Rate-decreasing Effects Of Morphine Research Articles

EFFECTS OF AMPHETAMINE-CNS DEPRESSANT COMBINATIONS AND OF OTHER CNS STIMULANTS IN FOUR-CHOICE DRUG DISCRIMINATIONS

Three pigeons were trained to discriminate among 5 mg/kg pentobarbital, 2 mg/kg amphetamine, a combination of these two drugs at these doses, and saline using a four-choice procedure (amphetamine-pentobarbital group). Three other pigeons were trained to discriminate among 5 mg/kg morphine, 2 mg/kg methamphetamine, a combination of these two drugs at these doses, and saline (methamphetamine-morphine group). After 10 to 13 months of training, the pigeons averaged more than 90% of their responses on the appropriate key during training sessions. In subsequent testing, dose-response curves were determined for the individual drugs, for a wide range of dose combinations of the training drugs, and for two drugs to which the pigeons had not been exposed previously (pseudoephedrine and nicotine). After low test doses of the training drugs, pigeons responded on the saline key. As the dose increased, responding on the key associated with that drug during training sessions increased. When training drugs were combined at doses that were not discriminable when given alone, responding occurred on the saline key. When a discriminable dose of one training drug was combined with a nondiscriminable dose of the other training drug, responding occurred on the key associated with the discriminable dose. When both drugs were given at discriminable doses, responding almost always occurred on the drug-combination key. The response-rate decreasing effects of pentobarbital and amphetamine were mutually antagonized when the drugs were combined, but the rate-decreasing effects of morphine and methamphetamine were not. After low doses of pseudoephedrine and nicotine, pigeons in both groups responded on the saline key. After higher doses of pseudoephedrine and nicotine, responding in the amphetamine-pentobarbital group occurred primarily on the amphetamine key. In the methamphetamine-morphine group, higher doses of pseudoephedrine and especially nicotine engendered more responding on the combination key than had occurred in the other group. The four-choice procedure can reveal subtle effects in the discrimination of individual drugs and drug combinations that are not apparent with procedures offering fewer response alternatives.

Naltrexone and beta-funaltrexamine antagonism of the antinociceptive and response rate-decreasing effects of morphine, dezocine, and d-propoxyphene.

Patterns of competitive and insurmountable antagonism provide important data to guide the classification and characterization of different types of opioid agonists as well as infer the mechanism of action for agonists. Experiments with the competitive antagonist, naltrexone, and the insurmountable antagonist, beta-funaltrexamine (beta-FNA), were conducted to determine whether the antinociceptive and rate-decreasing effects of the opioid agonists dezocine and d-propoxyphene are 1) mediated through muu opioid receptors in rats, and 2) differ from morphine with respect to relative efficacy. The rat tail-withdrawal assay was used to measure antinociception and a fixed ratio 20 (FR20) schedule of food delivery was used to measure rate suppression. Naltrexone (0.01-1.0 mg/kg) was approximately equipotent as an antagonist of the antinociceptive and rate-decreasing effects of both morphine and dezocine and as an antagonist of the antinociceptive effects of d-propoxyphene. Naltrexone failed to block the rate-decreasing effects of d-propoxyphene. beta-FNA (5 and 10 mg/kg) also antagonized the antinociceptive and rate-decreasing effects of morphine and dezocine as well as the antinociceptive effects of d-propoxyphene. beta-FNA failed to produce a dose-dependent antagonism of the rate-decreasing effects of d-propoxyphene. These data suggest that the antinociceptive effects of morphine, dezocine, and d-propoxyphene and the rate-decreasing effects of morphine and dezocine are mediated through mu opioid receptors. Overall, high doses of beta-FNA produced a greater degree of antagonism of the behavioral effects of dezocine than morphine or d-propoxyphene, confirming other reports that dezocine is a lower efficacy agonist than morphine. Additionally, the degree of antagonism produced by beta-FNA was greater for the antinociceptive effects of all three compounds than for the rate-decreasing effects.

In vivo apparent pA2 analysis in rats treated with either clocinnamox or morphine

Experiments tested the hypothesis that loss of agonist potency or effectiveness following irreversible antagonist or chronic agonist treatment may result from affinity changes at mu opioid receptors. Apparent affinity of naltrexone or nalbuphine for mu opioid receptors was measured in vivo in rats treated with either a single dose of the irreversible antagonist clocinnamox or repeated doses of morphine. Apparent affinity of each antagonist was estimated from its potency as an antagonist of discriminative stimulus or rate-decreasing effects of morphine in rats trained to discriminate 3.2 mg/kg morphine and saline. In control rats, apparent pA2 values for naltrexone and nalbuphine were 7.5-7.6 and 5.3, respectively. In clocinnamox-treated rats, apparent pA2 values for naltrexone were 7.2-7.7, suggesting that clocinnamox treatment did not alter affinity of naltrexone for sites through which morphine exerts behavioral effects. In rats treated repeatedly with morphine, apparent pA2 values for nalbuphine were 5.1-5.3, suggesting that repeated morphine treatment did not alter affinity of nalbuphine for these sites. The observation that neither clocinnamox nor repeated morphine treatment altered in vivo affinity estimates for naltrexone or nalbuphine, respectively, suggests that the reductions in agonist potency produced by these treatments do not result from changes in affinity at mu opioid receptors.

Nor-binaltorphimine

This study assessed the ability of naltrexone and nor-binaltorphimine (NBNI) to antagonize the rate-decreasing effects of opioid agonists. Food-restricted pigeons were trained to peck a lit key under a fixed-ratio (FR) 20 schedule of food reinforcement. Bremazocine, a kappa-opioid agonist, decreased food-reinforced responding (ED(50) = 0.02mg/kg), and naltrexone (5.6mg/kg) reduced the potency of bremazocine six-fold. The effect of naltrexone lasted less than 24h. A single injection of NBNI (1mg/kg) was given to four pigeons, and the time course of antagonism of the rate-decreasing effects of bremazocine was measured. One hour after NBNI was given, it was ineffective. Eight days later, NBNI produced a five-fold reduction in the potency of bremazocine. Between 12 and 20 days after NBNI, it reduced the potency of bremazocine 14-fold. NBNI continued to antagonize bremazocine for 11 weeks. Smaller doses of NBNI (0.001-0.1mg/kg) were ineffective. The effect of NBNI was not due to tolerance to bremazocine, since tolerance failed to develop to bremazocine administered repeatedly. NBNI (1mg/kg) did not antagonize the response rate-decreasing effects of morphine, a mu-opioid agonist, or BW373U86, a delta-opioid agonist. NBNI was an effective and extremely long-lasting kappa-opioid antagonist in the pigeon. The duration of action of NBNI is among the longest yet described in any species.

Pharmacological analysis of the rate-decreasing effects of mu and kappa opioids in pigeons.

The present study investigated the rate-decreasing effects of several mu (morphine and l-methadone) and kappa (bremazocine, U69,593 and U50,488) opioid agonists in pigeons. Mu and kappa agonists were examined alone, in combination with naltrexone or the mu-selective opioid antagonist, beta-funaltrexamine (beta-FNA), and in pigeons treated chronically with U50,488. Naltrexone was equipotent in shifting the morphine, l-methadone and bremazocine dose-effect curves to the right, but was less potent in shifting the U69,593 dose-effect curve and did not shift the U50,488 dose-effect curve. Beta-FNA shifted the l-methadone dose-effect curve to the right but did not shift the bremazocine, U69,593 or U50,488 dose-effect curves. Pigeons that developed tolerance to U50,488 following daily administration were cross-tolerant to bremazocine but not to l-methadone. Taken together, these experiments indicate that the rate-decreasing effects of morphine and l-methadone are mediated by mu opioid receptors, whereas the rate-decreasing effects of bremazocine, U69,593 and U50,488 in pigeons differ depending on the pharmacological procedures used to assess their effects.

Tolerance to the analgesic, but not discriminative stimulus effects of morphine after brief social defeat in rats

One of the most prominent consequences of defeat in a social confrontation is a long-lasting tolerance-like insensitivity to the analgesic effects of opiates, even when only small short-lived changes in nociception are detectable during the acute social stress. The present experiments examined (1) which kinds of social experiences lead to morphine tolerance, (2) whether or not the morphine tolerance in defeat-experienced rats extends from the analgesic effects to the discriminative stimulus and rate-decreasing effects of morphine, and (3) how long morphine tolerance lasts after a defeat experience. After five brief social confrontations including attack and threat by a resident rat leading to submission or defeat of the intruder, the latter exhibits marked tolerance to the analgesic effects of morphine, but not to the discriminative stimulus or behaviorally suppressive effects. Changes in social housing did not alter morphine's behavioral effects. Tolerance to the analgesic morphine effects was detected for 2 months after the defeat experience, whereas the discriminative stimulus and rate-decreasing effects were closely similar to those before defeat. This pattern was seen in animals for whom discriminative stimulus training with morphine was suspended after defeat as well as in those for whom it continued. In additional defeated and non-defeated animals, morphine's effects on the acoustic startle reflex was assessed. In contrast to the tail flick reflex to a noxious heat stimulus, the acoustic startle response remained unaffected by defeat experience or by morphine (up to 30 mg/kg). The long-lasting and large degree of tolerance after brief social defeat experiences appears to be limited to the analgesic effects of morphine.(ABSTRACT TRUNCATED AT 250 WORDS)

Magnitude of initial effect influences development of tolerance to morphine in rats responding under a fixed-ratio schedule of food presentation

This experiment examined whether development of tolerance to the rate-decreasing effects of morphine can be modulated by the magnitude of the initial effect of morphine. Lever pressing by rats was maintained under a fixed-ratio 30 schedule of food delivery in daily 30 min sessions. Subjects were assigned to two groups, which did not differ in initial sensitivity to morphine, and given daily injections of morphine under dosing schedules chosen to have different initial effects. Group 1 received daily pre-session injections of 10 mg/kg morphine, which initially suppressed lever pressing completely, and post-session injections of saline. Group 2 received morphine in two injections, one pre-session and one post-session. The initial daily doses 10 mg/kg pre- and 9 mg/kg post-session) decreased rates by 30% or less. The proportion of the 10 mg/kg dose administered pre-session was increased gradually over 10 weeks. Group 2 developed greater tolerance than did group 1, as assessed by changes in the dose of morphine required to suppress response rates by > 50%. After 3 months of repeated treatment, the ED(50) of morphine increased 2.5-fold in group 2, but only 1.4-fold in group 1. When the daily dose of morphine was raised to 20 mg/kg (10 mg/kg pre- and 10 mg/kg 14 h post-session) for all subjects, the ED(50) of morphine increased 6.7-fold in group 2, but only 2.6-fold in group 1. During repeated treatment, the groups did not differ in the dose of maloxene required to suppress response rates or elicit weight loss. Following termination of morphine treatment, the ED(50) of morphine returned to original values in group 2, but was 1.8-fold lower than initial values in group 1. Thus, a pronounced [??103] decreasing effect of morphine retarded development of tolerance, perhaps by a conditioning process.

Evaluation of the effects of opioid agonists and antagonists under a fixed-consecutive-number schedule in rats

The effects of several opioid agonists and the opioid antagonist naloxone were examined in rats responding under a fixed-consecutive-number (FCN) schedule. Under this schedule, a reinforced response run consisted of responding eight or more times on one response lever, and then responding once on a second response lever. In one component of this schedule, an external discriminative stimulus signalled the completion of the response requirement on the first lever, whereas no stimulus change was programmed in the other. Morphine, 1-methadone, U50488, ketocyclazocine, phencyclidine, and (±)N-allylnormetazocine decreased the percent of reinforced response runs (accuracy) under the FCN schedule without the external discriminative stimulus, but had no effect under the FCN schedule with the external discriminative stimulus. Naloxone and bremazocine, in contrast, had no effect on the accuracy of the discrimination under either FCN schedule. With the exception of bremazocine and U50488, which increased rates of responding at low doses, all drugs produced comparable decreases in rates of responding under both FCN schedules. During tests of antagonism, a 0.1 mg/kg dose of naloxone reversed completely the accuracy-decreasing effects produced by U50488 and morphine. The rate-decreasing effects of morphine and U50488 were reversed completely by a 0.01 and 1.0 mg/kg dose of naloxone, respectively. These results suggest that the addition of an external discriminative stimulus can modulate the disruptive effects the opioids, and that mu, sigma and some kappa agonists produce similar effects when evaluated under the FCN schedules.

Potentiation of disruptive effects of dextromethorphan by naloxone on fixed-interval performance in rats

A centrally acting antitussive agent dextromethorphan (DM) was tested to determine its possible interaction with naloxone in rats responding under a fixed-interval schedule of positive reinforcement. A sugar sweetened milk reward was used as a positive reinforcer. Under the same experimental conditions the effects of morphine alone and in combination with naloxone were also determined. Low dose DM (10 mg/kg) produced a slight increase, while higher doses (20-40 mg/kg) produced dose-dependent decreases in response rate. Morphine (0.3, 1.0 and 3.0 mg/kg) produced dose-dependent decreases in response rate. When doses of naloxone (0.1-1.0 mg/kg) were administered after the injection of DM the rate-decreasing effects of DM were potentiated even after the rate-increasing dose of naloxone (0.1 mg/kg) was used. When a dose of naloxone (0.1 mg/kg) was administered after the injection of morphine the rate-decreasing effects of morphine were markedly antagonized, i.e., the morphine dose-response curve was shifted to the right. The observed potentiation of DM disruption by naloxone on fixed-interval performance in rats is consistent with findings showing that naloxone potentiates the disruptive behavioral effects of a number of drugs that are psychotomimetic in man.

Effects of LY150720 (picenadol), a novel mixed-action opioid, on schedule-controlled responding in the squirrel monkey

The opioid LY150720 is a racemic mixture whose resolution results in a highly stereospecific separation of agonist and antagonist activity. The effects of LY150720 (0.3-3.0 mg/kg), its agonist (dextro) isomer LY136596 (0.3-1.7 mg/kg) and morphine (0.03-1.0 mg/kg) were studied alone and in combination with naloxone (0.001-1.0 mg/kg) in squirrel monkeys whose responding was maintained under a multiple fixed-ratio 30-response fixed-interval 5-minute (mult FR-30 FI 5-min) schedule of food presentation. LY150720, LY136596 and morphine generally decreased responding under both schedule components, although in several instances increases in responding under the FI component were noted, particularly following LY150720 and LY136596. Naloxone (0.1-3.0 mg/kg) generally had little effect on responding, whereas the antagonist (levo) isomer LY136595 (0.3-10.0 mg/kg) decreased responding under both schedule components. The rate-decreasing effects of morphine, LY150720 and LY136596 were reversed by naloxone; doses of naloxone required to reverse the effects of all three drugs were comparable. When combined with morphine, naloxone restored rates and patterns of responding to control values, whereas combinations of LY150720 or LY136596 and naloxone increased responding under the FI component in excess of control values. These increases appear to be due to anticholinergic actions of LY150720 and LY136596, as they are reversed by physostigmine (0.01 mg/kg) and similar increases are produced by scopolamine (0.01-0.1 mg/kg).

Narcotic discrimination in pigeons: Antagonism by naltrexone

In pigeons trained to discriminate between morphine (10 mg/kg) and saline, both morphine and ethylketazocine produced dose-related morphine-appropriate responding. The maximum effect produced by meperidine, however, was only 60% of that produced by morphine or ethylketazocine. Naltrexone (0.1–1.0 mg/kg) produced dose-related shifts to the right in the dose-response curves for the discriminative stimulus and rate-decreasing effects of morphine and ethylketazocine without affecting the response produced by meperidine. Thus, in contrast to the effects observed in other species, morphine and ethylketazocine produce similar discriminative effects in the pigeon. In addition, the morphine-like discriminative effects and the rate-decreasing effects of meperidine in the pigeon are not mediated by the naltrexone-sensitive mechanisms which mediate these effects of morphine or ethylketazocine.

Prior behavioral experience can reverse the effects of morphine

Morphine administration typically decreases responding of squirrel monkeys trained to avoid electric shock. However, the rate-decreasing effects of morphine on avoidance responding were reversed after either concurrent or prior exposure to a condition in which responding was maintained by shock presentation. These findings demonstrate that behavioral experience can play a significant role in determining the behavioral effects of drugs and that specific types of environmental conditions can completely reverse the usual effects those drugs have on behavior.

Behavioral effects of morphine and naloxone following chronic morphine administration.

The effects of morphine, naloxone, and combinations of these drugs were examined in squirrel monkeys under shock-postponement schedules. In the absence of a lever press, shocks could be presented every 4s. and each response postponed shock for 20s. Acutely, morphine (0.10-3.00 mg/kg) produced not only overall response-rate decreases, but also increases in the number of shocks, whereas naloxone (0.10-30.00 mg/kg) had little effect on responding. When given in combination with morphine, several doses of naloxone antagonized the rate-reducing and shock-increasing effects of morphine. Daily administration of morphine resulted in a substantial decrease in the number of shocks received and a moderate attenuation of the rate-decreasing effects of morphine (tolerance). Lower doses substituted for the fixed daily dose resulted in a smaller effect on behavior than under acute administration. Naloxone given in combination with the daily morphine dose or substitute for the daily morphine dose or substituted for the daily administration or morphine, produced effects similar to those seen prior to chronic drugging. Thus, behavioural effects of naloxone were not altered even though tolerance to morphine was observed. Larger doses of naloxone continued to antagonize the effects of morphine for at least 24 h. No signs of physical dependence were noted when naloxone was administered or when administration of morphine ended.

Interactions between narcotic agonists, partial agonists andd antagonists evaluated by punished an unpunished behavior in the rat.

The effects of morphine, ketocyclazocine, cyclazocine, and SKF-10,047 were tested alone and in conjunction with naltrexone or naloxone, in rats responding under a multiple fixed-interval 3-min schedule of food presentation. Under this paradigm, electric shock was delivered on a fixed-ratio schedule for responses occurring during alternate schedule components. All of the drugs (except naltrexone and naloxone) decreased average rates of responding maintained by the unpunished component in a dose-dependent manner. The rate-decreasing effects of morphine and ketocyclazocine were antagonized by naltrexone. The rate-decreasing effects of cyclazocine were only slightly reversed by the antagonists, while those effects of SKF-10,047 were not affected by naltrexone. In some animals, certain doses of SKF-10,047 increased unpunished responding. This rate-increasing effect was antagonized by naltrexone. Morphine, ketocyclazocine, cyclazocine, and SKF-10,047 increased responding that was suppressed by electric shock, and these increases were antagonized by naltrexone and naloxone. Thus, the antagonism of opiate effects by narcotic antagonists depends in part on the behavior being evaluated.

Effects of tetrabenazine and phenylpiperidine analgesics during daily clorgyline treatment

Pigeons responded under a multiple fixed-ratio 30-response, fixed-interval 5-min schedule of food presentation. Daily administration of clorgyline (10 mg/kg, IM) tended to decrease rates of responding in both schedule components. Before daily clorgyline, tetrabenazine had no effect or decreased responding in the FI component at doses that markedly increased responding during chronic clorgyline. The clorgyline treatment resulted in a slight increase in sensitivity to the rate-decreasing effects of morphine, but no increased sensitivity to the rate-decreasing effects of meperidine, anileridine, alphaprodine, or fentanyl.

Behavioral influences on tolerance to the effects of morphine on schedule-controlled behavior.

Responding of pigeons was maintained under a multiple fixed interval, fixed ratio schedule of food delivery, and 10 mg/kg morphine was administered daily. Responding during both schedule components was initially decreased and measurable tolerance developed to this effect after four daily injections. However, the rate of tolerance development differed depending on whether or not presence of the drug coincided with performance during experimental sessions. Tolerance developed more rapidly when morphine was given before daily experimental sessions than when morphine was given daily but animals did not perform daily in experimental sessions. Tolerance to the rate-decreasing effects of morphine depended on relations between presence of the drug and exposure to experimental sessions.

Effects of morphine, naloxone, d,l-cyclazocine, and d-amphetamine on behaviour controlled by a schedule of interresponse time reinforcement.

The separate effects of graded doses of morphine, naloxone, d,l-cyclazocine, and d-amphetamine on responding maintained by a differential reinforcement of low rate schedule of food presentation were examined in rats. Morphine did not alter response rates at doses of 1--5.6 mg/kg; at 10 mg/kg a 57% decrease in responding was observed and behaviour was even more severely depressed by 30 mg of morphine per kilogram. Naloxone did not affect responding at doses ranging from 0.1 to 10 mg/kg. d,l-Cyclazocine at doses of 3 and 5.6 mg/kg induced substantial increases in responding not observed when the dose was increased to 10 mg/kg. Cyclazocine, as well as morphine, produced dose-dependent decreases in the number of reinforcements per session. d-Amphetamine exerted a biphasic effect on responding; small doses increased response rates (0.3--3 mg/kg) and responding was suppressed by the drug at a dose of 10 mg/kg. Behaviourally active doses of d-amphetamine caused a dose-dependent reduction in the number of reinforcements per session. Naloxone at otherwise inactive doses (1--10 mg/kg) was found, in separate experiments, to antagonize the rate-decreasing effects of morphine, and to reduce the rate-increasing effects of d-amphetamine. The latter effect is not easily interpreted but confirms and extends other research employing rats in which naloxone was found to reduce the rate-increasing effects of small doses of d-amphetamine upon locomotor activity and responding maintained by a continuous electric-shock postponement procedure. In additional experiments morphine was given daily for 25 consecutive sessions at a dose of 30 mg/kg, 5 min preceding each test session. Responding was suppressed throughout this period and the dose of morphine given before each session was reduced to 10 mg/kg for 35 further sessions. Tolerance to the rate-decreasing effects of morphine was demonstrated; naloxone given in conjunction with morphine (10 mg/kg) in morphine-tolerant rats restored to control values the number of reinforcements per session without causing significant change in overall rates of responding. Few experiments have dealt previously with the development of tolerance to the behavioural effects of morphine under comparable dose regimens, time-course relationships, or behavioural testing procedures. Systematic analyses of these interrelated variables are needed since it is now evident that the schedule employed to maintain responding itself exerts significant effects.

Fixed-ratio escape and avoidance-escape from naloxone in morphine-dependent monkeys: effects of naloxone dose and morphine pretreatment.

Lever pressing by rhesus monkeys was maintained by morphine injections during four equally spaced sessions each day. During other periods, lever pressing was maintained by timeout from a continuous naloxone infusion (escape), or by timeout from a stimulus that preceded naloxone injections, or termination of the injections (avoidance-escape). As naloxone dose increased in the escape procedure, response rate increased to a maximum and then decreased. In the avoidance-escape procedure, response rate generally increased as naloxone dose increased, but the changes in rate were small compared to the excape procedure. Substitution of saline for naloxone in the escape procedure led to a very low response rates within three sessions. In the avoidance-escape procedure, rate decrements produced by saline substitution appeared to be related to the behavioral history of the monkey. Previous escape experience led to more rapid decreases in responding when saline was introduced, whereas responding was maintained for 15 sessions in a monkey without prior escape conditioning. Morphine pretreatment produced comparable, dose-dependent decreases in response rates in both procedures. The rate-decreasing effects of morphine were exacerbated when no naloxone was delivered in the escape procedure.