Potentiation of apomorphine and d-amphetamine effects by naloxone

The effects of naloxone, an opiate antagonist, on the stereotypic behavior and locomotor activity induced by apomorphine and d-amphetamine were studied. Groups of adult male Sprague-Dawley rats were first tested for stereotypy and locomotor activity after apomorphine (0.0 – 2.0 mg/kg) or d-amphetamine (0.0 – 10.0 mg/kg). Groups were subsequently tested with saline or naloxone (1.0 – 4.0 mg/kg) plus the previously used dosage of apomorphine or d-amphetamine. Naloxone alone did not produce stereotypy, but did significantly reduce locomotor activity. Naloxone potentiated apomorphine and d-amphetamine induced stereotypy. Apomorphine-induced activity was increased by naloxone, but d-amphetamine-induced activity at 2.5 mg/kg was reduced. The results are compatible with the suggestion that naloxone may potentiate both apomorphine and d-amphetamine by inhibiting an opiate receptor mechanism which normally interacts with catecholamine neuronal action.     

Interaction of MIF-I or alpha-MSH with D-amphetamine or chlorpromazine on thermoregulation and motor activity of rats maintained at different ambient temperatures

Administration of several doses of MIF-I or alpha-MSH did not modify colonic temperature or the level of motor activity of rats in ambient temperatures of 4 degree or 20 degrees C. However, the thermoregulatory but not motor effects of the interaction between MIF-I or alpha-MSH with d-amphetamine were dependent upon ambient temperature. At 4 degree C, 1.0 mg/kg of both peptides enhanced the d-amphetamine-induced hypothermia, but at 20 degrees C both peptides blocked the hyperthermic effects of d-amphetamine. The hypothermic effect of chlorpromazine (CPZ) at 4 degree C and 20 degrees C was blocked by 1.0 mg/kg MIF-I but not by 1.0 mg/kg alpha-MSH. No linear dose response relationships between various doses of MIF-I or alpha-MSH and thermal responses were found. Administration of melanin or the use of hypophysectomized rats did not alter the significant interactions observed after peripheral injections.     

Iron deficiency induces reversal of dopamine dependent circadian cycles: differential response to d-amphetamine and TRH

Rats made nutritionally iron-deficient (ID) have significantly diminished haemoglobin, serum iron and hypothermic response to d-amphetamine (15 mg/kg). The reduction of d-amphetamine induced hypothermia is comparatively greater in the dark than in the light period. Neither TRH (1 mg/kg) nor CG 3703, a peptidase resistant TRH analogue (1 mg/kg), induced hypothermia in control of ID animals. However, in combination with d-amphetamine, TRH and CG 3703 did not alter the hypothermic effect observed initially with d-amphetamine. In contrast to control animals, ID rats treated with saline or d-amphetamine (15 mg/kg) exhibited a greater degree of motor activity in the light as compared to the dark period. However, the overall activity (light plus dark) was unchanged in the ID group. The motor activity in response to TRH or CG 3703 was not changed as a result of iron-deficiency. These differential responses may be due to a more pronounced action of d-amphetamine on dopaminergic system, which is known to be changed in iron-deficiency, and of TRH and CG 3703 on the noradrenergic neurones.     

Analeptic and antianaleptic effects of naloxone and naltrexone in rabbits.

Naloxone (5 mg/kg), but not naltrexone, shortened the duration of anaesthesia in rabbits pretreated with pentobarbital. This analeptic effect was blocked by atropine, but not by methylatropine; it thus appears that a central cholinergic mechanism is involved. In contrast, smaller doses of both naloxone and naltrexone attenuated the arousal property of thyrotropin releasing hormone (TRH). Naloxone, but not naltrexone, also antagonized the analeptic property of d-amphetamine. In conscious animals naloxone potentiated, whereas naltrexone attenuated, the excitatory effects of TRH and d-amphetamine.     

Naloxone reversal of morphine elicited hyperactivity

When naloxone is administered during morphine elicited hyperactivity, hyperactivity is reversed and hypoactivity occurs in its place. The present experiment tested the hypothesis that this effect is the result of morphine induced supersensitivity to naloxone. Two groups of hamsters received equivalent pretreatment with 15 mg/kg morphine (Groups M/M and M/S) for three days while a third group received saline (Group S/S). During subsequent testing one group received a morphine injection (Group M/M) while the others received saline (Groups M/S and S/S) before being placed in running wheels for a three hour session. Two hours later half the animals in each group received an injection of 0.4 mg/kg naloxone and half received saline. Naloxone produced hypoactivity in animals running under the influence of morphine (Group M/M), but neither in those with an equivalent history of morphine pre-treatment (Group M/S), nor in saline controls (Group S/S). These results are inconsistent with the hypothesis under test, but congruent with a modified dual-action hypothesis.     

Dynorphin (1-13): analgesia, hypothermia, cross-tolerance with morphine and beta-endorphin

Intracerebroventricular administration of 20, 40 and 60 nmol of dynorphin (1-13) produced analgesia, as assessed by flinch/jump response to footshock, and hypothermia in the rat. Rats developed tolerance to both the analgesic and thermic effects of the 20 nmol dose of dynorphin. Dynorphin and beta-endorphin showed cross-tolerance with respect to their analgesic but not their thermic effects. Dynorphin and morphine also produced cross-tolerant analgesic effects. Naloxone (10 mg/kg, IP) completely blocked the barrel rolling produced by 20 nmol dynorphin but did not alter its analgesic or thermic effects.     

Hyperalgesia during naloxone-precipitated withdrawal from morphine is associated with increased on-cell activity in the rostral ventromedial medulla

Hyperresponsiveness to noxious stimulation (hyperalgesia) is observed with naloxone-precipitated morphine withdrawal in several experimental models, and may be due to changes in central nervous system neurons. Previous studies have demonstrated that certain neurons in the rostral ventromedial medulla (on-cells) discharge just prior to nocifensive withdrawal reflexes and are inhibited by morphine. Because the tail flick latency (TFL) is shorter when on-cells are active, it has been proposed that on-cells facilitate nocifensive reflexes. The present study examined the hypothesis that the hyperalgesia observed following naloxone-precipitated withdrawal from morphine is caused by increased on-cell discharge. Rats were maintained in a lightly anesthetized state with chloral hydrate. Administration of saline (1.25 cc, i.v.) or morphine sulfate (1.25 mg/kg, i.v.) was followed by naloxone (1.0 mg/kg, i.v.). On- and off-cell activity was continuously recorded and was correlated with TFL and paw withdrawal threshold (PWT). As previously reported, morphine increased off-cell activity, blocked on-cell activity, and suppressed the tail flick and paw withdrawal reflexes. When naloxone was given after morphine, TFL and PWT were reduced to values significantly below baseline (hyperalgesia). Both spontaneous and reflex-related on-cell activity increased to levels greater than the premorphine baseline. Spontaneous off-cell activity decreased abruptly to near zero when morphine was followed by naloxone. Linear regression analysis during the hyperresponsive state revealed a significant correlation between increased on-cell activity and reduced TFL, but not between decreased off-cell activity and TFL. These findings are consistent with the hypothesis that on-cells facilitate spinal nocifensive reflexes, and that the naloxone-precipitated hyperalgesia is at least in part accounted for by increased on-cell activity. A neural model of opiate dependence, tolerance, and withdrawal is proposed.     

Hyperalgesia during Naloxone-Precipitated Withdrawal from Morphine Is Associated with Increased On-Cell Activity in the Rostral Ventromedial Medulla

Hyperresponsiveness to noxious stimulation (hyperalgesia) is observed with naloxone-precipitated morphine withdrawal in several experimental models, and may be due to changes in central nervous system neurons. Previous studies have demonstrated that certain neurons in the rostral ventromedial medulla (on-cells) discharge just prior to nocifensive withdrawal reflexes and are inhibited by morphine. Because the tail flick latency (TFL) is shorter when on-cells are active, it has been proposed that on-cells facilitate nocifensive reflexes. The present study examined the hypothesis that the hyperalgesia observed following naloxone-precipitated withdrawal from morphine is caused by increased on-cell discharge.

Rats were maintained in a lightly anesthetized state with chloral hydrate. Administration of saline (1.25 cc, i.v.) or morphine sulfate (1.25 mg/kg, i.v.) was followed by naloxone (1.0 mg/kg, i.v.). On- and off-cell activity was continuously recorded and was correlated with TFL and paw withdrawal threshold (PWT). As previously reported, morphine increased off-cell activity, blocked on-cell activity, and suppressed the tail flick and paw withdrawal reflexes. When naloxone was given after morphine, TFL and PWT were reduced to values significantly below baseline (hyperalgesia). Both spontaneous and reflex-related on-cell activity increased to levels greater than the premorphine baseline. Spontaneous off-cell activity decreased abruptly to near zero when morphine was followed by naloxone. Linear regression analysis during the hyperresponsive state revealed a significant correlation between increased on-cell activity and reduced TFL, but not between decreased off-cell activity and TFL.

These findings are consistent with the hypothesis that on-cells facilitate spinal nocifensive reflexes, and that the naloxone-precipitated hyperalgesia is at least in part accounted for by increased on-cell activity. A neural model of opiate dependence, tolerance, and withdrawal is proposed.     

Higher environmental temperature-induced increase in body temperature: Involvement of serotonin in GABA mediated interaction of opioidergic system

Exposure (2 h) of adult male albino rats to higher environmental temperature (HET, 40°C) significantly increased body temperature (BT). Administration of (a) 5-HTP (5 mg/kg, i.p.) or morphine (1 mg/kg, i.p.) or physostigmine (0.2 mg/kg, i.p.) alone significantly increased and (b) methysergide (1 mg/kg, i.p.) or naloxone (1 mg/kg, i.p.) or atropine (5 mg/kg, i.p.) reduced the BT of both normal and HET exposed rats. Further, it was observed that morphine prevented the methysergide-induced hypothermia and 5-HTP potentiated the morphine-induced hyperthermia in both normal and HET exposed conditions. Biochemical study also indicates that serotonin metabolism was increased but GABA utilization was reduced following exposure to HET. 5-HTP or bicuculline-induced hyperthermia in control and HET exposed rat was potentiated with the coadministration of bicuculline and 5-HTP. The cotreatment of bicuculline with methysergide prevented the methysergide-induced attenuation of BT of heat exposed rat, rather BT was significantly enhanced indicating that inhibition of GABA system under heat exposed condition may activate the serotonergic activity. Further (a) enhancement of (i) morphine-induced hyperthermia with physostigmine (ii) physostigmine- or morphine + physostigmine-induced increase of BT with 5-HTP and (b) reduction of (i) morphine- or morphine + 5-HTP-induced hyperthermia with atropine and (ii) atropine-induced hypothermia with 5-HTP in both normal and HET exposed conditions suggest that HET exposure activates the cholinergic system through the activation of opioidergic and serotonergic system and hence increased the BT. Thus, it may be concluded that there is an involvement of serotonergic regulation in the opioidergic-cholinergic interaction via GABA system in HET-induced increase in BT.     

Effects of acute and subchronic delta 9-tetrahydrocannabinol administration on the plasma catecholamine, beta-endorphin, and corticosterone levels and splenic natural killer cell activity in rats

The effect of acute (1 day) or subchronic (25 days) treatment with delta 9-tetrahydrocannabinol (THC), the major psychoactive constituent of marihuana, on plasma norepinephrine (NE), epinephrine (E), corticosterone, beta-endorphin (beta-end), and splenic natural killer (NK) cell activity of the rat was studied. Groups of animals received subcutaneously, either THC in corn oil + saline (3 mg THC/kg); oil + saline; or THC + naloxone (2 mg naloxone/kg and 3 mg THC/kg). Acute injection of THC with or without naloxone did not significantly change plasma levels of NE, E corticosterone, beta-end, or the NK cell activity. However, subchronic treatment with THC significantly reduced plasma levels of NE, E, corticosterone, and NK cell activity, compared to controls. The plasma beta-end levels were significantly elevated in the THC-treated animals. In the THC + naloxone group of animals, the plasma hormone levels (corticosterone and beta-end) were similar to control levels and the NK cell activity was significantly higher than in THC-treated animals. These results indicate that subchronic exposure to THC results in suppression of splenic NK cell activity. The interaction of THC with the endogenous opiate system appears to be a contributing factor leading to the NK cell suppression in rats. A direct suppressive action of THC or its metabolites on the NK cell is not ruled out by this study.     

Is there an opiate receptor in the snail Megalobulimus sanctipauli? Action of morphine and naloxone

The effects of morphine sulfate (10, 15 and 20 mg/kg) or saline control (5 mg/kg) on the latency of the anterior body-lifting response to heat (avoidance response) were determined in four groups of snails Megalobulimus sanctipauli (n = 6) individually placed on a metal plate mounted on the surface of a water bath at 52 ± 1°C. The effects of pre-treatment with naloxone hydrochloride (5 mg/kg) or saline (2.5 ml/kg) control on the responses to morphine (15 mg/kg) were determined in two different groups of animals (n = 6). Administration of morphine resulted in an increase in the avoidance behavior latency with maximum effects occuring at 15 mg/kg, 10–15 min after injection. The effects of morphine disappeared within 90–120 min. Saline treatment had no detectable effects on the latency of the response to an aversive stimulus. Naloxone significantly blocked (P < 0.05, Student paired t-test) the increase in avoidance behavior latency. The present results indicate that: 1. morphine has an antinociceptive effect on the response of Megalobulimus sanctipauli to an aversive thermal stimulus; and 2. the morphine-induced “analgesia” may be caused by the stimulation of μ opiate receptors.     

Brain levels of morphine in mice following removal of a morphine pellet and naloxone challenge: no evidence for displacement

Male ICR mice were rendered tolerant to and dependent on morphine by subcutaneous implantation of a 75 mg morphine pellet for 72 hours. At 2, 4, and 6 hours after pellet removal groups of 7–10 mice were challenged with ip saline or naloxone and their brain concentrations of morphine estimated by radioimmunoassay (RIA). The brains were prepared for RIA by either organic or inorganic (0.01 N HC1) extraction and in most experiments the two methods were shown to be equivalent with respect to the final concentration of morphine. There was no difference in brain morphine between saline and naloxone (10 mg/kg) treated groups when they were challenged 4 hours after pellet removal and sacrificed 1, 5, 10, 15, 20, 30, 45, and 60 minutes later. In contrast, when the challenge was administered 6 hours after pellet removal the naloxone treated groups has higher concentrations of brain morphine than the saline controls. Brain levels in mice that received 0.10, 1.0, 10, 100 mg/kg naloxone did not differ consistently from saline controls. We found no consistent evidence that naloxone decreases the concentration of morphine in brain homogenates obtained from mice during the initial 6 hours after pellet removal.     

Naloxone-induced enhancement of carbon dioxide stimulated respiration

In unanesthetized rats, naloxone (5 mg/kg, s.c.) produced an increase in both respiratory frequency and tidal volume as compared to saline administered animals. Maximal respiratory stimulation was observed within 5 minutes after naloxone injection and duration of the response was greater than 30 minutes. Exposure to different atmospheres of carbon dioxide potentiated the increase in ventilation in a step-wise manner as the carbon dioxide concentration was increased. Pretreatment with low doses of morphine sulfate (2 mg/kg daily for 2 days) or naloxone HCl (5 mg/kg daily for 5 days) enhanced respiratory stimulation induced by naloxone. It was concluded that naloxone increases the sensitivity of central ventilatory response to carbon dioxide as a result of displacement of endogenous endorphins from central opioid receptors.     

A study of the actions of naloxone and morphine on gastric acid secretion and gastric mucosal damage in the rat

There exists a considerable controversy in the literature with regard to the effect of either opiate receptor blockade or that of morphine in different gastric and intestinal ulcer models in the rat. We performed experiments to evaluate the effects of naloxone and morphine on gastric acid secretion and gastric mucosal damage in different experimental models of gastric mucosal injury, namely in indomethacin-, HCl (0.6N)- and ethanol (96%)-models. We found that: 1) 10 mg/kg naloxone ip given twice, effectively protected gastric mucosa against indomethacin (30 mg/kg ip) and against the acid-dependent injury caused by 0.6 N HCl (1 mL ig), but not against the non acid-dependent injury caused by 96% ethanol (1 mL ig); 2) morphine (10 + 10 mg/kg ip) increased ulcers in the HCl-model, but had no effect in the two other models; 3) this ulcer-aggravating effect of morphine in the HCl-model was blocked by pretreatment of 2 mg/kg ip naloxone; and 4) both naloxone (5 + 5 and 10 + 10 mg/kg ip) significantly decreased gastric acid secretion in 1-h pylorus ligated rats. We conclude that: 1) naloxone dose-dependently protects against the indomethacin- and HCl-, but not against the ethanol-induced gastric mucosal damage; 2) morphine aggravates the HCl-induced ulcerogenesis; and 3) both opiod receptor agonist and antagonist decrease gastric acid secretion.     

Stimulation of either cholecystokinin receptor subtype reduces while antagonists potentiate or sensitize a morphine-induced excitatory response.

Cholecystokinin peptides (CCK) have been shown to antagonize many opioid-mediated effects. The present study was undertaken to determine whether peripheral injections of cholecystokinin sulphated octapeptide (CCK8), cholecystokinin tetrapeptide (CCK4), the CCK(1) (lorglumide) and the CCK(2) (PD-135,158 and LY-225910) receptor antagonists can influence a classic morphine excitatory effect, i.e. the display of Straub tail reaction in mice (STR). A total of 570 female Balb/C mice were tested. Experiment 1 was undertaken to determine whether i.p. injections of CCK8 or CCK4 can influence STR. Each animal was treated with i.p. injections of saline or CCK8 (10 and 20 nmol/kg) or CCK4 (20 and 40 nmol/kg). After 30 min all animals received an i.p. injection of morphine hydrochloride (10.0 mg/kg). The highest doses of both CCK8 (35% STR) and CCK4 (40% STR) significantly reduced STR as compared to saline (85% STR) treated mice (Fisher test; P < 0.01). In experiment 2 each animal was treated with ip injections of saline or 1.0 mg/kg lorglumide or PD-135,158 fifteen minutes before an injection of morphine at doses ranging from 1.0 to 50.0 mg/kg. In experiment 3 animals were treated with injections of saline, 0.1 or 10.0 mg/kg lorglumide or LY-225910 before an injection of a fixed MC dose (2.0 mg/kg). Both lorglumide and PD-135,158 induced a significant shift to the left in the morphine dose-response curves as well as a significant decrease in ED50 of the STR. ED50 for lorglumide was significantly lower than ED50 for PD-135,158. Both doses of lorglumide and the highest dose of LY-225910 significantly increased the percent of animals displaying STR. Experiment 4 was undertaken to determine whether repeated peripheral injections of morphine or the morphine-potentiating agents CCK(1) (lorglumide) and the CCK(2) (LY-225910) receptor antagonists can induce morphine sensitization. Each animal was treated with 5 daily i.p. injections of saline (control group), 1.5 mg/Kg morphine hydrochloride (group morphine), and 1.0 mg/Kg lorglumide (group LOR) or LY-225910 (group LY). One, two, three and four weeks after the last treatment day, all animals were challenged with one i.p. injection of morphine (1.5 mg/Kg). The morphine, LOR groups and group LY showed a significant increase in percentage of animals displaying STR. These data demonstrate that the blockade of endogenous CCK actions leads to morphine sensitization probably through both CCK receptors. The present data are consistent with the antagonistic effects of CCK and opioids in the control of morphine-induced STR. In addition, these results suggest that both CCK receptors are involved in the modulatory effects of CCK on this morphine effect.     

The effects of verapamil and ethanol on body temperature and motor coordination

Male, adult mice of the Binghamton heterogeneous stock received one of two doses of ethanol (1.0 g/kg or 2.0 g/kg in saline) alone or in combination with the calcium (Ca2+) slow channel blocker, verapamil (5.45 mg/kg in 25% v/v ethanol in saline). Hypothermic responses and motor incoordination were assessed in terms of rectal temperatures and rotorod activity both 20 and 60 min after drug administration. Verapamil alone did not affect body temperature, but it potentiated ethanol-induced hypothermia at both post-administration test times. Both verapamil and ethanol impaired muscular coordination and these effects were additive at the two observation periods. Verapamil did not affect ethanol blood levels from 10 to 80 min after administration of the drugs. Since motor impairment was observed when verapamil was administered with only its ethanol vehicle, this suggests a powerful interactive effect between the two drugs.     

Immobilization of gray wolves (Canis lupus) with sufentanil citrate

Gray wolves (Canis lupus) were immobilized with 0.5 mg/kg xylazine plus 7.5 micrograms/kg of either sufentanil (n = 8), etorphine (n = 8), or carfentanil (n = 2). Drug doses used in this study were selected to provide consistency for comparison and are not recommended doses for effective immobilization of wolves. Induction times were similar among groups (11.9 +/- 1.0 min). Thirty min after induction, wolves were given either 0.5 mg/kg naloxone hydrochloride plus 0.15 mg/kg yohimbine hydrochloride or saline only intravenously. Arousal times for wolves given naloxone and yohimbine (1.2 +/- 0.1 min) were shorter than wolves given saline (35.5 +/- 6.4 min). Respiratory rates were similar among the three drug groups (6.9 +/- 1.0 breaths/min). One animal given sufentanil then saline was found dead 108 min after induction. Presumptive diagnosis was renarcotization and hypothermia. Results indicated that sufentanil is an effective opioid immobilizing agent for gray wolves.     

The effects of naloxone on the changes in breathing and behaviour induced by morphine in the foetal sheep

In the foetal sheep, administration of morphine induces apnoea followed by hyperpnoea; during hyperpnoea the foetus arouses. We tested the hypothesis that naloxone, an opiate antagonist, would block these responses. In 14 foetal sheep between 123 and 140 days of gestation, we measured electrocortical activity (ECoG), eye movements (EOG), diaphragmatic activity (EMGdi), blood pressure and amniotic pressure. Morphine (1 mg/kg) was injected in the foetal jugular vein during low-voltage ECoG. Saline or naloxone (0.1, 0.5 and 2.0 mg) were given, in randomized order, before the morphine injection, shortly after morphine injection during apnoea, and during maximum hyperpnoea. Saline alone had no effect on breathing or behaviour. When saline and naloxone preceded the morphine injection the length of apnoea was 26.6 +/- 7.7 and 19.5 +/- 7.0 min (SEM, P = 0.25) while the length of sustained hyperpnoea was 104.8 +/- 11.4 and 29.6 +/- 8.4 min respectively (P = 0.001). When administered during the maximum breathing response, naloxone decreased the length of breathing from 92.2 +/- 8.4 (saline) to 8.8 +/- 2.9 min (P = 0.001). Respiratory output (fEMGdi x f) also decreased from 6545 +/- 912 arbitrary units post saline to 3841 +/- 629 arbitrary units after naloxone (P = 0.05). Arousal disappeared with the decrease in breathing response. The negligible effect of naloxone on apnoea and its strong inhibition of hyperpnoea suggest that morphine may act on two distinct central regions or on two subtypes of opioid receptors to produce apnoea, hyperpnoea and arousal.     

Effect of the opiate antagonist naloxone on the electrical activity of identified neurons in the edible snail

The opiate antagonist naloxone modifies the electric activity of some identified neurons of the Helix lucorum which have not been preliminary exposed to the effect of exogenous opioids. Some neurons are excited while others are inhibited by naloxone, and in both cases the reaction may have both a short and long latent period. The reactions depend on naloxone dose and become less expressed or are blocked when naloxone is administered together with the agonists of opiate receptor (morphine, D-Ala2, D-Leu5-enkephalin, bremazocine and beta-endorphin). Opioids alone do not produce any effect on neurons. The effect of naloxone on neurons is assumed to be a result of the elimination by the opiate antagonist of the tonic effect of endogenous opioids by their replacing on opiate receptors which are constantly stimulated by endogenous ligands.     

Discriminative stimulus,antagonist, and rate-decreasing effects of cyclorphan: Multiple modes of action

The discriminative effects of cyclorphan were studied in pigeons trained to discriminate 0.32 mg/kg ethylketazocine, 1.8 mg/kg cyclazocine, or 32 mg/kg naltrexone from saline. A fourth group of pigeons was administered 100 mg/kg/day morphine and trained to discriminate 0.1 mg/kg naltrexone from saline. Cyclorphan produced dose-related ethylketazocine-appropriate responding that reached a maximum of 83% of the total session responses at 0.3 mg/kg. Higher cyclorphan doses produced less ethylketazocine-appropriate responding. In pigeons trained to discriminate cyclazocine from saline, maximum drug-appropriate responding of greater than 90% occured at 5.6–10.0 mg/kg cyclorphan. In narcotic-naive pigeons trained to discriminate 32 mg/kg naltrexone from saline, cyclorphan produced a maximum of less than 50% drug-appropriate responding. In contrast, in pigeons chronically administered morphine and trained to discriminate 0.1 mg/kg naltrexone from saline, 1.0 mg/kg cyclorphan resulted in 100% drug-appropriate responding. In pigeons responding under a multiple fixed-interval, fixed-ratio schedule of food delivery, cyclorphan produced a complete dose-related reversal of the rate-decreasing effects of 10 mg/kg morphine, the maximally effective antagonist doses being 1.0–3.2 mg/kg. Higher cyclorphan doses (10 mg/kg) resulted in response rate decreases that were not reversed by naloxone (1 mg/kg). Thus, cyclorphan has discriminative effects that are similar to those of both ethylketazocine and, at 20-fold higher doses, cyclazocine. In addition, in morphine-treated pigeons, cyclorphan, across the same range of doses that produce ethylketazocine-appropriate responding, has discriminative effects that are similar to those of naltrexone, an effect that is probably related to the antagonist action of the drug.