Injection Of Morphine Sulfate Research Articles

Effects of intracerebroventricular corticotropin-releasing hormone and intravenous morphine on cortisol, prolactin and growth hormone secretion in sheep

It has previously been demonstrated that naloxone and morphine modify the adrenocortical and pituitary responses of sheep to stress. Since CRH acts within the brain to co-ordinate the stress response, the present experiment was conducted to determine whether morphine has similar effects in sheep given oCRH centrally. Plasma concentrations of cortisol, prolactin and growth hormone were measured in blood samples collected at 10 min intervals from sheep (N=5) over a 3-hr period. Intravenous injections of saline vehicle or morphine sulphate (0.4 mg/kg) were given after 40 min and intracerebroventricular injections of oCRH (0, 5 or 20 μg) were administered after 60 min. Sustained, dose-related, increases in cortisol were induced by oCRH and, in agreement with findings in stressed sheep, these responses were reduced by pretreatment with morphine. Prolactin levels appeared to increase after morphine but oCRH, on its own, did not increase prolactin secretion in this study. There was no change in growth hormone concentrations after oCRH whereas morphine transiently stimulated release.

A novel approach for the determination of the pain-producing potential of intravenously injected substances in the conscious rat.

The purpose of this study was to validate an experimental method for quantifying the pain producing potential of intravenously administered solutions. Response was measured in a Broome restraint tube modified by the addition of strain gauges. Struggling caused flexion of the tube, changing strain gauge output and increasing output variance. In experiment 1, five groups of 10 male Sprague Dawley rats were given intravenous injections of 1 ml of saline, acetate, HCl, citric acid vehicles, or KCl over a 1-min period. Results showed significant increases in output variance between saline and treated groups during the infusion period. In experiment 2, five groups of five rats were given intravenous injections of saline or 0.1, 0.05, 0.025, or 0.0125 M KCl. Rats responded in a dose-dependent manner, demonstrating the sensitivity of this technique. In experiment 3, two groups of four rats were given injections of morphine sulfate (2 or 4 mg/kg, ip) prior to administration of 0.05 M KCl. Two additional groups received no pretreatment prior to administration of saline or 0.05 M KCl. Results demonstrate that morphine ablates the response to intravenous administration of KCl. This model provides information concerning the pain producing potential of intravenously delivered compounds or formulations.

Amniotic-fluid ingestion enhances morphine analgesia during morphine tolerance and withdrawal in rats

Ingestion of placenta and amniotic fluid has been shown to enhance opioid-mediated analgesia in rats produced by morphine injection, footshock, vaginal/cervical stimulation, and during late pregnancy. The present study was designed to investigate the effects of amniotic fluid ingestion on the characteristics of morphine dependency and withdrawal. Tail-flick latencies in Long-Evans rats were determined before and after repeated daily injections of morphine sulfate. It was found that ingestion of amniotic fluid after establishment of the morphine dependency, coupled with an injection of an otherwise ineffective dose of morphine, enhanced analgesia in morphine-dependent rats, and reversed hyperalgesia seen during withdrawal from morphine dependency.

Stability of milrinone and epinephrine, atropine sulfate, lidocaine hydrochloride, or morphine sulfate injection

The stability of both drug components of admixtures of milrinone and epinephrine, atropine sulfate, lidocaine hydrochloride, morphine sulfate, calcium chloride, or sodium bicarbonate injections was studied. Duplicate solutions of admixtures of milrinone injection 1 mg/mL and epinephrine injection 1:10,000, atropine sulfate injection 1 mg/mL, lidocaine hydrochloride injection 1%, morphine sulfate injection 8 mg/mL, calcium chloride injection 10%, or sodium bicarbonate injection 7.5% were prepared and stored in glass containers at 22-23 degrees C under fluorescent light. Samples were taken immediately and after 20 minutes for assay by high-performance liquid chromatography (HPLC). Milrinone at initial concentrations of 0.10-0.73 mg/mL showed no degradation in any of the solutions during the study period, nor was any degradation observed for lidocaine, morphine, atropine, or epinephrine. Milrinone 0.10-0.73 mg/mL is compatible with atropine sulfate, lidocaine hydrochloride, epinephrine, calcium chloride, or sodium bicarbonate in glass containers stored for 20 minutes at room temperature. These results support the use of milrinone in combination with these agents immediately after the preparation of admixtures.

Opiates suppress carrageenan-induced edema and hyperthermia at doses that inhibit hyperalgesia

This study determined whether opiates alter vascular components of inflammation (hyperthermia, edema and plasma extravasation) in addition to the suppression of hyperalgesia. Rats were administered carrageenan into one hind paw and saline into the other hind paw, followed by i.p. injection of morphine (0.2–5.0 mg/kg) or saline at 60 min, and testing at 90 min after hind paw injections. Morphine produced a dose-dependent reduction in carrageenan-induced hyperalgesia (17–53%), hyperthermia (39–53%) and edema (24–36%). Morphine treatment did not alter the temperatures of the contralateral saline-injected paws, indicating that opiate suppression of hyperthermia was not confounded by alterations in systemic body temperature or blood flow. The opiate effects on inflammation were stereospecific since levorphanol (1 mg/kg), but not dextrorphan (1 mg/kg), suppressed carrageenan-evoked hyperalgesia, hyperthermia and edema. Pre-treatment with naltrexone (1.5 mg/kg) blocked the effects of a 5 mg/kg dose of morphine sulfate on hyperalgesia, hyperthermia and edema. In a separate study, i.v. injection of morphine sulfate (2 mg/kg) reduced plasma extravasation by 41% ( P < 0.01). Morphine administration resulted in significantly greater increases in paw withdrawal latencies in the inflamed (38–139%) than the contralateral, saline-treated paws (4–19%). The results indicate that opiates exert a moderate, though significant, reduction in the vascular signs of inflammation in addition to their reduction of hyperalgesia. The mechanisms for this vascular effect involve inhibition of both vasodilation (as indicated by a decrease in hyperthermia) and inhibition of vascular permeability. In addition, opiates exhibit enhanced antinociceptive effects in inflamed paws, even when compared to uninjured paws in the same animal.

Facilitation of sexual behaviors in the male rat associated with Intra-VTA injections of opiates

Male rats were tested for sexual behaviors after bilateral injections of morphine sulfate or dynorphin 1–13 into the ventral tegmental area. Both morphine and dynorphin 1–13 increased, in a dose-orderly manner, the number of males that mounted, and the display of female-directed behavior. Repeated administration of morphine, but not dynorphin 1–13, into the region of the ventral tegmental area increased dopamine (DA) metabolism in the nucleus accumbens, a terminal field of the mesolimbic DA system. These results suggest that activation of elements within the region of the VTA activated by mu and kappa selective agonists are able to facilitate some aspects of sexual behavior, but that only morphine appears to activate dopaminergic elements within the VTA.

Effect of negative air ions on morphine‐induced changes in the latency of the tail‐flick reflex

Adult male Long-Evans rats were exposed to negatively charged air ions at high concentrations (7 x 10(5)/cm3) for six days. Sham-exposed rats were treated identically except that the source of ions was not activated. At the end of the exposure, the latency of the tail-flick reflex was measured in each rat before and 30 and 60 min after an injection of morphine sulphate. The tail-flick reflex was initiated by thermal stimulation. Two heat settings were employed, the lower considered to impart a submaximal and the higher a maximal thermal stimulus. Three morphine doses were tested: 0.5, 1.0, and 1.5 mg/kg. Statistically significant differences between ion-exposed and sham-exposed rats were observed in tail-flick latencies 30 min after the administration of the two lower doses, but not after the highest dose of morphine sulphate. These differences were found at both intensities of thermal stimulation. Tail-flick latencies measured in each group prior to morphine injection were not affected by negative-ion exposure. The data indicate that exposure of rats to negative air ions tends to inhibit the action of morphine on the latency of the tail-flick reflex at morphine doses below 1.0 mg/kg.

Caudal epidural morphine for control of pain following open heart surgery in children

The safety and efficacy of epidural morphine injected into the caudal space for control of postoperative pain following open cardiac surgery in children was studied. Thirty-two children between the ages of 2-12 yr for whom early postoperative tracheal extubation was anticipated were randomly assigned to control and study groups. Study subjects received a caudal injection of preservative free morphine sulfate (0.075 mg/kg) in preservative-free normal saline (5-10 ml) following completion of surgery, but prior to awakening and extubation of the trachea. Supplemental intravenous morphine administration and pain scores were recorded for 24 h. Patients in the study group received significantly less (P less than 0.03) morphine (0.32 mg.kg-1.24 h-1) and had significantly lower pain scores than did patients in the control group (0.71 mg.kg-1.24 h-1). The mean duration of complete analgesia in patients receiving caudally administered morphine was 6 h (range 2-12), but decreased analgesic requirements were noted for the entire 24 h. No respiratory depression was evident by clinical variables or repeated arterial blood gas values. Nausea without vomiting occurred in 4/16 patients in the study group. No patient described pruritus. The authors were unable to evaluate the occurrence of urinary retention because all patients had indwelling urinary catheters. They found caudal epidural morphine to be safe and effective in the treatment of postoperative pain in children following open heart surgery.

Stability of morphine sulfate in portable pump reservoirs during storage and simulated administration

The stability of four concentrations of morphine sulfate injection in prefilled reservoirs for portable infusion pumps was studied after storage for 30 days at refrigerated and room temperature and after a three-day simulated administration period at body temperature. Thirty-milliliter samples of morphine sulfate injections in four concentrations--1, 5, 15, and 25 mg/mL--were loaded into a pump reservoir. The reservoirs were stored in the dark at 5 degrees C and 25 degrees C for 30 days. Samples were taken from each reservoir immediately after loading and after 7, 14, and 30 days of storage. The reservoirs were then connected to portable infusion pumps, which were run for three days at a flow rate of 0.4 mL/hr at 37 degrees C. The last sample was collected at the end of the three-day period. Samples were assayed for morphine sulfate content by high-performance liquid chromatography. The concentration of morphine sulfate increased up to 6% (for the 5-mg/mL sample) at refrigerated temperature and up to 16% (for the 15-mg/mL sample) at room temperature after 30 days' storage in the reservoirs. Evaporation of water from the reservoirs may have accounted for this phenomenon. No absolute relationship was found between the initial concentration of morphine sulfate and the percentage concentration increase after storage for 30 days. The change in morphine sulfate concentration before and after the three-day pumping period was not significant. Injectable solutions of morphine sulfate in concentrations ranging from 1 to 25 mg/mL are stable when stored at refrigerated temperature for 30 days in a prefilled drug reservoir.

Intravenous morphine infusion (IMF) to drug-naive, conscious rats evokes bradycardic, hypotensive effects, but pressor actions are elicited after IMF to rats previously given morphine.

Hemodynamic (blood pressure and heart rate) responses of conscious drug-naive rats were studied following intravenous (i.v.) infusion of sterile saline, morphine sulphate, and then naloxone hydrochloride, as well as of other groups previously injected with morphine sulphate. Those groups chronically given morphine sulphate received twice daily injections of morphine sulphate (5 mg/kg, s.c. per injection) for 3 or 6 days before testing with the i.v. infusion of morphine sulphate. Drugs were infused (135 microL/min) through an indwelling femoral venous catheter via a Harvard infusion pump, and blood pressure was recorded from the abdominal aorta via a femoral arterial catheter. Other pretreatment studies were done to determine the receptor mechanisms mediating the blood pressure responses of drug-naive and chronic morphine-treated rats, whereby equimolar doses (0.32 mumol) of specific receptor antagonists were given as a bolus i.v. injection 5 min after saline but before subsequent infusion with morphine sulphate. Intravenous infusion of morphine sulphate (7.5 mg/kg total over 15 min) to drug-native rats caused a transient but precipitous fall in mean arterial pressure and mean heart rate with an associated rise in mean pulse pressure; these effects were blocked in other groups pretreated with atropine. Interestingly, however, rats chronically injected with morphine sulphate for 3 days previously evoked a transient pressor response when subsequently infused i.v. with morphine sulphate, actions that were blocked in other groups when pretreated i.v. with 0.32 mumol of phentolamine, yohimbine, prazosin, or guanethidine. A greater and persistent pressor response occurred following morphine infusion to groups of rats previously injected over 6 days with morphine sulphate, which was associated with tachycardia during the later stages of the 15-min morphine sulphate infusion period. The prolonged pressor and tachycardic responses of this 6-day chronically injected group were completely blocked in another group pretreated i.v. with both phentolamine and propranolol (0.32 mumol). The results suggest that morphine sulphate infusion to conscious, drug-naive rats evokes classical hypotensive effects due to decreases in mean heart rate caused by activation of parasympathetic vagal activity. With 3 or 6 days of chronic morphine sulphate administration beforehand, subsequent i.v. infusion of morphine sulphate evoked pressor actions felt to be caused by a progressive activation of the sympathetic nervous system.(ABSTRACT TRUNCATED AT 400 WORDS)

Capsaicin pretreatment does not inhibit the opioid withdrawal response in guinea-pigs

The effects of capsaicin pretreatment on withdrawal responses of guinea-pig isolated ileum to [Met 5]enkephalin (ME) and morphine and on the locomotor withdrawal response of guinea-pigs following a single dose of morphine, were investigated. In vitrp treatment of ileum with capsaicin, 1.5 μmol/1 for 1 h, did not significantly affect the response to washout following 2 min contact with ME, 1 μmol/1, or the withdrawal response precipitated by naloxone, 1 μmol/1, following 2 min contact with morphine, 1 μmol/1, or the response to naloxone of tolerant-dependent ileum obtained from guinea-pigs treated with a total dose of 690 mg/kg of morphine over 3 days. Pretreatment of guinea-pigs with capsaicin 140 mg/kg subcutaneously (s.c.) over 4 days also did not affect the washout withdrawal response of the ileum to ME. Pretreatment of guinea-pigs with capsaicin did not affect the locomotor withdrawal response precipitated by naloxone hydrochloride 15 mg/kg s.c., 2 h after injection of morphine sulphate 15 mg/kg s.c. It was concluded that primary afferent neurones do not play an essential role in opioid withdrawal responses.

Synergy between the antinociceptive effects of intrathecal clonidine and systemic morphine in the rat

These experiments tested the hypothesis that intrathecal α 2-adrenergic antinociception could be potentiated by the concurrent administration of systemic morphine. Thirty-four male rats, implanted with chronic indwelling intrathecal catheters, received a subcutaneous injection of either morphine sulfate or an equal volume of saline, followed by an intrathecal injection of clonidine HCl or an equal volume of vehicle. Antinociception was assessed using the tail-flick test. Tail-flick latencies following subcutaneous morphine plus intrathecal vehicle, or subcutaneous saline plus intrathecal clonidine were not significantly different from baseline. However, the combination of subcutaneous morphine plus intrathecal clonidine produced a significant antinociceptive effect. Such potentiation may prove to be a useful clinical strategy to help maximize analgesia, minimize side effects and attenuate the development of tolerance.

Compatibility of esmolol hydrochloride with morphine sulfate and fentanyl citrate during simulated Y-site administration

The compatibility and stability of esmolol hydrochloride in admixtures during simulated Y-site injection of morphine sulfate or fentanyl citrate was studied. One milliliter of either morphine sulfate (15 mg/mL) or fentanyl citrate (0.05 mg/mL) was injected into a running infusion of esmolol hydrochloride (10 mg/mL) in 5% dextrose and 0.9% sodium chloride injection, and the solution was visually observed for changes. To determine the stability of the drugs during Y-site injection, esmolol hydrochloride 4 mL (1000 mg) in 5% dextrose and 0.9% sodium chloride injection was combined with 100 mL of either morphine sulfate 15 mg/mL or fentanyl citrate 0.05 mg/mL to simulate concentrations of the drugs that might be expected during Y-site injection. The admixtures were stored at ambient room temperature under normal light, and drug concentrations were determined using high-performance liquid chromatography at time zero and at two, four, and eight hours. Admixtures were also tested for pH and observed for visual changes. No immediate changes were observed in any of the admixtures, and the concentrations of the drugs varied by less than 4% throughout the study period. No precipitate or color changes were noted during Y-site injection of either drug into the running esmolol infusion. Under all of the conditions studied, esmolol hydrochloride in 5% dextrose and 0.9% sodium chloride injection is compatible with morphine sulfate or fentanyl citrate.

Release of a dynorhin A (1–8) degrading enzyme from the spinal cord by intraventricular morphine in the rat

Intraventricular injection of morphine sulfate, 40 μg, released an enzyme from the spinal cord into the perfusate which degraded dynorphin A (1–8) and, to a lesser extent, dynorphin A (1–13) in urethane anesthetized rats. The enzyme did not degrade dynorphin A (1–17), Met-enkephalin, Leu-enkephalin, substance P and neurotensin. This dynorphin A (1–8) degrading enzyme was inhibited by aprotinin, thiorphan, and, to a lesser extent, by bacitracin but was not inhibited by bestatin. A kinetic study of the interaction between dynorphin A (1–8) and aprotinin with the enzyme indicated that it is competitive in nature. The pharmacological significance of the findings is still unknown.

Effect of chronic intracerebroventricular morphine to feeding responses in male rats

Stainless steel cannulae were implanted stereotaxically in the third ventricle of male albino rats. The rats were fed with natural food pellets and water ad lib. After seven days of cannulation, daily body weight, food intake and water intake were recorded for the first five days, which was considered the preinjection control. Then increased and repetitive injections of morphine sulphate were administered intracerebroven-tricularly (ICV) in dosage of 30 μ g 2 μ l , 45 μ g 3 μ l , 60 μ g 4 μ l , 75 μ g 5 μ l , 90 μ g 6 μ l and 105 μ g 7 μ l on each following day respectively. In a separate set of experiments, the blood glucose levels were measured in animals injected with morphine to a dose corresponding to 15 μ g 1 μ l , 30 μ g 2 μ l , 45 μ g 3 μ l , 60 μ g 4 μ l and 75 μ g 5 μ l on days 1, 2, 3, 4 and 5 respectively. Statistically significant ( p<0.001) decreases in the body weight, food intake, water intake and increase in blood glucose were observed. The inferences derived from the above observations for the possible involvement and interaction of opioids in the regulation of feeding mechanisms have been discussed.

GABAergic modulation of the analgesic effects of morphine microinjected in the ventral periaqueductal gray matter of the rat

The possibility that GABAergic neurons in the ventral periaqueductal gray matter modulate the analgesic effects of morphine microinjected into this brain area was investigated in the rat. Microinjection of 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin 3-ol (THIP) (0.4 μg in 0.2 μl), a GABA agonist, in the ventral periaqueductal gray matter significantly reversed the increase of tail-flick latency induced by a prior injection of morphine sulfate (4 μg in 0.2 μl) at the same site. Conversely, microinjection in the same region of picrotoxin (10 ng in 0.2 μl), a GABA antagonist, significantly potentiated the analgesic effect of the same dose of morphine. These results suggest the existence of GABAergic neurons that tonically inhibit periaqueductal gray output neurons involved in centrifugal pain inhibition. The analgesic effects of opiates may, at least in part, result from disinhibition of these GABAergic neurons.

THE DETECTION OF HEROIN, COCAINE AND CANNABINOID METABOLITES IN THE STOOLS OF INFANTS OF DRUG DEPENDENT MOTHERS: CLINICAL SIGNIFICANCE

We have shown (Dev Pharm Ther 1:163, 1980) in morphine addicted fetal monkeys that the tissue concentration of morphine was highest in their intestines due to bile secretion or swallowed fetal urine. To test the corollary hypothesis that the stools from infants of drug dependent mothers (IDDM) will contain the drugs which the fetus has been exposed to, in utero, we collected stools (meconium) during the first 5 days from 10 IDDMs and 2 control infants and tested them for the metabolites of heroin (morphine), cocaine (benzoylecgonine), and cannabis (Δ 9 tetrahydrocannabinol or THC), three commonly abused drugs. In addition, we addicted a pregnant Sprague-Dawley rat by the daily subcutaneous injections of morphine sulfate (10-20 mgs/kg bid) from the 8th to the 21st day of gestation. Soon after birth, the rat pups were sacrificed and their intestines were collected for morphine analysis. The drug metabolites were extracted in appropriate solvents and quantitated by radioimmunoassay. The control stools were used for background correction.RESULTS: Four of the 10 IDDM stools contained morphine (range = 0.24-22.7 μg/gm stool, mean = 5.42) and 3 had cocaine metabolites (range = 0.24-0.67 μg/gm stool, mean = 0.42) up to the 2nd day of sampling. Five of 5 stools tested contained Δ 9 THC (range = 0.023-1.082 μg/gm stool, mean = 0.37) up to the 5th day sample. In the 9 rat pups, their intestinal contents collectively contained 1.65 μg of morphine or 0.18 μg morphine per pup.SIGNIFICANCE: This study shows that the stool (intestinal content) is a repository of the drugs which the fetus has been exposed to, in utero, and their detection may provide a unique insight into the drug exposure of the fetus throughout gestation. Likewise, since the complete evacuation of meconium occurs slowly, drug detection for diagnostic purposes in infants, is feasible even in late sampling.

SYNERGY BETWEEN THE ANTINOCICEPTIVE EFFECTS OF INTRATHECAL CLONIDINE AND SYSTEMIC MORPHINE IN THE RAT

Abstract These experiments tested the hypothesis that intrathecal α2-adrenergic antinociception could be potentiated by the concurrent administration of systemic morphine. Thirty-four male rats, implanted with chronic indwelling intrathecal catheters, received a subcutaneous injection of either morphine sulfate or an equal volume of saline, followed by an intrathecal injection of clonidine HCl or an equal volume of vehicle. Antinociception was assessed using the tail-flick test. Tail-flick latencies following subcutaneous morphine plus intrathecal vehicle, or subcutaneous saline plus intrathecal clonidine were not significantly different from baseline. However, the combination of subcutaneous morphine plus intrathecal clonidine produced a significant antinociceptive effect. Such potentiation may prove to be a useful clinical strategy to help maximize analgesia, minimize side effects and attenuate the development of tolerance.

Intravenous narcotic therapy for children with severe sickle cell pain crisis.

Few studies have been published about analgesic management practices during sickle cell pain crisis. Therefore, we reviewed the records of all hospitalized children with this complication during a recent five-year period. The 38 patients (98 painful episodes) who received intravenous narcotic therapy were the subjects of this review. In 76 patients, an initial intravenous bolus injection of morphine sulfate or meperidine hydrochloride was followed by a continuous intravenous infusion of one of these two drugs. To achieve adequate pain control, adjustments in infusion rates were made according to a written protocol. In 22 other patients, subsequent narcotic treatment consisted only of intermittent intravenous bolus injections of meperidine. Satisfactory pain relief was achieved in all 98 episodes. Patients given continuous infusions required more narcotic to control their pain and had more side effects than those treated with bolus injections alone, suggesting a dose-response relationship between narcotic dose and several known side effects. Common side effects included nausea and vomiting, lethargy, and abdominal distention. Although clinically evident respiratory depression was quite uncommon, chest syndrome was a frequent complication, and severe respiratory distress occurred in three patients. Narcotic withdrawal or addiction was not observed. With careful monitoring (including special attention directed to avoiding dosing error), continuous intravenous narcotic infusions are safe and provide effective pain relief for severe sickle cell pain crisis.

Demonstrating morphine's potentiating effects on sucrose-intake

Mildly deprived rats (18-hr of deprivation of water) were given the opportunity to take a solution of sucrose daily for periods of either 10, 18, 31, 56, or 100 min. After daily intakes stabilized and prior to a session, rats were given an injection of either morphine sulfate, 1.0 mg/kg, or naloxone hydrochloride, 2.5 mg/kg, an agonist and an antagonist, respectively, at the opioid receptors. Naloxone, as expected, decreased intakes regardless of the test-session's length. Morphine decreased intakes of the shorter sessions, but increased intake of the longest session. Subsequently, injections of morphine were given 56 min into a 100-min session. These injections also increased intake. Morphine's effects in potentiating intake seem to have special relevance with respect to the continuance of ingestion. Variations across experiments, in duration of test-sessions, could account for the variations in conclusions drawn about whether or not morphine and other agonists potentiate intake of ingesta.