Continuous Morphine Administration Research Articles

Effects of opiates on neuronal development in the rat cerebral cortex

Quantitative morphological characteristics of cells in the primary somatosensory cortex of 6-dayold rats were examined following continuous maternal administration of morphine (10 mg/kg/day), naltrexone (10 mg/kg/day), or saline vehicle from gestation day 12. Naltrexone reduced neuronal packing density and significantly increased cortical thickness but had no effect on neuronal number, while morphine reduced neuronal packing density and the number of neurons without affecting cortical thickness. These results suggest that blockade of endogenous opioid function during development enhances neuronal maturation in this brain region, while perinatal morphine administration might act to restrict cortical cell proliferation and maturation. Thus, the effect of ontogenetic activation of opioid receptors by endogenous opioid compounds could be similar to but less severe than the effect of exogenous opiate exposure on cortical cell development.

Cancer Pain Relief by Continuous Administration of Epidural Morphine in a Hospital Setting and at Home

Department of Anesthesia, Hospital Pharmacy, Clinical Bacteriological Laboratory, and Department of Surgery, Central Hospital, Kristianstad, Sweden

Cancer pain relief by continuous administration of epidural morphine in a hospital setting and at home

Fifteen patients with severe pain due to malignancy were treated by continuous epidural morphine infusions. A disposable external pump was used. Patients were treated in a hospital setting or at home for a total of 906 days. Pain intensity was estimated by VAS. The pumps functioned well. Bacterial growth was found in 0.6% of the balloon reservoirs used, while the epidural filters were free from growth. There were no clinical infections. It appears that this delivery system is safe, practical and suitable for use in the home environment.

Apparent pA 2 value of naltrexone is not changed in rats following continuous exposure to morphine or naloxone

Chronic opioid antagonist administration increases opioid binding sites and potentiates behavioral responses to morphine. Conversely, chronic opioid agonist administration attenuates behavioral responses to morphine, though this is not necessarily accompanied by a parallel loss of binding sites. We examined the possibility that the in vivo affinity of the μ receptors might be altered as a consequence of the continuous administration of either naloxone or morphine. Rats were implanted sc with naloxone- or morphine-filled osmotic pumps; control animals were implanted with sham pumps. One week later, 24 hr after removing the osmotic pumps, cumulative dose-response curves for fentanyl analgesia were generated in the presence of 0.0, 0.03, 0.1, or 0.3 mg/kg naltrexone, using a tail-flick procedure. The analgesic ED 50 (with 95% C.L.) of fentanyl in sham implanted animals, following saline pretreatment was 0.027 mg/kg (0.019, 0.039). The potency of fentanyl was decreased in rats infused with morphine, ED 50 = 0.051 mg/kg (0.028, 0.093), and increased in rats that received naloxone, ED 50 = 0.018 mg/kg (0.015, 0.022). The mean apparent pA 2 value for naltrexone (with 95% C.L.) in the control group was 7.7 (7.5, 7.9). No differences were detected in animals that had received either naloxone or morphine for 7 days, pA 2=7.8 (7.5, 8.1) and (7.3, 7.6), respectively. Our results indicate that there is no change in the apparent affinity of the μ-receptor following continuous exposure to either an opioid agonist or antagonist, at a time when the analgesic potency of the agonist is decreased or increased, respectively.

顎口腔領域疾患患者に対する中心静脈栄養の検討

Total parenteral nutrition (TPN) for 92 cases of maxillofacial diseases was reviewed in order to improve the nutritional management at Department of Oral and Maxillofacial Surgery, Ehirne University Hospital. It was concluded that: 1) TPN is effective for the adequate hydration and nutrition of preoperative or postoperative patients, who are impossible to take the water and food. 2) Patients, who have experienced TPN before, prefer that to the feeding tube. 3) A central venous catheter is also useful for the continuous administration of intravenous morphine for cancer pain control. 4) The education and cooperation of the staff and patients are important to prevent the sepsis, which is the most frequent complication due to TPN.

Continuous intraspinal morphine administration for management of cancer pain

Continuous intraspinal morphine administration for management of cancer pain

Continuous vs. bolus epidural morphine

The clinical evaluation of continuous administration of epidural morphine was undertaken using an infusion pump (Act-A-Pump 1000). Eleven patients who had undergone abdominal surgical procedures were treated with this therapeutic modality for postoperative pain control, and two cancer patients for chronic pain relief. The results were satisfactory and the advantages over repeated epidural injections are discussed.

Attenuation of pharmacological effects and increased metabolism of phencyclidine in morphine tolerant mice

Mice were used for a study of the interaction between morphine and phencyclidine (PCP) in relation to lethality, motor incoordination, locomotor activity and rearing, together with the half-life of PCP, following continuous administration of morphine by pellet (75 mg base) implantation for 72 h and after removal of the pellets for 6 and 24 h. PCP induced motor incoordination and suppressed locomotor activity and rearing; these effects were enhanced in morphine ‘pellet-implanted’ mice and were attenuated in morphine ‘pellet-removed’ groups. The enhancing effect of morphine on the PCP responses was attributable more to the presence of residual morphine than to the alterations in its disposition. The morphine-induced increase in locomotor activity and analgesia was attenuated in PCP (40 mg/kg per day i.p. for 5 days) tolerant mice. The rate of decay of PCP in serum and brain or morphine pellet-implanted animals was not different; however, in the 24 h ‘pellet-removed’ group, the rate of decay of PCP was increased. The results indicate that there is a two-way cross-tolerance development between PCP and morphine. The phenomenon appears to involve both dispositional and functional adaptation mechanisms.

Retardation of cerebral dopamine turnover after morphine withdrawal and its enhanced acceleration by acute morphine administration in rats.

To clarify the effects of withdrawal from chronic morphine treatment on cerebral dopamine (DA) turnover, we have measured the alpha-methyl-p-tyrosine (alpha MT)-induced depletion of DA in five brain areas of male Wistar rats given morphine twice daily for 40 or 60 days. After the last morphine dose (50 or 70 mg/kg) the rats were withdrawn for 1, 2 or 4 days. In order to study the development of tolerance some of the rats were challenged with 10 mg/kg of morphine. Withdrawal of morphine retarded the alpha MT-induced DA depletion in the limbic forebrain and after long enough chronic treatment in the striatum, too. The challenge dose of morphine accelerated the cerebral DA depletion slightly less in rats withdrawn for 1 day from 60-day chronic morphine treatment than in rats treated chronically with saline, but it enhanced the DA depletion more in rats withdrawn from morphine for 2 and 4 days than in chronic saline rats. This enhancement was clearest in rats withdrawn for 4 days from 60-day treatment. Thus withdrawal from morphine seems to sensitize the rats to the DA depletion accelerating effect of morphine. Our results show that repeated administration of morphine creates no marked tolerance to the DA depletion accelerating effect of morphine. In contrast, the dopaminergic neurones of the chronically treated rats seem to depend on continuous morphine administration for their normal functioning. Furthermore, the retarded DA turnover after discontinuation of morphine treatment seems to sensitize the dopaminergic neurones to the DA depletion accelerating effect of morphine.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of acute and continuous morphine administration on serum glutamate oxalacetate transaminase and glutamate pyruvate transaminase activities in the mouse

Mice were exposed continuously to morphine by implanting morphine pellets for 12 hr to 3 days. In mice receiving prolonged morphine pellet implantation, second and third morphine pellets were implanted at days 3 and 6, for a total of 9 days. Results showed morphine pellet implantation for 24 hr caused a 2-fold increase in glutamate oxalacetate transaminase (SGOT) and glutamate pyruvate transaminase (SGPT) activities, as compared with those of the placebo control group. SGOT and SGPT activities were returned to control levels after 3–9 days of morphine pellet implantation. In mice implanted with a morphine pellet for 24 hr, both SGOT and SGPT activities returned to normal levels at 3 and 6 days after the removal of the morphine pellet. In mice receiving morphine pellet implantation for 24 hr with three concurrent administrations of naloxone. 40 mg/kg, s.c., the morphine pellet-induced elevations of SGOT and SGPT activities were attenuated significantly. Acute administration of morphine sulfate by both subcutaneous and intraventricular administration elevated SGOT and SGPT activities. The elevations of SGOT and SGPT activities caused by morphine pellet implantation were prevented completely by hypophysectomy and prevented partially by adrenalectomy. These results substantiate our previous morphological and biochemical findings that initial administration with morphine by either injection or pellet implantation may alter hepatic function and the action may be mediated through the central nervous system.

Effects of acute and continuous morphine administration on the affinity of glutamic acid decarboxylase for pyridoxal 5′-phosphate

The studies showed that neither morphine nor naloxone at concentrations up to 10 −3 M exhibited any effect on the affinity of glutamic acid decarboxylase (GAD) for its cofactor, pyridoxal 5′-phosphate (P-5′-P) in vitro. Acute administration of morphine sulfate with respect to time course and dose-response studies also failed to modify the affinity of GAD for P-5′-P. In contrast, in mice rendered tolerant to morphine by morphine pellet implantation there was a significant attenuation in affinity of GAD for P-5′-P. The sensitivity of this enzyme for P-5′-P during the course of the development of tolerance to morphine was restored partially either when the morphine was abruptly withdrawn by removing the morphine pellet or when withdrawal was precipitated by naloxone. The recovery of the affinity of GAD for its cofactor was shown to be naloxone dose-dependent. These results further substantiate that the γ-aminobutyric acid (GABA) system may be involved in morphine tolerance and the development of dependence.

Acute and continuous morphine administration on the γ-aminobutyric acid system in the mouse

1. 1. Effects of acute and continuous morphine administration on γ-aminobutyric acid (GABA) and glutamate levels and activities of L-glutamate-1-carboxylase (GAD) and GABA-α-ketoglutarate aminotransferase (GABA-T) in whole or discrete areas of mouse brain have been investigated. 2. 2. Acute morphine administration resulted in a significant increased brain GABA content and decreased glutamate level. Neither brain GAD nor GABA-T activity were affected. 3. 3. Continuous morphine administration, on the other hand, caused no significant change in brain glutamate level. However, there were significant decreases in both GABA level and GAD activity. 4. 4. The rate of brain GABA accumulation, induced by aminooxyacetic acid (AOAA) in tolerant mice, was slower than in non-tolerant animals. 5. 5. Both acute and continuous morphine administration caused distinct effects on the GABA system in cerebral cortex, brain stem, hypothalamus and the remaining areas of the brain except cerebellum. These data may indicate that the CNS GABA system is linked with morphine analgesia, tolerance and physical dependence.

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.

Changes in sensitivity to operant effects of dopaminergic and cholinergic agents following morphine withdrawal in rats

Rats trained to bar-press on either a FI 15 sec or FR 30 schedule for water reinforcement were administered various doses of apomorphine, haloperidol, pilocarpine and scopolamine both before and 1–4 months after a 3-day period of continuous morphine administration. All drugs monotonically depressed response rates on both schedules with increasing dose. Chronic morphine administration produced a persistent increase in sensitivity to apomorphine and pilocarpine and a persistent decrease in sensitivity to haloperidol and scopolamine. The results suggest that both dopaminergic and cholinergic supersensitivity are likely to be involved in protracted abstinence phenomena.

Enhancement of pentobarbital effect by continuous administration of morphine in the mouse

These studies demonstrated that continuous morphine treatment from implantation of a 75 mg morphine pellet for 3 days potentiated pentobarbital narcosis and enhanced pentobarbital hypothermia. In the morphine implant mice, sleeping time after two different doses of pentobarbital was greater than 2.5 × the sleeping time in placebo pellet implant animals and also greater than sleeping time in animals treated acutely with morphine prior to pentobarbital. Moreover, in the morphine implant mice both the degree and duration of pentobarbital induced hypothermia were enhanced. The above findings were due to slower rate of metabolism of pentobarbital as evidenced by inhibition of hepatic N-demethylation, and higher levels of brain and serum pentobarbital in the morphine implant mice compared to both placebo and acute morphine mice.

14 C-catecholamine synthesis in mouse brain during morphine withdrawal.

AFTER a single injection of morphine or related narcotic analgesics, incorporation of 14C-tyrosine into 14C-catecholamines is increased markedly in the brains of mice1,2 and rats3. However, repeated administration of these drugs results in the development of tolerance to their effects upon 14C-catecholamine synthesis1,2. We have determined that once complete tolerance has developed, the mouse brain cannot maintain normal rates of catecholamine synthesis without the continued administration of morphine.

Influence of continued administration of morphine and of withdrawal on contraction of small intestines of dogs.

Two experiments were carried out on dogs with Thiry-Vella fistulae of ileum. The operations for formation of the fistulae were performed several weeks before the experiments were started. Graphic records of the intestinal contractions were made by introducing into the fistula a sausage-shaped rubber balloon fastened on a catheter and filled with water; the catheter was connected with a Brodie bellows-recorder which made the tracing on a slowly moving kymograph. Records were made in this way without anesthesia or operative procedure or discomfort to the animal. Experiment 1. Ascending doses of morphine sulphate: A female collie dog, weighing 21 kg. received daily hypodermic injections for 71 days and during this time the dose was increased from 1 mg. per kg. to 25 mg. per kg. There was some constipation and loss of appetite but the dog remained in good condition, losing only one kg. in weight. Narcosis and vomiting disappeared after the fourth week, but salivation continued throughout the experiment. The dog became shy and restless as the experiment progressed. Graphic records of the effect of the injections of morphine on the intestinal contractions were made at intervals of two to three days throughout the experiment. There was no change in the character of the reaction at any time. We have reported in a recent paper that hypodermic injections of morphine in dogs greatly increase the muscular activity of the intestine. In this experiment each injection produced the usual reaction; marked increase in tone and in amplitude and frequency of the contractions. From time to time small doses (0.15 mg. per kg.) were injected before the regular daily dose, and these invariably produced stimulation of the intestinal contractions.