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At least 19 recordsLinked to original sources
PubMed1986

Pharmacological effects of nalorphine and nalorphine-7,8-oxide (nalorphine-epoxide): interaction of the intrinsic activity, affinity and pharmacological responses.

We examined the relationship between the pharmacological effects and the interactions of the receptors of nalorphine and its epoxide. The abilities of nalorphine-epoxide to displace [3H]-dihydromorphine (mu-site) and [3H]-ethylketocyclazocine (kappa-site) were practically equal to those of the parent compound, nalorphine, using binding assay to the rat brain membrane preparations. Furthermore, the affinities of mu- and kappa-receptors are virtually uninfluenced by epoxidation of the 7,8-double bond of nalorphine using electrically stimulated mouse and rabbit vasa deferentia. The intrinsic activity of nalorphine, however, is considerably decreased by epoxidation. Moreover, the antagonistic effect of nalorphine to the morphine-induced antinociception (via mu-receptors) was little influenced by epoxidation, but the antinociceptive effect of nalorphine using the acetic acid writhing test was considerably reduced by epoxidation. These results suggest the presence of a higher receptor capacity for the antinociception mediated through kappa-receptors and that the differences between the pharmacological responses of nalorphine and its epoxide are due to the differences of their intrinsic activities.

Analgesics↗
PubMed1985

Intrinsic activity and effects of guanyl-5'-yl imidodiphosphate, Gpp(NH)p and sodium ion on the affinity of dynorphin 1-13, nalorphine and nalorphine-7,8-oxide to kappa-opioid receptor.

Nalorphine and nalorphine-7,8-oxide (nalorphine epoxide) behaved as partial agonists on the kappa-receptor in the electrically stimulated mouse vas deferens. The effects of a GTP-analogue, GppNHp and Na+ on the inhibition of [3H]ethylketocyclazocine binding by dynorphin 1-13, nalorphine, its epoxide and naloxone (antagonist) were studied with a synaptosomal fraction of guinea pig brain (except a cerebellum) and compared with the intrinsic activity of the test drugs, which was estimated in the electrically stimulated mouse vas deferens. The effects of GppNHp and Na+ on the affinity of the drugs to the kappa-receptor correlated with their intrinsic activities.

Animals↗
PubMed1991

Pharmacological characterization of nalorphine, a kappa 3 analgesic.

Nalorphine is an unusual opiate. Whereas low doses of nalorphine antagonize morphine analgesia, higher nalorphine doses are analgesic, with ED50 values (95% CL) of 13.4 (11.5, 15.8) mg/kg in the writhing and 39.5 (26.6, 60.1) mg/kg in the tail-flick assay. Although nalorphine analgesia is sensitive to naloxone, implying an opioid mechanism, neither beta-funaltrexamine, naltrindole nor nor-binaltorphomine antagonized nalorphine analgesia in the tail-flick assay at doses which reversed equianalgesic doses of their respective selective agonists. Nalorphine and the kappa 3 opiate naloxone benzoylhydrazone demonstrated analgesic cross-tolerance regardless of whether the mice were treated chronically with either nalorphine or naloxone benzoylhydrazone. Animals tolerant to nalorphine were not tolerant to either morphine or U50,488H (trans-3,4-dichloro-N-methyl-N-[2-(pyrrolindinyl)-cyclohexyl]- benzeneacetamide). Furthermore, nalorphine retained its analgesic potency in animals tolerant to U50,488H. Nalorphine exerts its analgesia predominantly through supraspinal mechanisms. Against systemically administered nalorphine, the opiate antagonist WIN44,441 ([2,6,11S-(-)-1-cyclopentyl-5-(1,2,3,4,5,6-hexahydro-8-hydroxy-3,6, 11-trimethyl-2,6-methano-e-benazocine-11-yl)-3-pentanone methylsulfonate) reversed nalorphine analgesia 1500-fold more potently when administered i.c.v. (ID50, 0.1 ng) than when given intrathecally (ID50,159 ng). Together these results indicate that nalorphine analgesia in the tail-flick assay does not involve mu, delta or the U50,488H-sensitive kappa 1 receptor and strongly suggest a role for supraspinal kappa 3 receptors.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1983

Discriminative stimulus properties of nalorphine in the rhesus monkeys.

The discriminative stimulus properties of nalorphine were studied in rhesus monkeys trained to discriminate i.m. injections of nalorphine (1 mg/kg) from saline. During training, a two-lever paradigm was employed where a single, 3-min extinction schedule was followed by fixed-ratio-20 schedules of food presentation. During the fixed-rate schedules, responses on one of the two levers produced food when nalorphine had been administered and responses on the other lever produced food when saline had been administered. During stimulus generalization tests, responses on either lever produced food under the fixed-ratio schedule. The discriminative stimulus effects of nalorphine were antagonized by naloxone which, by itself, did not generalize to nalorphine. The kappa opiate agonists, ethylketocyclazocine, U-50,488, bremazocine, tifluadom, as well as two mixed kappa-sigma agonists, dl-cyclazocine and dl-N-allylnormetazocine (SKF-10047), generalized to nalorphine with the following potency ranking order: bremazocine greater than ethylketocyclazocine greater than tifluadom greater than cyclazocine greater than U-50,488 greater than N-allylnormetazocine greater than nalorphine. The levo-isomers of cyclazocine, N-allylnormetazocine or U-50,488 generalized to nalorphine whereas the dextroisomers did not. Generalization to nalorphine did not occur with the mu opiate agonists, morphine, methadone and meperidine, or the nonopiate compounds, phencyclidine, ketamine and chlorpromazine. The results suggest that a kappa opiate receptor mechanism mediates the discriminative effects of nalorphine in the rhesus monkey, which may also be involved with the naloxone-sensitive, sedative and dysphoric effects of nalorphine in humans.

Animals↗
PubMed1999

Nalorphine's ability to substitute for morphine in a drug discrimination procedure is a function of training dose.

Rats trained to discriminate the mu agonists fentanyl or morphine from their respective vehicles generalize to the partial mu agonist nalorphine incompletely and inconsistently. Any number of factors may influence the generalization patterns obtained, one of which being the specific dose of the full opioid agonist used during training, a factor reported to influence generalization with other partial opioid agonists. To assess if training dose influences stimulus generalization to nalorphine and to support its role in the aforementioned variability across studies, in the present experiments rats were trained to discriminate either a low (5.6 mg/kg) or a high (10 mg/kg) dose of morphine from distilled water within the taste aversion baseline of drug discrimination learning. Subjects were then given a range of doses of morphine, nalorphine, methadone, or naloxone to assess the degree of substitution (if any) of these compounds for the training dose of morphine. For all subjects, morphine fully substituted for itself, and the opioid antagonist naloxone failed to substitute for the morphine cue. Rats generalized the morphine cue to nalorphine in subjects trained at the lower dose but not in subjects trained at the higher dose. Rats generalized the morphine cue to methadone in the latter group (the high dose group), indicating that the failure to generalize to nalorphine in this group was not a general inability of an opioid agonist to substitute for morphine. Naloxone blocked morphine stimulus control in all subjects and nalorphine control in the low-dose group for which nalorphine substituted for morphine, suggesting that morphine control (and the nalorphine substitution) was based on opioid activity. These results indicate that the substitution patterns of nalorphine in morphine-trained subjects are a function in part of the dose of morphine used in training and support the position that nalorphine is a partial opioid agonist with intermediate efficacy.

Animals↗
PubMed1988

Relation between renal and hepatic excretion of drugs: X. Excretion of nalorphine in young and adult rats pretreated with hormones or xenobiotics.

Different processes are involved in renal and hepatic excretion of organic anions and cations. In contrast to our knowledge of anion excretion, information about cation transport in kidney and liver is relatively scarce. In this study, the elimination of nalorphine was investigated to characterize the relation between renal and hepatic excretion of organic cations. Nalorphine is excreted effectively both via kidney and liver. However, its hepatic excretion dominates in adult rats. In young, 20-day-old animals biliary nalorphine elimination is immature and the excreted amounts are significantly lower. Renal excretion of nalorphine is quite similar in rats of both ages. After bile duct ligation renal excretion of nalorphine increases significantly in adult rats whereas it remains unchanged in young ones. Remarkably, after bilateral nephrectomy hepatic elimination of nalorphine is even diminished in both age groups. In further experiments renal excretion of nalorphine could be stimulated in adult rats after repeated administration of trometamol, triiodothyronine, or dexamethasone; these treatments had no consequences on biliary secretion of nalorphine.

Aging↗
PubMed1984

Potentiation of physical dependence by conjugation at the 6-position of nalorphine.

The experiments concerned the effects of glucuronate or sulfate conjugation at the 6-position of nalorphine on the analgesic and antagonistic activities and also on the development of tolerance and physical dependence. Nalorphine-3-and 6-sulfate ester were synthesized for the first time. The analgesic effect of nalorphine-6-sulfate and -glucuronide was higher than that of nalorphine when assessed in the acetic acid writhing test. However, these 6-conjugates exhibited less potent agonistic activity in the test with guinea-pig ileum muscle strip and revealed no analgesic effect in the tail pinch test. The antagonistic activity of these 6-conjugates to morphine analgesia was lower on their s.c. injection, but higher on i.c.v. injection than that of nalorphine. The development of tolerance to the analgesia caused by nalorphine was not affected by the 6-modifications. Frequent withdrawal signs were seen in mice treated chronically with anlorphine-6-conjugates by challenging with naloxone while mice treated with nalorphine showed no such signs. This potent enhancing effect of 6-conjugation on the development of physical dependence was suggested to be also the case with morphine. These changes of potency due to conjugation were interpreted as due to the altered interaction with multiple opioid receptors.

Analgesics↗
PubMed1976

Some behavioral effects of morphine, naloxone and nalorphine in the squirrel monkey and the pigeon.

Morphine, naloxone and nalorphine were studied for their effects on the performance of squirrel monkeys and pigeons responding under multiple fixed-interval (FI), fixed-ratio (FR) schedules of food presentation. Morphine generally produced only dose-related decreases in responding in both monkeys and pigeons; monkeys were 10 times more sensitive to morphine than pigeons. The only effect of lower doses of naloxone (0.01-1 mg/kg, monkeys; 1-10 mg/kg, pigeons) was to increase FI responding in some pigeons. Higher doses of naloxone (10-56 mg/kg), produced gross disturbances such as tremors and vomiting and decreased FI and FR responding of both monkeys and pigeons. Nalorphine had strikingly different effects on the behavior of the two species. In the pigeons, nalorphine consistently increased both FI and FR response rates at doses from 0.3 to 10 mg/kg and decreased responding only at doses of 30 to 100 mg/kg. Nalorphine did not increase responding at any dose in the monkeys and the pigeons, nalorphine was only one-tenth as potent as naloxone in antagonizing the effects of morphine on FI and FR responding. Decreasing response rates caused by nalorphine appeared to limit further its usefulness as a morphine antagonist. Antagonism of the rate-decreasing effects of morphine on FI and FR responding occurred over a narrower range of doses with nalorphine than with naloxone, especially in monkeys.

Animals↗
PubMed1976

Sigma effects of nalorphine in the chronic spinal dog.

The effects of graded doses of nalorphine and morphine were studied in nondependent chronic spinal dogs. Morphine and low doses of nalorphine produced behavioral changes characterized by indifference, whereas the largest dose of nalorphine produced canine delirium indistinguishable from that produced by SKF-10, 047 or cyclazocine. Nalorphine depressed the flexor reflex; however, a plateau was observed. The data suggest that nalorphine is a partial agonist of the kappa type and a sigma agonist in addition to being a competitive antagonist at the mu receptor, and further, that the dysphoric and hallucinogenic effects of nalorphine-like drugs are due to their sigma activity.

Animals↗
PubMed1980

[Effects of intracerebroventricular injections of nalorphine on feeding behaviour and rumination in sheep (author's transl)].

Two sheep were fitted with permanent cannulus in the first cerebral ventricule and permanent electrodes were stitched to the wall of the reticulum. They were housed in individual pens and fed lucern pellets twice a day (total duration 1.30 hour) at fixed hours. Food intake was weighed. Chewing movements were recorded permanently by means of a submandibular balloon. Reticular motility was recorded by electromyography during feeding periods. Feeding behaviour and rumination were previously recorded during two control periods. No treatment was applied during the first control period of 6 days (Ta). During the second one (Tb), daily intracerebroventricular (ICV) injections of saline (0.2 ml)) were given for 4 consecutive days. During the following 4 days (Na period), the sheep received isovolumic ICV injections of nalorphine (1 mg per day). Saline was injected again ICV for the last 4 days of the experimental period (Tc). During the period of nalorphine administration there was an important fall in the circadian percentage of rumination of one sheep and a total suppression in the other, discarding the possibility of a volumetric effect. There was also a significant decrease of food intake in the two sheep but nalorphine did not modify the frequency of reticular contractions in any case. Regarding to the general behaviour, the drug induced a general excitation with bleating and increased responsiveness to stimuli. Oral activity included compulsive and continuous chewing movement, creaking the teeth, gnawing, nipping and an apparent activity of searching food for up to 15 hours. In conclusion, nalorphine and morphine effects upon the sheep are compared. The effects of the two drugs are exactly the same regarding to the decrease of rumination and feeding intake and the modification of general behaviour, but morphine decreases markedly the reticular rhythm whereas nalorphine does not. Besides, it seems that the animals get tolerant more readily to morphine than to nalorphine.

Animal Feed↗
PubMed1982

The analgesic effect of quaternary analogues of morphine and nalorphine.

1. The effects of N-methyl morphine and N-methyl nalorphine were studied on the hyperalgesia induced by prostaglandin E2 in the rat paw. Morphine and N-methyl morphine injected intraperitoneally (2-8 mg/kg) caused a dose-dependent analgesia. The potency of N-methyl morphine was of the same order of magnitude as its parent compound in causing analgesia. 2. Nalorphine caused a short-lasting analgesia followed by an enhancement of prostaglandin-induced hyperalgesia. In contrast, its analogue, N-methyl nalorphine, injected intraperitoneally, induced analgesia but did not enhance the hyperalgesia induced by prostaglandin E2 or induce hyperalgesia in the control paw. 3. Treatment of the animals with N-methyl nalorphine at a dose which had no apparent analgesic effect antagonized the analgesic effect of morphine or N-methyl morphine. 4. Administration of a low dose of N-methyl nalorphine into the paw totally antagonized the analgesic effect of N-methyl morphine administered either locally into the paw, or intraperitoneally. 5. It is concluded that quaternary analogues of morphine and nalorphine, which do not have central effects because they do not cross the blood-brain barrier, retain the peripheral analgesic effects of the parent compounds.

Animals↗
PubMed1983

Relative ability of N-methyl nalorphine and N-methyl levallorphan to prevent antinociception and intestinal transit inhibition in morphine treated rats.

Nalorphine, levallorphan and their quaternary analogs, N-(eq)allyl derivatives of the two diastereoisomers at the nitrogen atom (N-methyl nalorphine and N-methyl levallorphan) were tested for their peripheral selectivity. We compared their relative ability to prevent morphine-induced (5 mg/kg i.v.) antinociception (central antagonism) and constipation (peripheral antagonism) in the same rats. Nalorphine and levallorphan reduced morphine-induced antinociception to half maximal response at doses of 5.1 and 0.89 mg/kg s.c. and restored the intestinal transit to 50% of controls (AD50) respectively at doses of 0.25 and 0.12 mg/kg. N-methyl nalorphine up to 24 and N-methyl levallorphan up to 30 mg/kg given s.c. 10 min before morphine did not antagonize narcotic-induced antinociception, fully preventing constipation (AD50 0.65 and 0.32 mg/kg respectively), but when injected 50 min before morphine they partially lost their antagonist potency (AD50 2.3 and 2.6 mg/kg respectively) and peripheral selectivity. N-methyl nalorphine and N-methyl levallorphan thus seem more peripherally selective than their tertiary analogs and more potent than quaternary narcotic antagonists tested to date.

Analgesia↗
PubMedDate not supplied

Comparative study of the action of naloxone (Narcan) and nalorphine in man.

The comparative study of 2 narcotic antagonists, naloxone and nalorphine, was performed in healthy volunteers. The influence of these drugs on the respiratory and cicularoty systems and on the psychical state was compared. The study was carried out in a double-blind, cross-over manner. Increasing doses of naloxone and placebo or nalorphine and placebo, were administered intravenously. Naloxone, even in very high doses, caused no changes in cardivascular system, acid-base balance, sensitivity of respiratory centre to carbon dioxide and psychical state of volunteers. After the administration of nalorphine, even in very small doses, changes in psychical state in all examined subjects were observed. Nalorphine caused the significant change in the ventilatory response to CO2. Based on their results, the authors conclude that naloxone has no agonist or intrinsic narcotic activity, as opposed to nalorphine possessing strong narcotic action.

Attention↗
PubMedDate not supplied

The effects of nalorphine and Micoren on blood oxygenation and acid-base equilibrium in patients with myocardial infarction treated with neuroleptanalgesia II.

Sixty-five patients with myocardial infarction were observed for comparison of the values of nalorphine and Micoren in prevention of respiratory depression caused by fentanyl. The patients were divided into 4 groups receiving NLA II with or without nalorphine, morphine or Micoren. In all cases paO2, paCO2 and acid-base equilibrium were determined before and after administration of drugs. In the group receiving only NLA II paO2 fell in 50% of cases, in other groups receiving nalorphine or Micoren it increased in most cases. The paCO2 increased in most cases in groups receiving only NLA II or NLA II with nalorphine with or without morphine and respiratory acidosis developed in 4 cases. In the group receiving NLA II with Micoren paCO2 fell. The results indicate the necessity of administration of respiratory stimulants with NLA II and Micoren appears to be preferable to nalorphine in this respect.

Acid-Base Equilibrium↗