Effects of full and partial kappa agonists and mu agonists on urine output of normally hydrated rats.
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Animals↗
Biomedical subjects
J D Leander
Publications and source records attributed to J D Leander.
Kappa opioid agonists and antagonists: effects on drinking and urinary output.
Several opioid antagonists have previously been shown to decrease drinking. The data have suggested that this was due to an antagonist action at kappa opioid receptors rather than mu or delta opioid receptors. Kappa agonists have a marked diuretic effect through suppression of vasopressin release. Antagonism of this kappa receptor-mediated effect can be used as an in vivo test for determining kappa-receptor antagonist activity. The potencies of opioid antagonists for antagonizing the diuretic effects of the kappa agonist bremazocine do not correlate directly with the potencies for decreasing deprivation-induced drinking. Further work should investigate the receptor specificity for effects on drinking and kappa-mediated diuresis.
3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
Elevation of serum corticosterone in rats by bremazocine, a kappa-opioid agonist.
Bremazocine at doses of 0.01 mg kg-1 s.c., and higher, increased serum corticosterone concentration several-fold in rats. The increase occurred within 20 min, was maximum at 40-60 min and subsided after 120 min. Pretreatment with naloxone (1-10 mg kg-1 s.c.) antagonized the corticosterone increase. These data support the view that kappa-opioid agonist activity of bremazocine mediated the corticosterone increase.
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Kappa-opioid diuretic effects of tifluadom, a benzodiazepine opioid agonist.
Tifluadom produced a dose-related (0.08-5 mg kg-1) diuresis in normally hydrated rats. This diuretic effect was antagonized by kappa-antagonist doses of naloxone and blocked by morphine administration. This is further in-vivo evidence that tifluadom is a fairly specific kappa-opioid agonist.
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Comparison of the effects of naloxone and picrotoxin on schedule-controlled responding in the pigeon: possible GABA-antagonistic effects of naloxone.
The effects of naloxone and picrotoxin were determined alone and in conjunction with pentobarbital, diazepam or clonazepam, in pigeons responding under a multiple fixed-ratio 30-response, fixed-interval 5-min schedule of food presentation. Naloxone (10.0-80.0 mg/kg i.m.) and picrotoxin (0.1-0.56 mg/kg i.m.) alone produced only dose-related decreases in responding in both fixed-ratio and fixed-interval components. Pentobarbital (3.0 and 10.0 mg/kg i.m.) administered in combination with naloxone and picrotoxin shifted dose-response curves for both naloxone and picrotoxin to the right. In contrast, both diazepam (1.0-10.0 mg/kg p.o.) and clonazepam (0.3-3.0 mg/kg p.o.) attenuated the rate-decreasing effects of 0.56 mg/kg of picrotoxin, but not those of 80.0 mg/kg of naloxone. Dose-effect curves for naloxone and picrotoxin were then determined during daily administration of 10.0 mg/kg of diazepam. Dose-response curves for both naloxone and picrotoxin were shifted to the right under these conditions. These data support previous evidence that naloxone exerts gamma-aminobutyric acid-antagonistic effects in addition to its potent opioid-antagonistic effects.
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Opioid antagonists and drinking: evidence of kappa-receptor involvement.
Diprenorphine, naloxone, MR-2266-BS and WIN-44,441-3 were compared for their ability to antagonize morphine analgesia and to decrease deprivation-induced drinking in rats. Diprenorphine and naloxone were markedly more potent (32x) than MR-2266-BS and WIN-44,441-3 in antagonizing the analgesic effects of morphine. In contrast, diprenorphine, naloxone and MR-2266-BS decreased deprivation-induced drinking over a similar dose range. The doses required to reduce fluid consumption were higher than those necessary to antagonize morphine. WIN-44,441-3 was ineffective in decreasing drinking. The relatively similar potencies of diprenorphine, naloxone and MR-2266-BS for decreasing deprivation-induced drinking suggest that the effect on drinking involves antagonist activity at a kappa-opioid receptor.
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Evidence that nalorphine, butorphanol and oxilorphan are partial agonists at a kappa-opioid receptor.
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.
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Interactions of clozapine, thioridazine, and mezilamine with oxotremorine on schedule-controlled responding.
The effects of clozapine (0.64-10 mg/kg IM), thioridazine (5-80 mg/kg IM), and mezilamine (0.1-10 mg/kg IM) were determined alone and the presence of 0.05 mg/kg oxotremorine on multiple fixed-ratio, fixed-interval responding in pigeons. All three drugs alone produced a dose-related decrease in responding. Thioridazine and mezilamine produced greater decreases in fixed-interval responding than fixed-ratio responding. Oxotremorine alone decreased responding to 10% of control. Clozapine and thioridazine produced a dose-related antagonism of the behavior-suppressing effects of oxotremorine with 5 mg/kg clozapine completely reversing the behavior-suppressing effects of oxotremorine. In contrast, mezilamine produced no antagonism of the behavior-suppressing effects of oxotremorine. It was concluded that the effects of clozapine on schedule-controlled responding in the pigeon are due to its anticholinergic effects, rather than to its antipsychotic-like effects. Thioridazine also has prominent anticholinergic effects, whereas mezilamine does not have anticholinergic effects.
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Effects of mu- and kappa-opioid receptor agonists on urinary output in mice.
The effects of ethylketazocine, morphine, bremazocine and naloxone were determined on urinary output and weight loss in Cox mice. Morphine and fentanyl were also studied in Harlan mice. Bremazocine, ethylketazocine and morphine markedly increased urinary output and weight loss within 5 hr after injection. Naloxone antagonized the diuretic actions of morphine (5 mg/kg) and bremazocine (0.06 mg/kg) over a similar dose range (0.3--10 mg/kg). By comparison with the other agonists, fentanyl had little effect on urinary output or weight loss. These results suggest that kappa agonist activity increases urinary output in mice just as reported for rats. The data also suggest that in mice morphine has some kappa agonist activity, whereas fentanyl does not.
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Attenuation of the behavioral effects of meperidine and normeperidine by daily administration of diazepam.
The effects of meperidine, normeperidine, morphine, pentobarbital and d-methadone were determined on the key-pecking behavior of pigeons responding under a multiple fixed-ratio (FR), fixed-interval (FI) schedule of grain presentation. Dose-effect curves were obtained for each drug alone and during daily administration of 10 mg/kg of diazepam. The daily administration of diazepam had little effect on the behavior itself. Meperidine and normeperidine caused dose-related decreases in both FI and FR responding. The dose-effect curves for these drugs during daily administration of diazepam were shifted to the right compared to the dose-effect curves determined in the absence of daily diazepam. In contrast, the effects of morphine, d-methadone and pentobarbital either were not affected by daily administration of diazepam or were shifted to the left by daily administration of diazepam. These data further support the hypothesis that the behavioral effects of meperidine and normeperidine are due to a proconvulsive action produced by these drugs. In contrast, the effects of morphine, d-methadone and pentobarbital are not due to such a proconvulsive action.
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Opioid agonist and antagonist behavioural effects of buprenorphine.
1 The agonist and antagonist effects of a range of buprenorphine doses (0.08-20 mg/kg) were studied on the responding of pigeons under a multiple fixed-ratio, fixed-interval schedule of grain presentation. Various doses (0.02-10 mg/kg) of buprenorphine were also tested in pigeons trained to discriminate between injections of 0.05 mg/kg of fentanyl and injections of distilled water. 2 Buprenorphine, over a broad dose range (0.08-5 mg/kg), increased the rates of responding in the fixed-interval component of the multiple schedule and disrupted patterning of responding within the fixed-interval, without affecting fixed-ratio responding even at a dose of 40 mg/kg. The effects of some of the high doses on fixed-interval responding were still evident one and two days after buprenorphine injection. 3 Doses of buprenorphine which produced increases in fixed-interval responding were also effective as antagonists of the behavioural depression produced by 40 mg/kg of morphine, and were discriminated as fentanyl-like by pigeons trained to discriminate between injections of fentanyl and injections of water. 4 These results show that buprenorphine produces marked agonist and antagonist effects over an extremely broad dose range without producing behavioural depressant effects.
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Further study of kappa opioids on increased urination.
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.
3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
A kappa opioid effect: increased urination in the rat.
The effects of various opioids (mu agonists, kappa agonists and mixed agonists/antagonists) were determined on urination in the normally dehydrated rat. Opioids considered as kappa agonists (bremazocine, ethylketazocine and ketazocine) produced a marked dose-related increase in urination. The mixed agonists/antagonists (cyclazocine, butorphanol and nalorphine) produced less urination than the kappa agonists, but more than the mu agonists (morphine and l-methadone). The mu agonists did not increase urine output compared with controls. The increased urination effect was blocked by opioid antagonists in a potency order which indicated that the effect was due to an action at a kappa opioid receptor. The data suggest the hypothesis that dynorphin, a kappa agonist, acts as an endogenous ligand for an autoreceptor which inhibits the corelease of dynorphin and antidiuretic hormone from the neurohypophysis. This decrease in antidiuretic hormone levels produces the increased urination. Increased urination is a simple in vivo test for studying the actions of compounds at kappa opioid receptors.
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Effects of picenadol and its agonist and antagonist isomers on schedule-controlled behavior.
The effects of picenadol and its (+)- and (-)-isomers were determined on the responding of pigeons under a multiple fixed-ratio (FR) 50-response, fixed-interval (FI) 5-min schedule of grain presentation. Picenadol decreased responding in both schedule components as a function of dose (0.64-10 mg/kg). Naloxone shifted to the right the picenadol dose-effect curve in the FR component (2.8-fold), but had little effect on the dose-effect curve for FI responding. Similarly, the (+)-isomer decreased responding in both schedule components, but naloxone was only able to shift to the right the dose-effect curve for the (+)-isomer on FR responding (2-fold). The effects of the (+)-isomer on FI responding were not affected by naloxone. The (-)-isomer decreased responding at high doses (20 and 40 mg/kg) and this effect was not antagonized by naloxone. The dose-effect curves for the (-)-isomer were shifted markedly to the left in animals maintained on daily doses (30 or 60 mg/kg p.o.) of methadone. Low doses (2.5-20 mg/kg) of the (-)-isomer antagonized the behavioral suppressant effects of 5 mg/kg of l-methadone. The (+)-isomer, but not the (-)-isomer, antagonized the complete behavioral suppression produced by 0.05 mg/kg of oxotremorine.(ABSTRACT TRUNCATED AT 250 WORDS)
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Modification of behavioral effects of morphine, meperidine and normeperidine by naloxone and by morphine tolerance.
Lever-press responding of morphine-tolerant and nontolerant squirrel monkeys was maintained under a multiple fixed-interval 5-min, fixed-interval 5-min schedule of food or electric shock presentation. Under the multiple schedule, the first response after a 5-min interval produced either food or shock depending on the prevailing stimulus. Responding maintained by either food or shock was characterized by patterns of positively accelerated responding during the 5-min interval. Morphine (0.1-1.0 mg/kg), meperidine (0.3-10.0 mg/kg) and normeperidine (1.0-17.0 mg/kg) produced dose-related decreases in rates of responding and produced small changes in the temporal pattern of responding in monkeys not tolerant to morphine. Food- and shock-maintained responding generally were affected similarly. Naloxone (0.1-3.0 mg/kg) had no effect when given alone to nontolerant monkeys. Both morphine tolerance and naloxone administration reversed the rate-decreasing effects of morphine and shifted the morphine dose-effect function to the right. Naloxone administration and morphine tolerance also reversed the rate-decreasing effects of meperidine and normeperidine, but unlike with morphine, combinations of naloxone and meperidine or normeperidine disrupted temporal patterns of responding and, at the higher doses, increased rates of responding well above control values. Drug effects in morphine-tolerant or naloxone-treated monkeys were not dependent on the event maintaining responding as comparable local rates of responding maintained by food or shock presentation were affected similarly. It was concluded that meperidine and normeperidine possess behavioral effects in common with those of morphine as well as pronounced non-morphine-like effects which are revealed by interference with the receptors upon which morphine acts.
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Novel phenylpiperidine opioid antagonists and partial agonists: effects on fluid consumption.
The effects of five opioid antagonists, a racemate partial agonist and its agonist and antagonist optical isomers were studied on deprivation-induced drinking. All compounds had a phenylpiperidine nucleus. The antagonists produced dose-related decreases in drinking, and the potencies for decreasing drinking correlated with morphine-antagonist doses. The racemic partial agonist and its agonist isomer decreased drinking at doses higher than those which produced marked analgesia. Within the class of phenylpiperidine drugs studied, some had less specificity than naloxone for the mu-receptors as compared to the delta-receptor, but the suppression of drinking was not related to changes in mu-to-delta ratios.
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Attenuation of normeperidine's suppressing effect on schedule-controlled behavior.
The purpose of the present study was to compare several central nervous system (CNS) depressant drugs in their ability to attenuate the suppressant effects of normeperidine on the responding of pigeons under a multiple fixed-ratio, fixed-interval schedule of grain presentation. The effects of pentobarbital (3 and 10 mg/kg i.m.), diazepam (1-10 mg/kg p.o.), clonazepam (0.03-3 mg/kg p.o.), aminooxyacetic acid (1-10 mg/kg i.m.), baclofen (5 and 10 mg/kg i.m.) and ethanol (0.5-2 g/kg p.o.) were determined alone and in the presence of 17.5 mg/kg (p.o.) of normeperidine, a dose which almost completely eliminates responding. Pentobarbital, diazepam and clonazepam attenuated the normeperidine-induced suppression of behavior, whereas aminooxyacetic acid, baclofen and ethanol failed to attenuate the effects of normeperidine. The results indicate that in the pigeon the non-opioid effects of normeperidine and related analogs are related to proconvulsive actions.
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Discriminative stimulus properties of naloxone.
Nonopioid-dependent pigeons were trained to discriminate IM injections of 30.0 mg/kg naloxone from water in the procedure in which 15 consecutive responses on one of two keys resulted in grain presentation. Naloxone-appropriate responding was maximal at doses of naloxone equal to and greater than the training dose. The onset of the naloxone discriminative cue was rapid (less than 5 min) and the duration of the cue was short (less than 60 min). Naltrexone (1.0-10.0 mg/kg). pentazocine (1.0-10.0 mg/kg), levallorphan (1.0-30.0 mg/kg), and nalorphine (3.0-30.0 mg/kg) produced dose-dependent increases in naloxone-appropriate responding, occasioning 100% naloxone-key selections. In contrast, cyclazocine, profadol, and diprenorphine, at doses up to those at which animals did not respond, produced only intermediate degrees of naloxone-appropriate responding. Morphine always produced selection of the water key. These results demonstrate that a pure opioid antagonist, such as naloxone, has discriminative stimulus effects in the nonopioid-dependent animals, that these stimulus effects are shared by certain other opioid antagonists, and that these effects are distinguishable from those produced by pure opioid agonists, such as morphine.
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