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PubMedDate not supplied

The metabolism of (-)-3-phenoxy-N-methylmorphinan in dogs.

The disposition of radioactive (-)-3-phenoxy-N-methyl[2-3H]morphinan in dogs after oral administration has been investigated. Unchanged drug was not found in bile, urine, or feces. Excretion of total radioactivity in feces ranged from 67 to 78% of an oral dose. Two unconjugated metabolites were isolated from feces and identified by NMR and GC/MS. Both were substituted on the phenoxy group; they were found to be the p-hydroxy (pOH-PMM) and the m-methoxy-p-hydroxy (mOCH3-pOH-PMM) metabolites. Further, levorphanol and norlevorphanol were identified in feces both as free and conjugated metabolites, as well as a small amount of levomethorphan. Urine contained mostly unknown metabolites and conjugated levorphanol and pOH-PMM. Although the glucuronide of mOCH3-pOH-PMM was the major metabolite in bile, smaller amounts of the glucuronide and sulfate conjugated of both levorphanol and pOH-PMM were also found. Estimates for the total urinary and fecal excretion (as percentages of the dose) by two dogs for the five known metabolites were as follows: levorphanol, 18.8-21.5%; pOH-PMM, 14.4-20.6%; mOCH3-pOH-PMM, 14.9%; norlevorphanol, 2.8-6.1%; levomethorphan, 0.5%. Two of these metabolites, pOH-PMM and levorphanol, are potent analgesics.

Animals↗
PubMed1999

Antinociceptive effects of opioids following acute and chronic administration of butorphanol: influence of stimulus intensity and relative efficacy at the mu receptor.

RATIONALE: A common treatment strategy for the management of severe pain involves the co-administration of multiple opioid analgesics. Due to the increasing popularity of this practice, it is becoming increasingly important to understand the interactions between clinically employed opioids under a wide range of conditions. OBJECTIVE: The purpose of the present investigation was to examine the effects of opioid combinations following acute and chronic administration of the low-efficacy mu-opioid butorphanol, and to determine if the effects of these combinations are modulated by the intensity of the nociceptive stimulus. METHODS: In a warm-water, tail-withdrawal procedure, rats were restrained and the latencies to remove their tails from 50 degrees C (low temperature) and 55 degrees C (high temperature) water were measured following both acute and chronic administration of butorphanol. Opioids possessing both high (etorphine, levorphanol, morphine) and low [dezocine, (-)-pentazocine, nalbuphine] relative efficacy at the mu receptor were examined. RESULTS: Under acute conditions, etorphine, levorphanol, morphine and dezocine increased tail-withdrawal latencies at both low and high temperatures, whereas (-)-pentazocine, nalbuphine and butorphanol increased latencies only at the low temperature. A dose of 30 mg/kg butorphanol increased the effects produced by these opioids at the low temperature, but antagonized the effects of etorphine, levorphanol, morphine and dezocine at the high temperature. During chronic treatment with 30 mg/kg per day butorphanol, tolerance was conferred to the antinociceptive effects of all the opioids examined, with greater degrees of tolerance conferred to those opioids possessing low efficacy at the mu receptor. During butorphanol treatment, etorphine, levorphanol and morphine increased tail-withdrawal latencies at both water temperatures, dezocine increased latencies at only the low temperature, and (-)-pentazocine, nalbuphine and butorphanol failed to increase latencies at either temperature. A dose of 30 mg/kg butorphanol antagonized the antinociceptive effects of etorphine, levorphanol, morphine and dezocine during chronic treatment, and these effects were observed at both water temperatures. CONCLUSIONS: These findings indicate that the interactions between butorphanol and other mu opioids vary quantitatively between low and high stimulus intensities, and between acute and chronic conditions. In most instances, however, these interactions can be predicted from the effects of the drugs when administered alone.

Analgesics, Opioid↗
PubMed1976

The mechanism of inhibition of neuronal activity by opiates in the spinal cord of cat.

Extra- and intracellular recordings from motoneurones, interneurones and dorsal horn neurones (laminae 4 and 5) were obtained from the lumbar segments (L6-L7) of spinalised (Th 9/10) or pentobarbital-anaesthetised and anaemically decorticated cats. In the majority of spinal neurones microelectrophoretically applied morphine and levorphanol reversibly depressed spontaneous as well as stimulus-evoked and L-glutamate- or acetylcholine-induced activity. There is evidence that opiates block L-glutamate-induced depolarisations by impairing the Na+-influx triggered at the postsynaptic membrane. These depressant effects of opiates could be antagonised by naloxone, and, except in a few cases, were not associated with hyperpolarisation of the cell. Dextrorphan, the D+ enantiomer of levorphanol, displayed no such depressant actions, indicating that stereospecific receptors mediate the depressant effects of opiates. Phoretically applied atropine, procaine and Ca2+ ions have anti-glutamate and anti-acetylcholine actions similar to opiates, but these actions were not antagonised by naloxone. The hyperpolarising effect of glycine was not influenced at dose levels of opiates sufficient to suppress depolarisation induced by L-glutamate or acetylcholine. Microelectrophoretically administered morphine and levorphanol slowed the rate of rise of mono- and polysynaptic EPSPs by a naloxone-antagonisable mechanism at dose levels where almost no alteration in spike shape was detectable. Increased doses of morphine and levorphanol reduced the amplitude of IPSPs and completely blocked or reduced the amplitude of both direct- and antidromically-evoked spikes. These effects of increased doses of opiates were not antagonised by naloxone. Intravenous injection of 2 mg/kg of morphine or 20 mug/kg of Fentanyl mimicked the suppression of spontaneous and evoked neuronal activity observed after phoretic administration. This depressant action of systemically applied opiates could be transiently antagonised by phoretic administration of naloxone. The results are discussed with respect to a stereospecific action of opiates at a postsynaptic receptive site in the spinal cord.

Acetylcholine↗
PubMed1985

Receptor stereospecificity in opiate-ethanol interaction using the preexposure-conditioned taste aversion (CTA) paradigm.

In the first experiment, rats were conditioned with different doses of levorphanol or dextrorphan to a novel tasting saccharin solution. In the second experiment, rats were either preexposed to levorphanol or dextrorphan and conditioned with either morphine or ethanol to the saccharin solution. The results showed that levorphanol, but not dextrorphan, at 1, 5 and 10 mg/kg doses effectively induced a CTA. Preexposure to the 5 mg/kg dose of levorphanol blocked both morphine- and ethanol-induced CTAs. Dextrorphan at the same dose did not affect the CTAs. These findings are discussed in terms of the involvement of the opiate receptors in opiate-ethanol interaction.

Animals↗
PubMed1986

Characterization of the effects of (+/-)-meptazinol, its individual enantiomers and N-methyl meptazinol on food consumption in the rat.

Both (+/-)-meptazinol (2 mg kg-1) and levorphanol (1 mg kg-1) produced hyperphagia over a 4 h period after intraperitoneal injection in free feeding rats during the daylight phase. The individual (+)- and (-)-enantiomers of meptazinol (2 mg kg-1 i.p.) induced comparable increases in cumulative food intake. N-methyl meptazinol (2-10 mg kg-1 i.p.), the quaternary analogue of meptazinol, produced no modification of food intake though it increased food consumption when injected intracerebroventricularly (10-100 micrograms per animal). Meptazinol and levorphanol hyperphagia was abolished by 1 mg kg-1 doses (i.p.) of the opioid antagonists naltrexone, naloxonazine and (-)-Mr 1452 but not by its (+)-enantiomer Mr 1453 which is not effective as an opioid antagonist. Intracerebroventricular administration of the delta-opioid antagonist ICI 154,129 (10 micrograms per animal) suppressed meptazinol but not levorphanol hyperphagia. It was concluded that meptazinol produces centrally mediated stereospecifically reversible hyperphagia through a mu-opioid receptor mechanism common to levorphanol, and also through delta-opioid receptor mechanism(s).

Animals↗
PubMedDate not supplied

Differential effects of morphinan drugs on haloperidol-induced catalepsy in rats: a comparative study with an N-methyl-D-aspartate antagonist.

The effects of the morphinan drugs dextrorphan, dextromethorphan and levorphanol were tested towards the cataleptic activity induced by 1 mg/kg of haloperidol i.p. in rats. The influence of the morphinans was compared to that of the N-methyl-D-aspartate competitive antagonist, 2-amino-5-phosphonovaleric acid. 2-Amino-5-phosphonovaleric acid (0.5 mumoles, i.c.v.), dextrorphan (7.5-15 mg/kg, i.p.) and dextromethorphan (15-30 mg/kg, i.p.) significantly reduced the degree of catalepsy in the haloperidol-treated rats within 15 min. Conversely, levorphanol (15-30 mg/kg, i.p.) significantly increased the degree of catalepsy in the haloperidol-treated rats within 15 min. Naloxone (2 mg/kg, i.p.) counteracted the potentiating effects of levorphanol. These findings demonstrate a differential influence of the morphinan stereoisomers dextrorphan and levorphanol on experimental catalepsy, and suggest a potential use of dextromethorphan in the treatment of Parkinson's disease.

2-Amino-5-phosphonovalerate↗
PubMed1990

Assessment of relative intrinsic activity of mu-opioid analgesics in vivo by using beta-funaltrexamine.

Morphine is the prototypic mu-opioid analgesic; however, in certain situations in vitro, morphine behaves as a partial agonist. To assess the relative intrinsic activity of morphine and three other mu-opioid analgesics in vivo, beta-funaltrexamine (beta-FNA), an irreversible antagonist selective for the mu receptor, was used to reduce the effective receptor reserve. By using a stereotaxic device, 1.25 to 20 micrograms of beta-FNA was infused into the lateral ventricle of rats. Twenty-four hours later, animals were tested in the tail-flick assay with cumulative doses of morphine, levorphanol, methadone or fentanyl. Pretreatment with 2.5 micrograms of beta-FNA induced parallel rightward shifts of both the morphine and levorphanol dose-effect curves and 5.0 micrograms of beta-FNA reduced the maximum analgesic effect of these agonists. Methadone surmounted the antagonism of 5.0 micrograms of beta-FNA; 10 micrograms was required to reduce the maximum analgesic effect of methadone. Fentanyl overcame the blockade induced by both 5.0 and 10 micrograms of beta-FNA. Only with a pretreatment dose of 20 micrograms of beta-FNA was the maximum analgesic effect of fentanyl reduced. Thus, when a certain proportion of mu receptors is inactivated, i.e., with 5.0 micrograms of beta-FNA, fentanyl and methadone have the capacity to surmount the blockade, whereas morphine and levorphanol do not. This suggests that fentanyl and methadone have higher intrinsic efficacies than do morphine and levorphanol. Thus, a strategy used widely in vitro was applied successfully in vivo to assess relative intrinsic activities of a series of mu-opioid agonists.

Analgesics↗
PubMedDate not supplied

Effects of opioids on the ACh-induced contraction of the toad rectus.

The inhibitory effect of morphine, nalorphine, oxymorphone, naloxone, naltrexone, N-methylnaloxone, levorphanol, levallophan, dextrorphan, dextrallophan, levo-methadone, dextro-methadone, pethidine, leu-enkephalin and U-50 488 on the acetylcholine (ACh)-induced contraction of the toad rectus was investigated. The dose-response curves obtained in the absence and presence of increasing concentrations (0.1-3.2 or 10-320 mumol/l) of each opioid were subjected to three types of inhibition model discrimination, namely competitive, noncompetitive and uncompetitive. The results show that the opioids, except morphine, nalorphine and levorphanol, inhibit the ACh-induced contraction by multiple modes of action. Except for the morphinans, the opioids inhibit competitively indicating that they are able to compete with ACh for cholinergic receptors at the nicotinic site. The opioids also inhibit noncompetitively (except oxymorphone and N-methylnaloxone) and uncompetitively (except oxymorphone) indicating the possible existence of separate opioid binding sites and the combination of the opioids with the ACh receptor complex, respectively. The effect of morphine and levorphanol on the ACh-induced contraction varies with the concentration of the two opioids. At concentrations below 80 mumol/l both opioids tend to inhibit the contraction while at concentrations of 80 mumol/l and above there is no apparent effect. Nalorphine has no effect on the contraction at the concentrations (10-320 mumol/l) employed in the study. An apparent structure-activity relationship between the phenanthrenes and the various binding sites is noticeable; so also is the difference in the activity between the dextro and levo-isomers of levorphanol and levallorphan indicating that the receptors exhibit stereospecificity.

Abdominal Muscles↗
PubMed1995

Subgroups among mu-opioid receptor agonists distinguished by ATP-sensitive K+ channel-acting drugs.

1. We evaluated the effects of the i.c.v. administration of different K+ channel blockers (gliquidone, 4-aminopyridine and tetraethylammonium) and an opener of K+ channels (cromakalim) on the antinociception induced by several mu-opioid receptor agonists in a tail flick test in mice. 2. The s.c. administration of all agonists of mu-opioid receptors tested (morphine, 1-16 mg kg-1; metadone, 1-6 mg kg-1; buprenorphine, 0.04-0.64 mg kg-1; fentanyl, 0.02-0.32 mg kg-1 and levorphanol, 0.2-3.2 mg kg-1) elicited a dose-dependent antinociceptive effect. 3. The ATP-sensitive K+ channel blocker, gliquidone (0.06-16 micrograms per mouse, i.c.v.) antagonized the antinociception induced by buprenorphine, morphine and metadone. In contrast, gliquidone (0.25-160 micrograms per mouse) did not modify the antinociceptive effects of fentanyl and levorphanol. 4. Cromakalim (4-64 micrograms per mouse, i.c.v.), an opener of ATP-sensitive K+ channels, enhanced the antinociception produced by buprenorphine, morphine, and methadone, and did not significantly modify the antinociceptive effects of fentanyl and levorphanol. 5. The i.c.v. administration of the K+ channel blockers tetraethylammonium (10 micrograms per mouse) or 4-aminopyridine (25 ng per mouse) did not significantly modify the antinociception induced by any mu-opioid receptor agonist tested. 6. These results suggest that the opening of ATP-sensitive K+ channels is involved in the antinociceptive effect of morphine, buprenorphine and methadone, but not in that of fentanyl or levorphanol. Consequently, we suggest that at least two subgroups can be distinguished among mu-opioid receptor agonists, each inducing antinociception through different effector mechanisms.

4-Aminopyridine↗
PubMed1975

Stereospecific binding of morphine to phosphatidyl serine.

By measuring the adsorption of 14C-morphine to a surface film at an air-water interface, it was shown that morphine binds to phosphatidyl serine in a 1:1 molar ratio. With the use of levorphanol and the inactive d-isomer, dextrorphan, it could be demonstrated that the interaction was stereospecific. A Lineweaver-Burk plot disclosed that levorphanol and morphine competitively interacted with the lipid; the Km for morphine was 1.6 X 10(-5)M and the Ki for levorphanol was 4.8 X 10(-5)M. Heroin, a stronger opiate, had a greater affinity for phosphatidyl serine than did morphine or levorphanol.

Adsorption↗
PubMed1976

Oral ingestion of narcotic analgesics by rats.

Rats drank solutions of narcotic analgesics as the only drinking fluid available in their cages. Relative to their daily water intake before the drug solutions were introduced, the rats drank more etonitazene solution, less methadone solution, and about the same volume of morphine, meperidine and levorphanol solution as water, although some rats would not drink the higher concentrations of morphine (1.0 mg/ml), levorphanol (1.0 mg/ml) and methadone (1.0 mg/ml). When naloxone (1.0 mg/kg) was administered after 12 days of drinking the drug solutions, the severity of the abstinence syndromes based on scoring of symptoms and on weight loss was morphine greater than or equal to etonitazine greater than levorphanol greater than meperidine greater than methadone. The animals showing the most severe syndrome after naloxone usually consumed more drug solution than usual during the next 24 hours, so that body weights were normal at the end of the 24-hour period. Nonprecipitated abstinence was also studied in these rats by replacing the drug solutions with water 3 to 5 days after the naloxone injection. Rats that had been drinking morphine, etonitazene and levorphanol lost weight for 2 or 3 days and then began to regain their lost weight. In contrast, rats which had been switched from methadone and meperidine solutions to water gained weight rapidly. Morphine and etonitazene drinkers which had been switched to water drank a lesser volume of water than they had been drinking of drug solution whereas some ex-methadone drinkers drank more water.

Administration, Oral↗
PubMed1975

The stimulus properties of morphine and ethanol.

The present investigation sought (a) to establish the efficacy of morphine and ethanol as discriminative stimuli when each is paired with the administration of saline and (b) to compare, in a qualitative sense, the stimulus properties of the two drugs. Additional experiments examined the effects of treatment with naloxone or l-propranolol upon morphine and ethanol-mediated discriminated responding. Finally, the stereospecificity of the stimuli produced by morphine was determined by a comparison, in morphine-trained rats, of levorphanol and dextrorphan. Discriminated responding developed rapidly in both the morphine and ethanol groups. In tests in which ethanol was administered to morphine-trained animals and vice versa, no similarity to stimulus properties was apparent. Antagonism of discriminated responding induced by morphine and ethanol was attempted using naloxone and l-propranolol. Naloxone blocked the actions of morphine but was without effect upon ethanol. No evidence of antagonism of either drug by propranolol was found. When a range of doses of levorphanol (0.1-3 mg/kg) and dextrorphan (3-100 mg/kg) was tested in morphine trained animals, only levorphanol was able to substitute for morphine. The present results suggest that the stimulus properties of morphine represent typical opiate effects.

Animals↗
PubMed1982

Histamine release from isolated rat mast cells induced by opiates: effect of sterical configuration and calcium.

The stereospecificity of the action of opiates on rat mast cells was investigated by means of the l- and d-isomers levorphanol and dextrorphan. The dose-response curves for histamine release induced by the 2 drugs were of a similar shape with a maximum at 2 X 10(-3) M and a pronounced minimum at 5 X 10(-3) M. At concentrations below 5 X 10(-3) M the effect of both drugs resembled that of morphine, i.e. the release occurred rapidly and inhibition was observed with naloxone, codeine, and antimycin A. Levorphanol, dextrorphan, and the antagonist levallorphan at concentrations above 5 X 10(-3) M seemed to be toxic to mast cells. The uptake of 45Ca in connection with histamine release induced by pethidine, levorphanol, and dextrorphan was lower than that of control cells, whereas the uptake induced by morphine did not differ from that of controls. The inhibition of compound 48/80-induced histamine release by morphine was paralleled by a reduced 45Ca uptake. The time course for the inhibitory effect of preincubation with morphine was similar for the histamine released induced by morphine and by compound 48/80. Washing of the cells after preincubation with morphine was without effect on the inhibition of morphine-induced histamine release, whereas the inhibition of compound 48/80 was reduced. The present observation with morphine and compound 48/80 support our previous impression of similarities in their mode of action, but a mechanism implying an interference by morphine with the disposition of calcium could also account for the findings. The observed antagonism between morphine and calcium resembles that of opiate receptors, but histamine release induced by opiates does not involve stereospecific opiate receptors.

Animals↗
PubMed2005

Social and environmental influences on opioid sensitivity in rats: importance of an opioid's relative efficacy at the mu-receptor.

RATIONALE: Evidence indicates that social and environmental enrichment can influence the functional maturation of the central nervous system and may affect an organism's sensitivity to centrally acting drugs. OBJECTIVE: The purpose of the present study was to examine the effects of social and environmental enrichment on sensitivity to mu-opioids possessing a range of relative efficacies at the mu-receptor. METHODS: Rats were obtained at weaning (21 days) and divided into two groups immediately upon arrival. Isolated rats were housed individually in opaque laboratory cages with no visual or tactile contact with other rats; enriched rats were housed socially in groups of four in large cages and given various novel objects on a daily basis. After 6 weeks under these conditions, the effects of morphine, levorphanol, buprenorphine, butorphanol, and nalbuphine were examined in the warm-water, tail-withdrawal procedure and the place-conditioning procedure. RESULTS: In the tail-withdrawal procedure, isolated and enriched rats did not differ in sensitivity to morphine (1.0-30 mg/kg) and levorphanol (0.3-10 mg/kg), but enriched rats were more sensitive to buprenorphine (0.03-3.0 mg/kg), butorphanol (0.3-30 mg/kg), and nalbuphine (0.3-30 mg/kg). In drug combination tests, butorphanol and nalbuphine antagonized the effects of morphine in isolated rats under conditions in which they produced high levels of antinociception in enriched rats. In the place-conditioning procedure, doses of 10 morphine and 3.0 levorphanol established a place preference in both groups of rats, whereas doses of 0.3 buprenorphine, 3.0 butorphanol, and 10 nalbuphine established a place preference only in enriched rats. CONCLUSIONS: These findings may be taken as evidence that enriched rats are more sensitive than isolated rats to the effects of lower-efficacy mu-opioids and that social and environmental enrichment leads to functional alterations in opioid receptor populations.

Analgesics, Opioid↗
PubMed1981

Opiate antagonism of glycine-evoked membrane polarizations in cultured mouse spinal cord neurons.

The effect of several opiate receptor agonists on the responses of spinal cord neurons to putative inhibitory and excitatory amino acids was studied using an in vitro model system, cultured fetal mouse spinal cord neurons, and bath application of opiates. Intracellular recordings were made from the cultured neurons with conventional voltage recording techniques or under voltage clamp conditions. The putative amino acid neurotransmitters were applied by iontophoresis or micropressure ejection. Our main finding is that the opiate agonists, morphine and levorphanol (5-100 microM), consistently depressed the responses evoked by the putative inhibitory amino acid neurotransmitters glycine and beta-alanine but not GABA. Dextrorphan, the inactive isomer of levorphanol, also depressed the glycine and beta-alanine responses, but higher concentrations were required. The excitatory glutamate response was unaltered by these opiates. Leucine enkephalin, an opioid peptide, had no effect on the amino acid responses in the neurons where it was also tested. The opiate antagonist naloxone (10-100 microM) did not reverse the morphine or levorphanol depressions of the amino acid responses making it unlikely that opiate receptors mediate this effect. Strychnine was considerably more effective than morphine as a glycine antagonist, producing depressions at nM concentrations compared to the microM concentrations required for morphine. Preliminary studies indicate that both morphine and strychnine act in a non-competitive manner. However, additional studies will be required before the sites of action for these agents can be identified. The possible pharmacological or toxicological significance of the present work remains to be determined. Considering the high doses of opiates (microM concentrations) required to depress the glycine and beta-alanine responses, it is unlikely that this action is relevant to normal therapeutic situations. However, such concentrations of opiates are often utilized in pharmacological studies and may be achieved when opiates are applied by iontophoresis. Our data indicate that consideration of the present opiate action should be made when microM concentrations or iontophoretic application of opiates are used for pharmacological studies of CNS tissue.

Amino Acids↗
PubMed1985

Behavioral response to apomorphine and its interaction with opiates in domestic pigeons.

Domestic pigeons received peripheral injections of saline or the dopamine agonist apomorphine (AM) at doses of 0.025, 0.05, 0.1, 0.25, 0.5 or 1 mg and their behavior was studied for 30 min after these treatments. Given at a dose of 0.025 mg, AM decreased pecking, whereas doses ranging from 0.1 to 1 mg strongly stimulated this behavior. The frequency of headshaking was enhanced by the administration of each dose of AM; at the 3 higher doses, the drug also attenuated the frequency of preening. In another experiment, AM was administered 40 min after the injection of either naloxone (0.5, 1 or 4 mg), the opiate agonist levorphanol (0.25, 0.5 or 1 mg) or its dextroisomer, dextrorphan (0.25, 0.5 or 1 mg), while the birds were observed as before. No interaction between AM and either naloxone or dextrorphan was detected. By contrast, injection of each dose of levorphanol attenuated preening, and completely antagonized the stimulating effect of AM treatment on headshaking. At a dose of 1 mg, levorphanol also slightly decreased the frequency and increased the latency of occurrence of pecking. It is concluded that in pigeons, opiates modulate the behavioral response to apomorphine in a complex fashion.

Animals↗
PubMed1982

Determination of the analgesic 3-phenoxy-N-methylmorphinan in plasma by gas chromatography using either positive chemical ionization mass spectrometric or nitrogen-phosphorus-specific detection analysis.

The compound 3-phenoxy-N-methylmorphinan (I) is under development as an analgesic agent. Studies on the biotransformation of the drug in the rat and in the dog have shown that I is extensively metabolized by N-demethylation to yield the nor-analogue (I-A), by para-hydroxylation of the 3-phenoxy ring to yield the phenolic analogue (I-B), cleavage of the ether linkage to yield levorphanol (I-C), and its N-demethylation to yield nor-levorphanol (I-D). The presence of these four metabolites (two of which, I-B and I-C, have analgesic potential) in addition to the parent drug, necessitated the development of sensitive and specific assays for their quantitation in plasma. This was accomplished by the development of (a) a high-performance liquid chromatographic assay using UV detection to obtain a qualitative/semi-quantitative profile of the metabolites present in plasma; (b) a gas chromatographic--nitrogen--phosphorus-specific detection method for the determination of the parent drug (I) for pre-clinical drug evaluation; and (c) a sensitive and specific gas chromatographic--positive chemical ionization mass spectrometric assay for eventual clinical evaluation for the determination of I and a key metabolite levorphanol (I-C). This report presents some preliminary pharmacokinetic data on I and I-C in the dog obtained during pre-clinical development.

Analgesics↗
PubMed1987

Effects of opiate manipulations on latent inhibition in rabbits: sensitivity of the medial septal region to intracranial treatments.

The effects of opiate manipulations were examined on latent inhibition of classically conditioned heart rate in rabbits. Animals were exposed to an auditory stimulus that was later used as a conditioned stimulus (CS). Administration of the agonist levorphanol into the medial septal region either preceding or immediately following CS preexposure sessions attenuated latent inhibition of the conditioned response. This effect was observed in animals that showed no change in long-term retention of habituation. Administration of levorphanol into the central nucleus of the amygdala, a sensitive site for opiate manipulations on aversive conditioning tasks, was ineffective. Further analysis of the effect obtained within the septal region revealed pharmacological specificity. The effect of posttraining levorphanol was also time dependent and exhibited neuroanatomical specificity. Posttraining opiate antagonist administration into the medial septum produced a modest augmentation of latent inhibition. The medial septal region appears to provide a site where opiate manipulations alter some aspect of retention for events that occur in the absence of reinforcement.

Acoustic Stimulation↗