Daily Injections Of Morphine Research Articles

Effects of morphine, naltrexone, and dextrorphan in untreated and morphine-treated pigeons.

Six pigeons, trained to peck a response key on a fixed-ratio 20 schedule of food reinforcement, were used to examine the effects of morphine, naltrexone, and dextrorphan, before, during, and after chronic treatment with increasing doses of morphine (10.0-100.0 mg/kg/day). Tolerance developed to the rate-decreasing effect of the daily maintenance doses of morphine within 2 days of each dose increase. A small amount of tolerance to morphine and supersensitivity to naltrexone was evident within the 1st week of morphine treatment (10.0 mg/kg/day). Continued administration of morphine (32.0-100.0 mg/kg/day) produced further tolerance to morphine and supersensitivity to naltrexone, as evidenced by a 5-fold increase in the dose of morphine, and 1,000-fold decrease in the dose of naltrexone, necessary to suppress responding. By the 4th week of treatment (100.0 mg/kg/day), a modest tolerance had also developed to the rate-decreasing effects of dextrorphan. Suppression of responding by naltrexone, but not morphine or destrorphan, was accompanied by a loss in body weight over the 1- to 2-h session in morphine-maintained pigeons; both weight loss and reduced response rates also occurred on termination of morphine treatment. Sensitivity to the rate-decreasing effects of morphine and naltrexone was near normal within 10 days following termination of morphine treatment. The dramatic changes in sensitivity to naltrexone and morphine produced by daily morphine injections, as well as the ability to generate complete dose-effect curves within a single session, indicate that this behavioral preparation may provide sensitive concurrent measures of narcotic tolerance and supersensitivity to antagonists in the pigeon.

Arginine vasopressin enhances retention of morphine tolerance

The hot plate method was used to assess tolerance in rats following daily injections of morphine. Following analgesia assessment, or a time equated rest period, rats were injected with either saline or a pituitary peptide. Arginine vasopressin, but not ACTH 4–10, prolonged the retention of morphine tolerance when assessed five weeks after the last injection. Neither the rate nor the degree of tolerance development were influenced by either peptide. These hormones had no effect on retention of tolerance in rats not assessed for analgesia during the period of tolerance development. The effects of pituitary peptides on morphine tolerance are analogous to the effects they have on learning and memory processes, suggesting that similar adaptational processes are occuring in both phenomena.

Acute stimulation of feeding with repeated injections of morphine sulphate to non-obese and fatty Zucker rats

1. 1. Food intake studies with genetically obese rodents show that these hyperphagic animals, which have increased central and peripheral levels of endogenous opioid peptides (E.O.P.), have an increased sensitivity to the suppressive feeding effects of narcotic antagonists compared to lean controls. Feeding experiments were conducted to determine if genetically obese rats, with enhanced E.O.P., have a reduced sensitivity toward the narcotic agonist property of stimulated feeding seen in non-obese rats. 2. 2. Food intake was monitored continuously over each experimental day in groups of female Sprague-Dawley (S.D.,), fatty Zucker (fa/fa) and their lean heterozygote littermates (Fa/ fa) following subcutaneous a.m. injections of sterile saline, morphine sulphate (5 or 10 mg/kg) or naloxone HCl (10 mg/kg) and during recovery. 3. 3. Acute 4-h post-injection feeding was reduced in all groups with the first 10 mg/kg injection of morphine sulphate. With repeated morphine administration, a phase of stimulated feeding occurred in both obese and non-obese groups. 4. 4. Due to the post-injection phase of vigorous feeding with repeated morphine injections, the circadian pattern of day/night food intake of all groups was altered such that daytime feeding increased from saline control levels. 5. 5. Naloxone HCl abolished the post-injection phase of stimulated feeding seen with chronic morphine injections and reduced 4-h post-injection food intakes. 6. 6. Plasma glucose and serum insulin levels were decreased in non-obese rats from saline controls of blood samples taken 2-h following the 7th daily M.S. injection. These levels increased again by the end of the recovery period. No blood glucose or insulin changes were seen in the obese Zucker rats with morphine administration. 7. 7. The results show that daily morphine injections can cause acute stimulated feeding in obese, fatty Zucker rats as well as in non-obese rats.

Morphine analgesia and tolerance in the tail-flick and formalin tests: dose-response relationships.

The dose-response relationships for morphine analgesia were studied in morphine-tolerant and non-tolerant rats using two pain tests: the tail-flick test which measures the threshold for an escape response, and the formalin test which assesses the behavioral response to continuous pain generated in injured tissue. The effects of prior experience with both pain tests on tolerance were also examined. In the formalin test, effective analgesia was obtained in non-tolerant rats at doses that produce minimal depression of locomotor behavior. Morphine tolerance was produced by 20 daily injections of morphine with increments that reached 16 mg/kg, a dose over the LD100 for barrier sustained Long Evans rats. This dose regimen produced a 1.8-fold increase in the ED50 in the tail-flick test and a 2.7-fold increase in the formalin test. Daily experience of the pain test, as well as the morphine regimen produced a 4.8-fold increase in the ED50 in the tail-flick test but did not affect the potency of morphine in the formalin test. The magnitude of tolerance in the absence of daily behavioral testing is consistent with recent clinical reports that little tolerance occurs after prolonged administration of morphine in cancer patients and that tolerance is not an important consideration in the management of pain.

Intrathecal and intraventricular morphine for pain in cancer patients: initial study.

Intractable pain in six cancer patients was treated with lumbar intrathecal morphine (two patients) and intraventricular morphine (four patients). Daily percutaneous injections of morphine through Ommaya reservoirs were made. Initially, 1 mg of lumbar intrathecal morphine resulted in pain relief for 10 to 14 hours, and 2.5 to 4.0 mg of intraventricular morphine gave relief for 12 to 24 hours. This treatment was continued for 3 to 7 months in three of the adults. Morphine requirements gradually increased. Side effects were minimal, and there were no complications.

Apparent lack of tolerance in the formalin test suggests different mechanisms for morphine analgesia in different types of pain

Tolerance to morphine analgesia was examined using the Formalin test in which pain lasting about 2 hrs associated with minor tissue injury is produced by subcutaneous injection of dilute Formalin. To distinguish behavioral from pharmacological tolerance, different groups of rats received their daily morphine injection (7 mg/kg) in the test environment or in their home environment for 5 days. Another group of rats was given morphine for 15 days in the home cage followed by 5 days in the test environment. None of the morphine injected groups differed from saline injected control groups in the amount of analgesia. These findings add to previous evidence that the Formalin test measures a type of pain which is different from that assessed in withdrawal reflex tests, and which more closely resembles clinical pain in man. Moreover, the fact that analgesia in the Formalin test shows little tolerance while analgesia in withdrawal tests shows rapid tolerance suggests that the underlying neural mechanisms are different.

Behavioral changes produced in the cat by acute and chronic morphine injection and naloxone precipitated withdrawal

To address the issue of feline manic responses to morphine, studies were designed to examine the effects of low doses of intravenous morphine on cat behavior with emphasis placed on motor activity changes. An adaptation of an existing scoring system was used in an effort to quantify and describe behavioral patterns or shifts in activity patterns occurring during a cycle of addiction. The acute administration of 1, 2 or 4 mg/kg of morphine induces a response pattern characterized by sitting with fixed staring. An increase in motor activity with dose was also observed. When naloxone was administered prior to morphine injection all behavioral changes normally elicited by morphine were blocked completely. After 7 days of daily morphine injections certain changes in activity profiles occurred, indicating that some degree of tolerance although not complete, was beginning to occur by this time. Naloxone administered to cats maintained for 12 days on 1, 2 or 4 mg/kg/day consistently produced a number of withdrawal signs including wet-dog shakes and a catatonic-like posturing. This is the first report describing behavioral responses of the cat during a complete cycle addiction to low doses of morphine. We not only found that morphine will elicit definite quantifiable changes in behavior in the absence of any feline mania but that cats become readily dependent on these low doses of morphine as evidenced by a characteristic naloxone precipitated withdrawal syndrome.

Interoceptive conditioning through repeated suppression of morphine-abstinence

The reinforcing properties of etonitazene, both conditioned and unconditioned, were measured in rats that had received saline only by continuous intravenous infusion (“saline” group) and in two groups of rats that had been physically dependent on morphine to equal degrees (and presumably had developed equal degrees of tolerance to morphine): one by once daily passive intravenous injection of morphine (“injection” group) and the other by passive continuous intravenous morphine infusion at the same daily doses for approximately the same number of days (“infusion” group). Prior to passive saline and morphine administration, all rats were trained to press right and left-sided levers for water reinforcement from 1600 to 0800 hrs to a not more than 60–40 split, and these and other measures (“baselines”) were repeated after recovery from the early (acute) morphine-abstinence syndromes. Then etonitazene, 5 μg/ml, was substituted for water on the nonpreferred side and all measures were repeated from 1600 to 0800 hrs once every two weeks for 20 weeks (10 “relapse” tests). It was postulated that the daily cycles of morphine-abstinence and suppression of abstinence in the injection group only would generate latent interoceptively conditioned reinforcing properties of morphine because of conditioning of suppression of abstinence to the concomitant internal sensorial effects of morphine, which would persist after morphine withdrawal and be transferred to the internal effects of another opioid, etonitazene. It was found that across the first nine relapse tests, the injection group consumed significantly more etonitazene than the infusion group, while there were no significant differences in water consumption. Also, the number of response-contingent etonitazene drinking tube presentations in the first 30 min period of lever availability in the first relapse test (when the unconditioned reinforcing effects and other pharmacological actions of etonitazene were minimal) was significantly greater for the injection group than for either the infusion or saline group, whereas there were no significant differences among the three groups in response-contingent water tube presentations. These findings support the interoceptive conditioning hypothesis.

Interoceptive conditioning through repeated suppression of morphine-abstinence. II. Relapse-testing.

The reinforcing properties of etonitazene, both conditioned and unconditioned, were measured in rats that had received saline only by continuous intravenous infusion ("saline" group) and in two groups of rats that had been physically dependent on morphine to equal degrees (and presumably had developed equal degrees of tolerance to morphine): one by once daily passive intravenous injection of morphine ("injection" group) and the other by passive continuous intravenous morphine infusion at the same daily doses for approximately the same number of days ("infusion" group). Prior to passive saline and morphine administration, all rats were trained to press right- and left-sided levers for water reinforcement from 1600 to 0800 hrs to a not more than 60-40 split, and these and other measures ("baselines") were repeated after recovery from the early (acute) morphine-abstinence syndromes. Then etonitazene, 5 micrograms/ml, was substituted for water on the nonpreferred side and all measures were repeated from 1600 to 0800 hrs once every two weeks for 20 weeks (10 "relapse" tests). It was postulated that the daily cycles of morphine-abstinence and suppression of abstinence in the injection group only would generate latent interoceptively conditioned reinforcing properties of morphine because of conditioning of suppression of abstinence to the concomitant internal sensorial effects of morphine, which would persist after morphine withdrawal and be transferred to the internal effects of another opioid, etonitazene. It was found that across the first nine relapse tests, the injection group consumed significantly more etonitazene than the infusion group, while there were no significant differences in water consumption.(ABSTRACT TRUNCATED AT 250 WORDS)

Prevention by naltrexone of tolerance to the rate-decreasing effects of morphine on schedule-controlled responding in the pigeon.

Key-pecking in the pigeon was maintained under 10-min fixed-interval and 30-response fixed-ratio schedules of food presentation. Naltrexone alone (0.003–17 mg/kg) had no systematic effect on responding at any dose studied, and 10 and 17 mg/kg morphine practically eliminated responding. When naltrexone regularly preceded daily injections of morphine, tolerance was prevented for some dose combinations but not for others. If the daily dose of morphine was 17 mg/kg, tolerance was prevented by 1.0 mg/kg naltrexone but not by 0.3 mg/kg naltrexone. If the dose of naltrexone was 0.56 mg/kg, tolerance was prevented for 10 mg/kg morphine but not for 17 mg/kg morphine. Thus naltrexone prevented the development of tolerance to the rate-decreasing effects of morphine, although there were doses of naltrexone which completely antagonized the acute effects of morphine but which did not prevent tolerance development. The relative doses of naltrexone and morphine, not the absolute doses, determined whether or not development of tolerance was prevented. When combinations of naltrexone (0.3 or 1.0 mg/kg) and morphine (17 mg/kg) preceded experimental sessions by 6 h, the effects of the combination with 0.3 mg/kg naltrexone were more like those of 17 mg/kg morphine alone, whereas the effects of the combination with 1.0 mg/kg naltrexone were almost indistinguishable from those of saline. Differences in prevention of tolerance by doses of naltrexone that antagonized the acute effects of morphine were probably due to differences in duration of effect.

Changes in the hyperthermic responses of rats to daily injections of morphine and the antagonism of the acute response by naloxone

Core temperatures of unrestrained male rats were measured by rectal probe over a 4-h period following seven daily subcutaneous injections of morphine sulphate in doses of 5, 20, or 80 mg/kg. With the smaller doses, rapid hyperthermia occurred and was maximal after 20 mg/kg; with 80 mg/kg, two of eight rats had immediate hypothermia, with the group response being a small, delayed hyperthermia. The results with repeated administration of morphine give statistical validity to earlier findings suggesting that peak hyperthermia increased and occurred progressively sooner after each injection of morphine. In groups of naive rats a single injection was given of saline or of 1, 10, or 40 mg naloxone hydrochloride per kilogram in saline. In these rats saline led to a slight increase in core temperature; when the first injection was one of the three doses of naloxone, no transient increase was seen. In nine other groups each of the three doses of naloxone was given 15 min before each of the morphine doses. All three doses of naloxone significantly reduced the hyperthermia induced by 5 and 20 mg morphine sulphate per kilogram, but this was less apparent in the group treated with 80 mg/kg, although naloxone at 40 mg/kg prevented any increase in temperature for over 3 h. The results obtained in this study demonstrate that morphine-induced temperature changes and perhaps stress-induced changes can be suppressed by naloxone.

Thermoregulatory responses of the unrestrained cat to acute and chronic intravenous administration of low doses of morphine and to naloxone precipitated withdrawal

Morphine in doses of 1, 2, and 4 mg/kg i.v. produced dose related elevations in cat body temperature while doses of 0.25 and 0.50 mg/kg had no such effect. Tolerance was found to develop to the hyperthermic response after seven days of daily morphine injection. Pretreatment with naloxone at a dose one-fourth the dose of morphine prevented the morphine induced rise in body temperature in all cats tested. When the cats received naloxone after twelve days of daily morphine a withdrawal syndrome resulted and was accompanied by a hypothermia that was proportional to the morphine maintenance dose and severity of withdrawal.

Stress-produced analgesia and morphine-produced analgesia: Lack of cross-tolerance

Animals exposed to cold-water swims, rotation, inescapable shocks, abrupt food deprivation and other stressors display temporary analgesia. Since repeated exposures result in adaptation of this analgesia in much the same way that repeated administration of opiates results in tolerance, the possibility of cross-tolerance between cold-water stress-induced and morphine-induced analgesia was investigated. Flinch-jump thresholds were determined in ten experimental groups of six rats each. Three groups showed dose-dependent analgesia following single injections of morphine at 5, 10 and 15 mg/kg, respectively. A fourth group, subjected to a single cold-water swim at 2°C for 3.5 min, displayed analgesia comparable to that produced by 10 mg/kg of morphine. Groups subjected either to 14 daily cold-water swims or to 14 daily morphine injections at 10 mg/kg showed normal thresholds on the 14th day indicating that adaptation and tolerance had developed, respectively. The cross-over groups were exposed to either 13 days of cold-water swims followed by morphine or the reverse arrangement. Both groups showed profound analgesia instead of cross-tolerance, suggesting that a non-opiate neural mechanism may mediate stress-induced analgesia.

Addictive agents and intracranial stimulation (ICS): Naloxone blocks morphine’s acceleration of pressing for ICS

Ten rats were fixed with chronically indwelling electrodes for intracranial stimulation (ICS) of the lateral hypothalamus. The rats were then trained to press a lever for the self administration of ICS at two current intensities; one intensity produced a low rate of pressing and the other a high rate of pressing for ICS. Subsequent to obtaining stable press rates for each intensity of ICS, five rats received daily injections of morphine (10 mg/kg) 4 h prior to testing and five rats were injected with saline. After a significant acceleration of pressing for ICS was demonstrated by the morphine group, both groups were injected with naloxone (1 mg/kg) 15 min prior to testing. No effect was shown for the placebo group, while naloxone blocked morphine’s potentiation of pressing for ICS. The blocking effect persisted for 3 days after the single dose of naloxone despite the continued administration of morphine (10 mg/kg/day), which had previously accelerated pressing for ICS.

Effects of morphine pellet implantation in neonatal rats.

SummaryA morphine pellet implantation method has been modified for use in very young rats. Compared to P-implanted controls, implantation of an M pellet on either Day 5 or 11 results in diminished body weight for periods at least up to 15 weeks. Such treatment on Day 11 is associated with reduced sensitivity to the analgesic action of morphine (10 mg/kg) when tested on Day 48 using the hot-plate technique. Resting pituitary-adrenal activity in animals implanted with morphine on Day 5 or 11 was within normal limits when examined on Day 43. Corticosterone responses to a challenge dose of morphine (40 mg/kg) on Day 68 failed to demonstrate tolerance unequivocally. These findings are consistent with those obtained earlier with daily injections of morphine and demonstrate that the long-lasting ponderal effect and tolerance to the analgesic actions of morphine may be produced without the confounding effects of daily handling and stress of abrupt withdrawal in neonatally addicted rats. This convenient method of ...

Duration of interferon inhibition following single and multiple injections of morphine

The increase in mouse serum interferon that occurs in response to poly I:C administration is markedly attenuated by injection of a narcotic preceding the polynucleotide challenge. A single injection of morphine is capable of inhibiting the mechanism(s) responsible for increasing serum interferon levels for a period of at least 9 days following the narcotic injection. Daily single injections of morphine for 5 or 10 days prior to poly I:C challenge do not amplify the extent of the decrease in serum interferon over that measured for a single injection, even though the amount of narcotic injected is increased on each successive day of the 5 or 10 day period. The implications of this relationship for the phenomenon of narcotic tolerance are evaluated and discussed as they relate to the immune processes.

Addictive agents and intracranial stimulation: Daily morphine and lateral hypothalamic self-stimulation

Rats were allowed to press for electrical stimulation of the lateral hypothalamus on days before, during, and after daily morphine or placebo injections. During tests 1 h after morphine injections, press rates were initially depressed at doses of 10 mg/kg or greater. As days of testing under daily morphine doses of 10 or 15 mg/kg continued, pressing gradually increased 1 h after injections. Four hours after morphine injections with doses of 10 and 15 mg/kg, pressing rates were greater than rats’ previous rates of pressing and control groups’ pressing, and this facilitation did not wane across 20 days of injections. With termination of 20 days of injections, pressing rates generally returned to levels seen prior to days of injections. The facilitation of intracranial self-stimulation at 4 h after injections of moderate doses of morphine might reflect processes germane to morphine’s positively reinforcing properties.

Chronic morphine effects on regional brain amines, growth hormone and corticosterone

This study was designed to examine the relationship between regional levels of brain amines (norepinephrine, NE; dopamine, DA; serotonin, 5-HT) and plasma hormone levels (corticosterone, CS; growth hormone, GH) in rats following chronic morphine administration (40 mg/kg twice daily). Rats were sacrificed at 4:00 pm (and the final injection was made at 9:00 am). Amine and hormone levels were determined after 1, 2 and 6 weeks of daily injections of morphine. Increased plasma CS was found after 1 and 2 weeks of injections and decreased GH levels were present after 2 and 6 weeks. In another 2 week study when morphine was administered 1 hr before sacrifice, plasma levels of CS were decreased and GH increased. Serotonin levels were decreased in all brain regions after 2 and 6 weeks of morphine administration and DA was decreased in the amygdala after 6 weeks. In 2 weeks treated rats injected 1 hr before sacrifice 5-HT levels had returned to control levels and DA was decreased. Inverse correlations were found to relate with 5-HT and CS levels, CS with GH levels and GH with brain DA. A direct correlation was present in GH and 5-HT levels.

Chronic administration of morphine in cats: Effects on adrenal and urinary catecholamines

Adrenaline and noradrenaline levels in the adrenal glands and the excretion of both bioamines in urine of adult cats were investigated after chronic administration of morphine and nalorphine-induced withdrawal. After 7 days of daily consecutive morphine treatment, a significant increase in the adrenal noradrenaline content and a drop in adrenaline content were observed. After 2 weeks of daily injection of morphine, no significant changes were obsrved in the adrenal catecholamine level. One month of treatment with the opioid caused a significant increase in the adrenal content of both adrenaline and noradrenaline. Urinary excretion of catecholamines was significantly increased during the 4 weeks of treatment. In animals subjected to spontaneous or induced withdrawal with nalorphine, the adrenal content of catechomamines was altered and the ratio adrenaline/noradrenaline in the adrenal gland was shifted towards noradrenaline. A first injection of morphine produced an excitant manic response characterized by hyperexcitement and aggressive behaviour; animals chronically treated with the drug showed a progressively diminished response to this effect of the drug. It is concluded that physical dependence on morphine is reached by cats chronically treated with morphine and that this effect of the drug influences adrenomedullary function in a different fashion depending on the stage of morphine treatment.

On the possible interrelationship in mechanism of action between morphine, amphetamine and neuroleptic drugs

Publisher Summary This chapter elaborates the possible interrelationship in mechanism of action between morphine, amphetamine and neuroleptic drugs. Morphine interacts with the brain catecholamines, dopamine and noradrenaline. The simultaneous injection of morphine, and amphetamine led to the inhibition of morphine type excitation, bursts of locomotion, and rearing, increased grooming. The mutal antagonism was evident since morphine antagonized the stimulation of locomotion, and rearing after higher doses of amphetamine. Stimulation of central dopamine mechanism with apomorphine, or l -dopa given after a peripheral decarboxylase inhibitor also produced a significant inhibition of the morphinetype excitation. The simultaneous injection of amphetamine with the daily injection of morphine to chronically morphinized rats antagonized the stereotyped licking/biting activity which otherwise would have been present.