Small Doses Of Morphine Research Articles

Mesolimbic sites mediate the discriminative stimulus effects of morphine

The neuroanatomical basis of opiate addiction has been studied using a variety of behavioural techniques. Mesolimbic structures such as the ventral tegmental area and nucleus accumbens appear to be critical in mediating the expression of rewarding effects of opiates. However, the role of these brain structures in mediating the discriminative stimulus effects have not been fully examined. The aim of the present study was to investigate the role of the ventral tegmental area and the nucleus accumbens in a two-lever operant drug discrimination paradigm. Male Wistar rats were trained to discriminate morphine (3.0 mg/kg s.c.) from saline with a fixed ratio schedule of food reinforcement (FR10). Once rats had acquired the discrimination, a randomised sequence of morphine muinjections (1–10 μg) were evaluated. Subsequently, tests with morphine (1.0–10.0 mg/kg s.c.) administered systematically were performed to confirm the integrity of the discrimination. Small doses of morphine (1–3 μg) administered into the ventral tegmental area proved sufficient to produce generalisation to the systemic cue, whereas similar injections into the nucleus accumbens produced only partial generalisation. Furthermore, these intra-nucleus accumbens injections (3–10 μg) produced significant increases in the latency to complete the first ratio. Similar doses of morphine administered into the striatum failed to show generalisation. These results demonstrate that activation of opioid receptors located within mesolimbic structures mediate, in part, the discriminative stimulus effects of morphine. Furthermore, the finding that the discriminative stimulus effects and rewarding effects share common neural pathways suggest a possible linkage between the two stimulus properties.

A small dose of morphine leads rats to drink more alcohol and achieve higher blood alcohol concentrations.

Male Sprague-Dawley rats were maintained on a daily regimen of 22 hr of fluid deprivation followed by a 2-hr opportunity to take a sweetened alcoholic beverage and water for over 6 months. During the week before the formal procedures of the experiment described herein, access to the alcoholic beverage was limited to 1.5 hr, but access to water was still for 2 hr. Intakes of ethanol, in terms of g/kg, were tabulated at 30 min for half of the rats and at 90 min for the rest. On the day of formal procedures, half of the rats of the 30- and 90-min measures were given 1 mg/kg of morphine sulfate just before the drinking session, whereas the rest received physiological saline. Morphine increased mean g/kg intakes of ethanol, as compared with controls, at 30 and 90 min. Blood alcohol levels were also increased. These data suggest that the well-documented ability of small doses of morphine to increase rats' intake of ethanol is probably not related to its ability to produce gastrointestinal effects, but rather due to its ability to modulate central motivational mechanisms associated with ingestion.

Even Small Doses of Morphine Might Provoke “Luxury Perfusion” in the Postoperative Period after Craniotomy

Even Small Doses of Morphine Might Provoke “Luxury Perfusion” in the Postoperative Period after Craniotomy

Even Small Doses of Morphine Might Provoke ???Luxury Perfusion??? in the Postoperative Period after Craniotomy

Even Small Doses of Morphine Might Provoke ???Luxury Perfusion??? in the Postoperative Period after Craniotomy

Effect of Naloxone on the Morphine Concentration in the Central Nervous System and Plasma in Rats

We investigated whether the distribution (concentration) of morphine in the central nervous system (CNS) after systemic administration could be an index for the in vivo binding of morphine. Neither the morphine concentration nor its decline correlated with the density of opiate receptors. Naloxone decreased the morphine concentration in some CNS regions and plasma after a high dose of morphine, but not after a small dose of morphine. The CNS regions in which naloxone decreased the morphine concentration did not correlate with the density of opiate receptors, and the concentration ratios (CNS regions versus plasma) of morphine were not affected by naloxone. These results suggested that the morphine concentration in the CNS did not reflect the in vivo binding of morphine and that the naloxone-induced decrease in morphine concentration was not due to a displacement of morphine from its receptor sites but due to a change in morphine kinetics. Pharmacokinetic studies suggested that naloxone decreased the morphine concentration through an increased volume of morphine distribution. This naloxone-induced decrease in morphine concentration may contribute to the naloxone-induced inhibition of morphine action in addition to the competitive antagonism at opiate receptors.

Effects of morphine on the electrochemical signal modified by noxious stimuli in the nucleus raphe magnus of anesthetized rats

The effects of noxious stimuli and morphine on the serotonergic system in the nucleus raphe magnus were examined by in vivo voltammetry studies, using anesthetized rats. The normal electrochemical signal of 280–300 mV was essentially due to the presence of 5-hydroxyindoles in the nucleus raphe magnus. Heating or pinching produced mean decreases of 21.9 ± 5.2% and 18.0 ± 6.1% of control, respectively in the 5-hydroxyindole signal. Nonnoxious (brushing or warm water) stimulation did not affect the 5-hydroxyindole signal. A small dose of morphine (0.5 mg/kg, i.p.) enhanced the inhibition of the signal by noxious stimuli but large doses (2.0 or 5.0 mg/kg, i.p.) resulted in lesser reductions of the signal. The value of the 5-hydroxyindole signal was unaffected by morphine alone (0.5, 2.0 and 5.0 mg/kg). Effects of both small- and large-doses of morphine were antagonized by naloxone (1 mg/kg, i.v.). Allopurinol (20 mg/kg, i.p.), a xanthine oxidase inhibitor, decreased the steady signal (40.7 ± 16.2%). After pretreatment with allopurinol, noxious stimuli-induced decreases, both with and without administration of morphine, were similar to those in nontreated rats.In brief, noxious stimulation was found to decrease 5-hydroxyindole signal in the nucleus raphe magnus; morphine enhanced or attenuated this decrease in the anesthetized rat.

Comparison of isomers of ketamine on catalepsy in the rat and electrical activity of the brain and behavior in the cat

The present study compared the relative potency and efficacy of the two isomers of ketamine on the duration of catalepsy (loss of righting reflex) in female rats and on the behavior and electroencephalogram of cats. In the rat, at small doses, the S(+) isomer was more potent than the R(−) isomer or racemic ketamine, while at larger doses, the S(+) isomer and the racemate were equipotent and the R(−) isomer was significantly less potent. Tolerance developed rapidly to the effects of either isomer and both were equally cross-tolerant to racemic ketamine. Sub-effective doses of morphine significantly increased the potency of S(+), R(−) and racemic ketamine on the duration of catalepsy. Sub-effective doses of either isomer augmented the duration of catalepsy, induced by small doses of morphine, but reduced that of large doses. In cats, there was a parallel time course and progression of behavioral and electroencephalographic states in response to equal total doses of either racemic ketamine, an artificial 50:50 mixture of S(+) and R(−) isomers, or the S(+) isomer alone; approximately equivalent effects required twice the dose of the R(−) isomer. It is concluded that there is a common site of action for the two isomers, but there is also a stereospecific difference in potency, as regards the induction of catalepsy in the rat and behavioral and electroencephalographic effects in the cat. Stereospecificity was not apparent in the development of tolerance, cross-tolerance or the augmentation of the response to morphine.

Small doses of morphine and intake of water

Rats deprived of water for 19 h were given an opportunity to drink water for 30 min and for another 4.5 h. Prior to drinking, rats were injected with saline or morphine (1.0 mg/kg) to test whether morphine’s effects persisted when given day after day. Surprisingly, we did not observe that morphine enhanced drinking. Subsequently, when rats were deprived of water for 23.5 h, morphine still did not increase intake. When we continued testing, with a demonstration replicating an experiment in which morphine increased drinking and with other demonstrations, it became apparent that small doses of morphine do not always enhance intake of water.

Further studies of opioids and intake of sweetened alcoholic beverage

Rats were placed on a daily regimen of water deprivation followed by a limited opportunity to take either water or a sweetened alcoholic beverage. Across days of opportunity, they took less water and more alcohol until they were taking considerable amounts of alcohol. Naloxone, the classic antagonist at opioid receptors, was given prior to opportunity to drink and it reduced intakes of alcoholic beverage. Small doses of morphine, the classic agonist, increased intakes of alcoholic beverage at doses as low as 0.41 mg/kg. The effects of two other antagonists at opioid receptors (LY117413 and MR2266) were also tested. Both reduced intakes of alcohol. The data showing that more than one or two opioid antagonists reduce intakes of alcoholic beverages, even palatable beverages usually taken in large amounts, and that morphine increases intakes at very low doses, strengthen the idea that endogenous opioid systems are involved in modulating intake of alcohol.

Morphine antagonizes TRH-induced intestinal transit and hyperserotonemia in rabbits

Thyrotropin releasing hormone (TRH), administered intracerebroventricularly (i.c.v.) in microgram quantities to anesthetized rabbits, produces marked stimulation of colonic motility, transit, and fluid accumulation, and is accompanied by a portal hyperserotonemia. In this study we found that pretreatment of rabbits with morphine (10 mg/kg i.v.) completely blocked the TRH-induced colonic transit and increase in luminal fluid, as well as the hyperserotonemia. A small dose of morphine (200 μg) given i.c.v., but not i.v., also inhibited the intestinal transit and portal hyperserotonemia. These results suggest that morphine inhibits TRH-induced intestinal transit and fluid accumulation, at least in part, by inhibition of a neural pathway mediating intestinal serotonin release.

COMBINED INTRATHECAL MORPHINE AND BUPIVACAINE FOR CESAREAN SECTION

The effects of adding 0.2 mg preservative-free morphine sulfate in 0.2 ml solution to hyperbaric spinal bupivacaine were evaluated in a double-blind randomized prospective study of 34 patients undergoing elective repeat cesarean section. In the control patients (n = 17), 0.2 ml saline instead of morphine was added to bupivacaine. The intrathecal morphine significantly improved intra- and postoperative analgesia, e.g., 82% of patients given morphine compared with 41% of the control patients did not require analgesic supplementation to the spinal anesthesia during surgery; postoperatively, the former patients did not request additional analgesia for 27 +/- 0.7 hours (mean +/- SEM) compared with 2 +/- 0.3 hours in the control patients. Neonatal condition was not adversely affected by this small dose of morphine administered 11 +/- 1 minutes before delivery. Combining 0.2 mg morphine with hyperbaric spinal bupivacaine for cesarean section is a safe and effective method of improving intraoperative pain relief and providing adequate prolonged postoperative analgesia.

Electroacupuncture and morphine analgesia potentiated by bestatin and thiorphan administered to the nucleus accumbens of the rabbit

The endogenous opioid peptide enkephalin (EK) is known to be degraded mainly by two enzymes, the depeptidyl car☐ypeptidase ‘enkephalinase’ and aminopeptidase. Microinjection of the enkephalinase inhibitor thiorphan or the aminopeptidase inhibitor bestatin into the nucleus accumbens of the rabbit produced a dose-dependent analgesic effect. This analgesic effect was totally reversed by the narcotic antagonist naloxone or by antibodies against [Met 5]enkephalin (MEK) administered to the same site. Antibodies against [Leu 5]enkephalin were not effective. Moreover, microinjection of thiorphan or bestatin into the nucleus accumbens resulted in a marked potentiation of the aftereffect of electroacupuncture (EA) produced analgesia, as well as the analgesia induced by a small dose of morphine. It is concluded that the analgesic effect elicited by EA and morphine is mediated, at least in part, by MEK-like immunoreactive substance(s) in the nucleus accumbens.

Potentiation of Systemic Morphine Analgesia in Humans by Proglumide, a Cholecystokinin Antagonist

Proglumide, a cholecystokinin antagonist, potentiates analgesia produced in rats by morphine and endogenous opiates, and appears to reverse tolerance in rats to opiate analgesia. Therefore, proglumide and other cholecystokinin antagonists may be clinically valuable. We have tested proglumide's possible opiate analgesic potentiating effects by examining, in volunteers, the effects of morphine and proglumide on human pain visual analogue scale responses to 45-51 degrees C skin temperature stimuli. Proglumide (50-100 micrograms intravenously) potentiated both the magnitude and duration of analgesia produced by small doses of morphine. This study provides indirect evidence for a cholecystokinin-opiate interaction in humans. Therefore, cholecystokinin antagonists such as proglumide may serve to potentiate exogenous or endogenous opiate action.

Effects of morphine on somatocardiac sympathetic reflexes in spinalized cats

The effects of morphine on sympathetic reflexes, recorded in the inferior cardiac nerve, to myelinated A and unmyelinated C afferent stimulation were tested in 17 acutely spinalized cats. Stable sympathetic A and C reflexes of short latency (approximately 30 ms and 140 ms in the case of the ulnar nerve, respectively) could be recorded in the inferior cardiac sympathetic nerve to stimulation of somatic A and C afferents in the ulnar and upper thoracic intercostal nerves, ipsilaterally. Spinal sympathetic A reflexes, which were primarily evoked from stimulation of Aδ afferent fibers, could be elicited from more segmental levels than could sympathetic C reflexes. Additionally, smaller reflexes, only from A afferent fiber activation, were identified from stimulations on the contralateral side of the body. Small doses of morphine (0.02 mg kg −1, i.v.) proved to be ineffective at altering sympathetic A and C reflexes, while somewhat larger doses (0.2 mg kg −1, i.v.) produced a clear 62% decrease in C reflexes and a 33% decrease in A reflexes, Dosages of 1 and 2 mg kg −1 severely depressed both A and C reflexes. All of the above effects of morphine administration were completely and immediately reversible by naloxone (i.v.). The results are discussed with regard to the effects of morphine on sympathetic A and C reflexes in CNS intact, anesthetized cats.

Feline analgesia following central administration of opioids

Activity of opioids in cats was assessed by employing the tail-flick method. Microinjection of morphine (100 μg) or etorphine (2.5 μg) into the ventrolateral periaqueductal gray (VLPAG) region resulted in significant analgesia. Smaller doses of morphine (10 and 50 μg) or etorphine (0.62 and 1.25 μg) were without significant effect. Methadone likewise produced no significant analgesic action in doses as large as 360 μg in the ventrolateral periaqueductal gray. Rank order potency, i.e. etorphine > morphine >> methadone, was similar following systemic administration. Increased latency of tail-flick response after injection of etorphine was diminished by administration of naloxone, either systemically or centrally, thus indicating a specific opiate-mediated response.

Changes in thalamic nociception resulting from morphine- and meperidine-dependence in rats

Rats were injected with progressively increasing doses of morphine or meperidine during a period of 3 to 40 days. From this colony of animals individual rats were used at 3- to 4-day intervals for electrophysiologic experiments to analyze the activity of nociceptive neurons in the somesthetic thalamus. After an i.p. injection of chloralose-urethane and the appropriate preparation for a stereotaxic microelectrode penetration of the thalamus, a nociceptive neuron was identified in the nucleus ventralis posterolateralis by its unique spacing of spike potentials emitted in response to pricking the foot with a pin. In addition to the short-latency response that formed a high activity peak on poststimulus time histograms, spikes following the stimulus up to 500 ms also formed activity peaks. Single-pulse stimulation of the sciatic nerve evoked the same response as pinpricks, but innocuous stimuli (pin shielded with a piece of cork) evoked a response without the late activity peaks. Only neurons that exhibited this differential response were regarded as nociceptive. Their response and spontaneous activity were accumulated separately on a digital computer. Following this, naloxone was infused i.v. and the computer accumulations were repeated. It was found that during naloxone-precipitated narcotic withdrawal, innocuous stimuli evoked responses indicative of pain; the nociceptive system was sensitized. Furthermore, a small dose of morphine or meperidine heightened the sensitization. This action of the narcotic agents was reversed by 5-hydroxytryptophan, which assisted the narcotics in suppressing pain in morphine- or meperidine-dependent rats but had no demonstrable effect in control animals. The spontaneous tonic activity of the nociceptive neurons of the somesthetic thalamus was high in rats exhibiting narcotic dependence. Naloxone decreased the count, but not to the value of the control animals. The sensitization of nociception can be explained by a decreased action of a neural pathway that descends from the periaqueductal gray matter via the nucleus raphe magnus to the spinal cord and there blocks the excitation of the spinothalamic tract cells by A-delta and C fibers. The mechanisms that increase the spontaneous activity of the thalamic nociceptive neurons remain unclear.

Morphine antagonizes pentobarbital-induced anesthesia

Morphine was administered by the intracerebroventricular (i.c.v.) route to pentobarbitalanesthetized rabbits. Small doses of morphine (<150 μg) potentiated, but larger doses (>250 μg) shortened, the duration of anesthesia. In naltrexone-pretreated animals, all doses of morphine employed acted only as an analeptic. Atropine, but not atropine methylbromide, blocked the analeptic effect of morphine, indicating that a central cholinergic mechanism was involved in this response. Tolerance to the analeptic effect was not evident. These results suggest that morphine exerts an arousal action which is usually masked by the dominant narcotic properties, but which becomes evident when administered intracerebroventricularly or in the presence of naltrexone.

Continuous epidural morphine treatment for intractable pain in terminal cancer patients

In patients with intractable cancer pain who failed to respond to conservative and neurosurgical procedures for pain relief, repeated injections of epidural morphine were found to be beneficial. A small dose of morphine (2–4 mg per injection) relieved pain for 6–24 h. A permanent subcutaneous epidural catheter led to successful ambulatory treatment without complications. The implantation of the epidural catheter is a minor surgical procedure, done under local anesthesia and is considered safe even in terminal cancer patients.

Behavioral alterations produced by chronic naloxone injections

Repeated blockade of the endorphin receptors eventually induces symptoms resembling an opiate abstinence syndrome, despite the complete absence of opiate narcotics. Rats were injected with 0.6 mg/kg naloxone or with injection vehicle alone twice a day for six days. They were observed twice a day for four subsequent days. Body shakes, head shakes, scratches and total symptoms were significantly elevated in the naloxone treated group over controls. Symptoms were completely reversed by a small dose of morphine but not by naloxone. In a second experiment, rats were injected for ten days with the same dosage of naloxone. The abstinence-like syndrome began after six days of naloxone and continued for several days after cessation of injections. Total symptoms, body shakes, scratches and aggression were significantly elevated over controls and were reversed by morphine but not by naloxone.

Clinical Study of Postoperative Pain Relief after Regional Anesthesia with Small Doses of Morphine - II. In Barchial plexus block

Clinical Study of Postoperative Pain Relief after Regional Anesthesia with Small Doses of Morphine - II. In Barchial plexus block