motor cortex and cerebellum and an equally significant increase in its concentration in the pons.

The inspiration inhibiting vagal reflex as elicited in rabbits by tracheal occlusion in inspiratory position, is strongly increased by etorphine and its derivatives, the 19-isoamylderivative benig of outstanding activity.

Confined and unconfined fallow deer (Dama dama) of the black variety kept at Whipsnade Park were sedated with etorphine in combination with acepromazine, or xylazine or both, with or without atropine. Induction, sedation and recovery times were recorded. During the period under sedation, systemic and pulmonary arterial pressures, electrocardiographs, body temperature, arterial blood gas pressures and pH, packed cell volume and plasma electrolytes and enzymes were monitored. In both groups, and with all drug combinations, heart rates (except where atropine was used and respiratory rates were depressed, pulmonary arterial pressures were elevated, and blood oxygen tension and pH lowered compared with interspecies norms. In confined animals, systemic arterial pressures were depressed. Unconfined animals and animals in which atropine was used showed higher and more varied systemic arterial pressures and more varied heart rates. Cardiac arrests occurred in eight animals, five during induction and three during sedation, one of which was revived with oxygen. Severe arrhythmia occurred in an animal in which atrioventricular block was confirmed and reversed by oxygen treatment.

The dopamine-stimulated adenylate cyclase activity was studied both in vivo and in vitro in the central nervous system of the bivalve mollusc Mytilus edulis. Dopamine, epinine, and apomorphine stimulated the enzyme system. Fluphenazine, haloperidol, chlorpromaxine, and to a lesser extent BOL inhibited the dopamine-stimulated adenylate cyclase. Etorphine, beta-endorphine, DALA, and methionine enkephalin depressed cyclic AMP levels. This phenomena was naloxone reversible. In addition, the opioids inhibited the stimulation of adenylate cyclase by dopamine. This phenomena was also naloxone reversible. The study demonstrates an interaction among dopamine, the opioids, and cyclic AMP.

Sixteen 3- to 5-year-old African elephants were anesthetized one or more times for a total of 27 diagnostic and surgical procedures. Xylazine (0.1 +/- 0.04 mg/kg of body weight, mean +/- SD) and ketamine (0.6 +/- 0.13 mg/kg) administered IM induced good chemical restraint in standing juvenile elephants during a 45-minute transport period before administration of general anesthesia. After IM or IV administration of etorphine (1.9 +/- 0.56 micrograms/kg), the mean time to lateral recumbency was 20 +/- 6.6 and 3 +/- 0.0 minutes, respectively. The mean heart rate, systolic blood pressure, and respiration rate during all procedures was 50 +/- 12 beats/min, 106 +/- 19 mm of Hg, and 10 +/- 3 breaths/min, respectively. Cardiac arrhythmias were detected during 2 procedures. One elephant with hypotension responded to a decrease in the concentration of halothane and IV infusion of dobutamine HCl. Alterations in systolic blood pressure, ear flapping, and trunk muscle tone were useful for monitoring depth of anesthesia. Results indicated that halothane in oxygen was effective for maintenance of surgical anesthesia in juvenile African elephants after induction with etorphine.

Respiratory function and acid-base variables were studied in Welsh Mountain ponies before and at predetermined times after the intravenous injection of Immobilon and Revivon.A marked depression of respiratory rate was accompanied by large reductions in arterial blood oxygen tension and saturation and the development of a mild respiratory acidosis following the injection of Immobilon. It was concluded that at least three factors contributed to the hypoxic hypoxia produced by Immobilon; the posture of lateral recumbency, the decrease in respiratory rate and the laboured character of the respiration. Arterial oxygen and carbon dioxide tensions returned towards control levels soon after administering Revivon. Mixed venous oxygen tensions were little affected by either Immobilon or Revivon, and mixed venous carbon dioxide tensions were increased to smaller degrees that those of arterial blood. Haemoglobin was increased initially by Immobilon, had returned to the control level by 30 min and fell below the control following the administration of Revivon.

In NG108-15 hybrid cells ascorbate suppresses the delayed etorphine-induced compensatory increase in the levels of cyclic AMP. It has, however, no effect on the early response of the cells to etorphine, as manifested in a transient decrease in the levels of cyclic AMP.

1. This report further demonstrates that etorphine influences presynaptic dopamine release, which in turn centrally modulates peripheral cilioinhibition. 2. In older animals cilioinhibition has become enhanced due to a lack of responsiveness to endogenous opioids which results in greater dopamine release, causing a higher level of cilioinhibition as demonstrated by challenging the visceral ganglia with etorphine or destroying the dopaminergic component with 6-hydroxydopamine. 3. Only the central cilioinhibitory, not the peripheral inhibitory response, mechanism appears to be altered in older animals. Thus, the alteration appears in the central integrative mechanisms involved with regulating ciliary activity. 4. The KCl-stimulated release of dopamine is unaltered in both young and old organisms, whereas the opiate inhibition of the KCl-stimulated release of dopamine is reduced in older organisms. Thus, the aging-associated alteration is associated with a specific process. 5. The reduction of opioid influence and the resulting enhanced cilioinhibitory activity may make the organisms more susceptible to environmental stress.

The efficacy of the neuroleptanalgesic combinations of fentanyl-fluanisone with diazepam; and etorphine-methotrimeprazine, either alone, or with diazepam, was investigated in the rabbit. The effects of these drugs on some cardiovascular variables were studied in chronically catheterized rabbits. Fentanyl-fluanisone and diazepam produced good surgical anaesthesia. Although respiratory depression occurred, this had little effect on blood gas values. In contrast, etorphine-methotrimeprazine and diazepam produced severe respiratory depression with consequent hypercapnia and acidosis.

Etorphine (1-4 microM) dose dependently reduced the sympathetic response induced by trains of field pulses in guinea-pig isolated atria stimulated at 4 Hz; this effect was antagonized by 10 microM naloxone. Since etorphine did not modify the dose-inotropic effect curve of exogenous noradrenaline in the same preparation, it is suggested that the depressant effect of the opioid agonist was due to stimulation of presynaptic inhibitory opiate receptors on adrenergic nerve terminals of the heart.

Some in vivo agonist and antagonist properties of the putative k-compound bremazocine were characterized in rats. Bremazocine, at doses from 0.015-32 mg/kg i.p., delayed nociceptive reaction on a 55 degrees C hot-plate with a dose-response curve not readily fitting a single straight line; this effect was antagonized by high doses of naloxone. In the same rats bremazocine did not delay the intestinal transit of a charcoal meal fed 5 min earlier and prevented morphine-induced constipation. This antagonism appeared to be opioid-specific and competitive, with apparent pA2 value 8.56. Catatonia induced by etorphine (0.004 mg/kg s.c.) and constipation induced by etorphine (0.004 mg/kg s.c.) and D-Ala2-D-Leu5-enkephalin (0.1 mg/kg i.p.) were completely antagonized by bremazocine (0.03-8 mg/kg i.p.). Antinociception induced by morphine (10 mg/kg i.v.) and etorphine (0.004 mg/kg s.c.) was only partly prevented. Naloxone (1 mg/kg) and bremazocine (0.015-1 mg/kg i.p.) precipitated a withdrawal syndrome, evaluated as jumping frequency, in rats rendered dependent to morphine. These data suggest the involvement of more than one opioid receptor population in bremazocine action in vivo.

Retrograde perfusion was used to investigate the effect of an opiate agonist and an opiate antagonist on the release of catecholamines and [Met5]-enkephalin immunoreactive material (ME-IRM) from bovine adrenal glands. Etorphine (5 X 10(-7) M) inhibited the spontaneous outflow of ME-IRM by approximately 10 percent but had no significant effect on the spontaneous catecholamine release. Acetylcholine (ACh, 5 X 10(-5) M) or 1,1-dimethyl-4-phenylpiperazinium (DMPP, 5 X 10(-5) M) stimulated release of ME-IRM and catecholamines was significantly decreased by the addition of etorphine. Diprenorphine (5 X 10(-7) M) had no significant effect on the spontaneous outflow of either ME-IRM or catecholamines. Diprenorphine reversed the inhibition of the DMPP-stimulated release caused by etorphine. After submaximal stimulation of the gland with DMPP (1 X 10(-5) M), a further stimulation of release of ME-IRM and catecholamines was observed after the addition of diprenorphine alone, i.e., in the absence of etorphine. These results provide further evidence supporting the contention that opiates modulate the secretion of catecholamines and ME-IRM from the adrenal gland.

Chronic treatment of neuroblastoma X glioma NG108-15 hybrid cells with opiate agonist resulted in loss of the acute opiate inhibition of adenylate cyclase activity with a concomitant increase in the enzymatic activity observable on addition of the antagonist naloxone. The role of membrane lipids in the cellular expression of these chronic opiate effects was investigated by the hydrolysis of phospholipids with various lipases. Treatment with phospholipase C from Clostridium welchii produced an enzyme concentration-dependent decrease of prostaglandin E1-stimulated adenylate cyclase activity in control or etorphine-treated (1 microM for 4 h) hybrid cells. In addition, incubation of hybrid cells with phospholipase C concentrations of greater than or equal to 0.5 U/ml completely abolished the compensatory increase in adenylate cyclase activity after chronic opiate treatment. This attenuation of the increase in adenylate cyclase activity by phospholipase C could be prevented by inclusion of phosphatidylcholine but not of phosphatidic acid during the enzymatic incubations. The specificity of the phospholipids involved in expression of the chronic opiate effect could be demonstrated further by the absence of effect exhibited by phospholipase C from Bacillus cereus and phospholipase D. Hydrolysis of the acyl side chains of phospholipids with phospholipase A2 did not alter the chronic opiate effect after removal of lysophosphatides with bovine serum albumin. Because the guanylylimidodiphosphate- and NaF-sensitive adenylate cyclase activities were not affected by these phospholipase treatments, the expression of the compensatory increase in adenylate cyclase activity is mediated via an increase in the coupling between hormonal receptor and adenylate cyclase with the participation of the polar head groups of the phospholipids and not the hydrophobic side chains.

Rats were trained to turn rewarding electrical brain stimulation on and off by crossing back and forth in a shuttle-box. Moderate doses of the narcotic analgesic, etorphine, increased mean ON times while having little effect on OFF times. Tolerance did not develop to the reward enhancement action over five consecutive days of injections. This paradigm seems valuable for exploration of the reinforcing properties of narcotic drugs.

Chronic morphine treatment of rats decreased the level of phosphorylation of synaptic membrane proteins of the striatum assayed in vitro. Although the patterns of phosphorylated proteins separated on SDS-gel electrophoresis from morphine-tolerant rats resembled patterns produced by lowering Ca2+ levels in the assay, supplementation of the protein kinase assay with Ca2+ and its binding protein, calmodulin, did not restore full kinase activity. The addition of methadone or etorphine to the protein kinase in vitro however, was able to block the Ca2+-calmodulin stimulation of phosphorylation in both synaptic membranes and intact synaptosomes. These data suggest that opioids produce an irreversible (or slowly reversible) defect in the Ca2+-dependent protein kinase system of striatal membranes.

The analgesic effect of etorphine was compared with that of morphine in rats with electrolytic lesions of the nucleus medianus raphe or injected intraventricularly with 6-hydroxydopamine. The effect of both compounds was markedly reduced in animals with raphe lesions, but not significantly modified in those receiving 6-hydroxydopamine. Etorphine and morphine significantly increased the forebrain levels of 5-hydroxyindolacetic acid when administered subcutaneously at doses of 5mg/kg and 2 microgram/kg, respectively. Neither drug significantly affected the forebrain levels of monoamines. It is concluded that, as for morphine the integrity of the serotoninergic system in the brain is important for the full analgesic effect of etorphine.

In order to find a suitable analgesic for the treatment of postoperative pain in pigs the analgesic effect of buprenorphine, etorphine and pethidine has been compared in 8 domestic pigs. For assessment of the analgesic action on thermal (hot plate) and two mechanical (cannulation of ear vein, needle prick) noxious stimuli have been employed. In a pilot experiment on 2 pigs in which methadone was included the maximal effective doses were estimated for each drug. Methadone was found unsuitable because of unacceptable side effects (respiratory dysfunction, hyperactivity) at effective dose levels. Next buprenorphine 120 micrograms/kg, etorphine 3 micrograms/kg and pethidine 20 mg/kg all given intramuscularly were compared in a randomized blind trial with a balanced cross-over design on 6 pigs. Etorphine proved to have the highest and pethidine the lowest maximal analgesic effect which was especially evident in the needle-prick test. Buprenorphine proved to have the longest duration of action in all three analgesic tests, in the hot plate test lasting between 7 and 24 hrs. Etorphine had a duration of 3 to 5 hrs whereas the effect of pethidine was short, only lasting about 2 hrs. Etorphine provides a complete analgesia but has a small safety margin for which reason it should be used with caution in the pig. The experimental results indicate that buprenorphine should be the first drug of choice in the treatment of pain after surgical intervention due to its long duration of action and lack of side effects.

Rats were rendered tolerant to etorphine by administering it daily for 5 days at doses of either 10 microgram/kg i.v. or 5 microgram/kg s.c..3H-etorphine was then injected to tolerant and non-tolerant rats; after 15 min their brain and spinal cord were removed for 3H-etorphine assay. Tolerant rats had lower 3H-etorphine levels in both tissues than control rats.

Binding characteristics of [3H]-etorphine and [3H]-ethylketocyclazocine are different in the lumbo-sacral spinal cord of guinea-pig. [3H]-etorphine binds to a single class of high affinity sites whereas [3H]-ethylketocyclazocine interacts with two components, a high affinity and a low affinity components. In the presence of 5 microM (D-Ala2, D-Leu5) enkephalin (DAL), the total high affinity sites can be resolved in two classes of sites, DAL sensitive sites (DALs sites) and DAL insensitive sites (DALI sites). In these conditions, [3H]-etorphine binding is completely abolished, and the binding capacity and properties of [3H]-etorphine correspond to the DALs sites. Pharmacological investigations indicated that DALI sites represent the kappa sites, whereas DALs sites closely correspond to benzomorphan sites described in rat brain and spinal cord. From these results, a new subclassification of "kappa" sites is proposed.

The effects of naloxone and three oripavine derivatives, diprenorphine, an antagonist, buprenorphine, a mixed agonist-antagonist, and etorphine, an agonist, were examined on food-reinforced responding in squirrel monkeys. Behavior was maintained under a multiple-component 1-min variable-interval schedule in which 12-min periods of unpunished responding alternated with 4-min periods in which each response produced a brief electric shock to the tail. Daily sessions were 1 hr. Responding in the two components was not differentially affected by any of the drugs. Naloxone decreased responding in both components only slightly at high doses (ED50 greater than 10 mg/kg). In contrast, the three oripavines produced prominent dose-related decreases in responding with the following order of potency for the nonpunishment component: etorphine (ED50 = 0.0005 mg/kg) greater than buprenorphine (ED50 = 0.02 mg/kg) greater than diprenorphine (ED50 = 0.11 mg/kg). Etorphine had a short duration of action (approximately 1 hr) whereas the actions of diprenorphine (1.0 mg/kg) and buprenorphine (0.1 mg/kg) persisted for 24 to 48 hr. Concurrent administration of naloxone (0.1 and 1.0 mg/kg) antagonized the response rate-decreasing effects of etorphine and buprenorphine in a dose-dependent manner (i.e., dose-response curves were shifted to the right) but failed to block the effects of diprenorphine. Although all three oripavines produced comparable decreases in food-reinforced responding, there are qualitative as well as quantitative differences between the drugs. Diprenorphine appears to act through a different mechanism from that of buprenorphine and etorphine.

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.

The effect of etorphine on dopamine and noradrenaline concentrations in different central nervous system structures in the rat. Acta Physiol. Pol., 1977, 28 (6): 529-540. Intramuscular administration of etorphine in immobilizing doses (0.008 mg/kg) was followed by a rise in dopamine concentration in the examined motor structures of the central nervous system (striopallidum, pons, cerebellum, lumbosacral intumescence of the spinal cord). Only in the motor centres of the frontal cortex dropamine concentration was decreased. At the time etorphine decreased the concentration of noradrenaline in striopallidum and raised it in the other examined structures of the central nervous system. A correlation was found between the concentrations of both substances, especially in the frontal motor centres and striopallidum. Post etorphine accumulation of dopamine in the striopallidum (for 6.369 to 11.322 mcg/g of fresh tissue) with simultaneous inhibition of motor activity of the animals suggests that etorphine inhibits the release of dopamine from the presynaptic elements in the motor centres of the central nervous system in rats. This leads to a decreased dopamine action on its receptors. Some post etorphine behavioral changes (rigidity, spastic flexion, muscle tremor) support this hypothesis.

Seventeen coastal grizzly bears (Ursus arctos horribilis) from southwestern British Columbia were captured and immobilized a total of 27 times with etorphine hydrochloride (M99). Effective dosages administered ranged from 0.011 to 0.132 mg/kg. Drug dosages (on a body weight basis) were not significantly related to induction times (R=-.040); however, it appeared that induction could be reduced with an increased dosage. At higher dosage levels respiratory rate was reduced to 2/minute.

A commercial neuroleptanalgesic acepromazine-etorphine combination administered intramuscularly to four horses produced a severe tachycardia and an increase in muscular tone, together with hypoxaemia, hypercapnia, metabolic acidosis associated with an increase in the packed cell volume and hyperglycaemia. No electrolyte changes were found. After reversal of the action of etorphine with diprenorphine, there was a prolonged decrease in the calcium and phosphorus serum concentrations and decreases in the packed cell volume and the total protein serum concentration. In a second experiment on the same four horses, glyceryl guaiacolate (10 g/100 kg body weight intravenously) was given as soon as the horses were anaesthetized with acepromazine-etorphine. The muscular rigidity disappeared and the tachycardia was less evident. There was a more pronounced hypoxaemia but the changes in the other parameters were similar to those in the first experiment. It was concluded that the neuroleptanalgesic-glyceryl guaiacolate combination is not a safe anaesthetic procedure in horses.

Previously in the analgesic tail flick assay, mice and rats implanted with morphine pellets were shown to be highly tolerant to subcutaneously administered morphine but not to etorphine. The present purpose was to see whether the same differential response would be found to the antidiuretic response of morphine and etorphine in water-loaded rats because the presence of such a differential response would be value in studying mechanisms of tolerance. Etorphine injected subcutaneously was about 1000x more potent than morphine in producing an antidiuretic response. Following chronic administration of morphine by pellet implantation, where the pellets remained in place during the drug challenge, profound tolerance developed to the antidiuretic effect of both morphine and etorphine. The dose-response curves for both were shifted to the right in non-parallel fashion with decreased slopes and antidiuretic efficacies. The large degree of tolerance developed to the antidiuretic effect of etorphine in morphine pellet implanted rats in contrast to the lack of development of tolerance to etorphine in the tail flick assay indicated that different mechanisms of development of tolerance exist for the two responses.