morphinans and oxilorphan

Topics: Blood Pressure; Creatinine; Cyclazocine; Cyclopropanes; Diuresis; Dose-Response Relationship, Drug; Humans; Morphinans; Naloxone; Narcotic Antagonists; Osmolar Concentration; Placebos; Time Factors; Vasopressins; Water Deprivation

Pigeons were trained to discriminate a dose of either 0.01 mg/kg of bremazocine or 0.05 mg/kg of fentanyl from water using a two-key drug discrimination procedure. During tests of substitution, the selective kappa-opioid agonists bremazocine, U50, 488 and tifluadom substituted for the bremazocine stimulus, whereas the less selective kappa-opioid agonists ethylketocyclazocine, levallorphan, proxorphan and nalorphine substituted for the fentanyl stimulus. The full mu-opioid agonists fentanyl, morphine, I-methadone and levorphanol, as well as the partial agonists nalbuphine, butorphanol and buprenorphine, substituted for the fentanyl stimulus. Compounds with partial-opioid agonist effects, namely nalbuphine, butorphanol, buprenorphine, proxorphan, levallorphan and nalorphine, produced 50% fentanyl-appropriate responding at doses 25 to 369.2 times smaller than the doses required to decrease response rates to 50% of control values. In contrast, the full mu-opioid agonists fentanyl, morphine, I-methadone and levorphanol produced 50% fentanyl-appropriate responding at doses only 1.3 to 10.9 times smaller than those required to decrease response rates by 50%. During tests of antagonism, both naloxone and Mr2266 produced a dose-dependent attenuation of the stimulus effects of bremazocine and fentanyl, whereas beta-funaltrexamine antagonized the stimulus effects of fentanyl but not bremazocine. Although bremazocine has been reported to have mu-opioid antagonist effects, it failed to antagonize the stimulus effects of the training dose of fentanyl. The present investigation establishes further that pigeons can discriminate selective kappa-opioid agonists from mu-opioid agonists and that in pigeons the classification of numerous opioid compounds on the basis of their kappa-like or mu-like stimulus effects differ from those in rat and monkey. In addition, under the drug discrimination procedure the actions of compounds classified as partial-opioid agonists can be differentiated from those of full mu-opioid agonists on the basis of the ratio of the dose required to engender fentanyl-like stimulus effects to the dose required to reduce response rates.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Animals; Benzodiazepines; Benzomorphans; Columbidae; Cyclazocine; Discrimination Learning; Ethylketocyclazocine; Fentanyl; Morphinans; Naloxone; Narcotics; Pyrrolidines; Receptors, Opioid; Receptors, Opioid, kappa; Receptors, Opioid, mu

Nine mixed agonist-antagonist opioids were evaluated in macaque monkeys for their ability to serve as positive reinforcers and for their discriminative stimulus similarity to etorphine and ethylketazocine. For tests of reinforcing properties, various doses of each drug were substituted for codeine under a fixed-ratio 30 time-out 600 sec schedule of i.v. delivery. Discriminative properties were assessed in separate groups of monkeys for which etorphine and saline, or ethylketazocine and saline, were established as discriminative stimuli for responses maintained under a fixed-ratio 20 schedule of food delivery. Two patterns of reinforcing and discriminative stimulus properties were observed. Buprenorphine, butorphanol, GPA 1657, nalbuphine, propiram and WY 16225 (dezocine) functioned as positive reinforcers and occasioned etorphine-appropriate but not ethylketazocine-appropriate responses. dl-Profadol also functioned as a positive reinforcer; its stereoisomers occasioned etorphine-appropriate but not, in general, ethylketazocine-appropriate responses. In contrast, levallorphan and oxilorphan did not function as positive reinforcers and occasioned ethylketazocine-appropriate but no more than 30% etorphine-appropriate responses. Under these experimental conditions, the reinforcing and discriminative stimulus profiles of the mixed agonist-antagonist opioids paralleled those of etorphine-like (mu) or ethylketazocine-like (kappa) opioid agonists.

Topics: Animals; Bridged Bicyclo Compounds, Heterocyclic; Buprenorphine; Butorphanol; Cycloparaffins; Discrimination Learning; Female; Levallorphan; Macaca mulatta; Male; Morphinans; Nalbuphine; Narcotic Antagonists; Narcotics; Pyridines; Pyrrolidines; Reinforcement, Psychology; Tetrahydronaphthalenes

Nalorphine, butorphanol and oxilorphan were compared in their ability to increase urinary output in the normally hydrated rat and to antagonize the increased urinary output produced by the full kappa-agonist, bremazocine. Nalorphine, butorphanol and oxilorphan increased 5-h cumulative urine output compared to controls, but the maximal effect was less than half the amount excreted after injection with 0.08 mg/kg of bremazocine. The effects of bremazocine were antagonized by nalorphine, butorphanol and oxilorphan. These effects of nalorphine, butorphanol and oxilorphan satisfy the criteria for classifying these agents as partial agonists at the kappa-opioid receptor responsible for mediating the effect of increased urinary output.

Topics: Animals; Butorphanol; Male; Morphinans; Nalorphine; Narcotic Antagonists; Rats; Receptors, Opioid

The effects of various opioid agonists and antagonists on urination were studied in the normally hydrated rat. Two kappa agonists, U-50,488H and proxorphan, markedly increased urination. The increased urination produced by U-50,488H was antagonized by opioid antagonists in a potency order which indicated that the effects were due to an action at kappa opioid receptors. Mu agonists decreased urination and were blocked by low doses (0.01 and 0.1 mg/kg) of naloxone, whereas kappa agonists increased urination and were only blocked by a high dose (10 mg/kg) of naloxone. The diuretic effects of U-50,488H and ketazocine, but not proxorphan and bremazocine, were reduced by morphine, consistent with the idea that proxorphan and bremazocine have morphine antagonist activity. Water deprivation produced a shift to the right for the dose-effect curve for bremazocine-induced diuresis. Kappa agonists were ineffective in increasing urination in Brattleboro rats that were homozygous for diabetes insipidus, whereas mu agonists were still effective in decreasing urination. The data are consistent with the hypothesis that kappa agonists inhibit release of vasopressin from the neurohypophysis and this decrease in vasopressin release leads to increased urination. The effects of opioids on urination in the normally hydrated rat can be extremely useful in classifying the activities of opioid on mu and kappa receptors in vivo.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Animals; Benzomorphans; Cyclazocine; Diuresis; Ethylketocyclazocine; Male; Morphinans; Naloxone; Narcotic Antagonists; Narcotics; Piperidines; Pyrrolidines; Rats; Rats, Inbred Strains; Receptors, Opioid; Receptors, Opioid, kappa; Receptors, Opioid, mu; Urination

Recent reports have suggested that opioid peptides may be involved in renal water excretion. The present in vivo experiments, therefore, were undertaken to determine the effect of opioid peptides on the osmotic and nonosmotic release of arginine vasopressin (AVP) in the conscious rat. Experimental animals were infused intravenously with naloxone (20 mug/kg per min) or oxilorphan (40 mug/kg per min), chemically dissimilar opioid antagonists. Control rats were infused with normal saline, the vehicle for the opioid antagonists. In all three groups the osmotic release of AVP was examined during an acute hypertonic saline (3%) infusion (2 ml/100 g body wt). The antidiuresis following the hypertonic saline infusion was significantly attenuated in naloxone- and oxilorphan-treated rats, as the peak urinary osmolality (Uosm) rose to 581.4+/-22.4 and 558.2+/-27.6 mosmol/kg H(2)O in naloxone- and oxilorphan-treated rats as compared with the value in control rats of 735.3+/-24.2 mosmol/kg H(2)O (both P < 0.001 vs. control). At the same time the plasma AVP levels of 5.4+/-1.3 and 5.2+/-1.1 pg/ml in naloxone- and oxilorphan-treated rats, respectively, were significantly lower than the plasma AVP in control rats of 16.9+/-2.5 pg/ml (P < 0.001). In another three groups of rats the nonosmotic release of AVP was examined during hypovolemia induced by intraperitoneal 6% dextran (1.8 ml/100 g body wt). Following intraperitoneal administration of dextran the peak Uosm of 703.0+/-87.8 and 734.8+/-99.1 mosmol/kg H(2)O in naloxone- and oxilorphan-treated rats, respectively, was significantly less than the value in control rats of 1,169.3+/-135.5 mosmol/kg H(2)O (both P < 0.02 vs. control). A comparable decrease in blood volume of 13% occurred in all three groups of animals. During the dextran administration plasma AVP levels in naloxone- and oxilorphan-treated rats increased to 4.3+/-1.0 and 6.0+/-2.0 pg/ml, respectively; both of these values were significantly lower than the plasma AVP of 12.9+/-1.4 pg/ml in control rats (P < 0.02). The effect of opioid antagonists to impair the osmotic and nonosmotic release of AVP occurred in the absence of differences in mean arterial pressure, glomerular filtration rate and the renal response to AVP. These results, therefore, indicate that opioid peptides are involved in renal water excretion primarily by modulating the central release of AVP.

Topics: Animals; Arginine Vasopressin; Consciousness; Dextrans; Endorphins; Kidney Concentrating Ability; Male; Morphinans; Naloxone; Narcotic Antagonists; Osmolar Concentration; Osmosis; Rats; Rats, Inbred Strains; Saline Solution, Hypertonic

Studies were carried out in normal human subjects to determine the effect of two narcotic antagonists, oxilorphan and butorphanol, on antidiuretic hormone (ADH) release. Oxilorphan given to eight subjects on ad libitum fluid intake resulted in a transient but significant increase in 24-h free water clearance and a decrease in urine osmolality. These changes were not accompanied by an increase in creatinine or solute excretion, and urinary ADH levels did not rise even though plasma osmolality rose significantly from 289.4 +/- 0.9 to 292.9 +/- 0.8 mosmol/kg. Treatment with oxilorphan did not interfere with the response to ADH infusion in water-loaded subjects. Both oxilorphan and butorphanol significantly elevated the plasma osmolality at which ADH release became evident after the infusion of hypertonic saline in water-loaded subjects. Oxilorphan suppressed urinary ADH excretion at the time of the osmotic threshold for ADH release in spite of the greater plasma osmolality. The data indicate that the narcotic antagonists are capable of inhibiting ADH release in man during ad libitum fluid intake and in response to an osmotic stimulus by elevating the osmotic threshold for ADH release. It is concluded that narcotic antagonist inhibition of endogenous opioid action provides further evidence supporting a role for the brain opiates in the normal regulation of neurohypophysial hormone release in man.

Topics: Adult; Butorphanol; Creatinine; Endorphins; Humans; Morphinans; Osmolar Concentration; Pituitary Gland, Posterior; Plasma; Potassium; Sodium; Urine; Vasopressins

Alternative pharmacologic adjuncts are needed for the management of opiate abuse. Oxilorphan, a narcotic antagonist, was studied at 5 different dose levels (1, 2, 4, 6, and 8 mg) in 30 normal subjects to determine the relation of single oral doses and toxicity. The drug causes pupillary constriction and mild central nervous system side effects (nausea, dizziness) at all doses. Mean urine volume increased (P less than 0.05) during the 12 hours after 1 and 2 mg. Oxilorphan has partial agonist properties similar to dl-cyclazocine.

Topics: Adult; Humans; Male; Middle Aged; Morphinans; Narcotic Antagonists; Pupil; Time Factors

Oxilorphan (levo-BC-2605) is a new, long-acting, narcotic antagonist that has agonist properties. Twenty-one (21) heroin addicts in Los Angeles were detoxified and given at least one oral dose of oxilorphan. Only three (14.3%) patients took daily doses for 14 days, which was the maximal time allowed for oxilorphan administration in this study. The remainder discontinued oxilorphan because of subjective side effects or for unknown reasons. Side effects most responsible for dropouts were dysphoria, insomnia, weakness, hallucinations, nausea, drowsiness and anorexia. Oxilorphan provided 24-hour protection with a single, oral dose, but subjective side effects encountered during inductiolinical trials with oxilorphan should be attempted with other addict populations to fully determine its potential therapeutic value.

Topics: Adult; Drug Evaluation; Female; Heroin Dependence; Humans; Male; Morphinans; Narcotic Antagonists; Substance Withdrawal Syndrome