Effective Dose Of Morphine Research Articles

The Effect of Probiotic Supplementation on Morphine Preference in Rats: Possible Antioxidative/Oxidative Signaling Pathway

Background: Many studies have revealed various aspects of the relationship between the stomach and the brain, but there has been no systematic study of the role of gut microbiota in drug addiction to date. This investigation is based on the novel concept that gut dysbiosis plays an important role in addiction disorders. Probiotic supplements (PBS) are thought to be a useful therapy method for opiate addiction and substance misuse. Therefore, it is postulated that changes in gut flora can play a significant part in the addiction process. Objectives: The aim of this study was to observe whether PBS, through the gut-brain axis in drug addiction, can decrease morphine (Mor) tendency in rats by affecting oxidative stress (OS) markers, using a conditioned place preference (CPP) paradigm. Methods: Forty-two rats (weight 180 - 200 g) were divided into six groups (n = 7 in each). The effective dose of morphine (Mor) was 7.5 mg/kg. Two probiotic supplements were used: Prodigest (Prd) containing Lactobacillus acidophilus, Bifidobacterium bifidum, and Bifidobacterium longum, and Prokid (Prk) containing Lactobacillus acidophilus, Bifidobacterium lactis, Lactobacillus rhamnosus, and Bifidobacterium bifidum. These were administered via gavage for 14 days. The animals were given PBS after each conditioning session in the conditioned place preference (CPP) model. The animals' locomotor activity was then evaluated using an open field apparatus. The brain was tested for malondialdehyde (MDA), nitric oxide (NO), catalase (CAT), superoxide dismutase (SOD), total antioxidant capacity (TAC), and thiol levels. Results: Only the Prd group, but not the Prk group, significantly increased the time spent in the Mor chamber (the location preference index) during the acquisition phase (P < 0.05). The anti-oxidation/oxidation profiles (MDA, NO, CAT, SOD, TAC, and thiol) were altered by PBS. Conclusions: Given the elevated location preference index generated by Mor, it may be argued that PBS influences mood and behavior via antioxidative/oxidative signaling, thereby potentiating the effect of Mor.

Involvement of AMPA receptors of lateral habenula in the expression and acquisition phases of morphine-induced place preference

The lateral habenula (LHb), known as the brain structure of the epithalamic, plays the main role in depression and drug addiction. The glutamatergic system influences morphine reward. The effect of activation/inhibition of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-type glutamate receptors (AMPARs) in the LHb on different phases of morphine-induced conditioned place preference (CPP) remains unknown. In this research, the effect of bilateral intra-LHb microinjection of AMPARs agonist and antagonist on the acquisition and expression phases of CPP in male rats has been investigated. Different doses of NBQX, the antagonist of AMPARs, in combination with the effective dose of morphine, increased the CPP score during the acquisition phase. While AMPA, the agonist of AMPARs, significantly reduced the conditioning scores in the acquisition phase. Pretreatment with NBQX (0.5 and 1 μg/rat) reversed the inhibitory effect of AMPA (1 μg/rat) on the acquisition phase of morphine-induced CPP. The antagonist (1 μg/rat) increased the effect of a high dose of agonist (2 μg/rat) on CPP. On the other hand, NBQX significantly increased CPP scores during the expression phase. AMPA did not significantly affect CPP scores in the expression phase, but significantly reduced locomotor activity in the test phase. These results confirmed the importance of AMPARs in the LHb in morphine reward. Our data also suggest that injection of an AMPARs antagonist into the LHb may alter the AMPA-induced morphine response in a dose-dependent manner.

Pharmacokinetics, adverse effects and effects on thermal nociception following administration of three doses of codeine to horses

BackgroundIn humans, codeine is a commonly prescribed analgesic that produces its therapeutic effect largely through metabolism to morphine. In some species, analgesic effects of morphine have also been attributed to the morphine-6-glucuronide (M6G) metabolite. Although an effective analgesic, administration of morphine to horses produces dose-dependent neuroexcitation at therapeutic doses. Oral administration of codeine at a dose of 0.6 mg/kg has been shown to generate morphine and M6G concentrations comparable to that observed following administration of clinically effective doses of morphine, without the concomitant adverse effects observed with morphine administration. Based on these results, it was hypothesized that codeine administration would provide effective analgesia with decreased adverse excitatory effects compared to morphine. Seven horses received a single oral dose of saline or 0.3, 0.6 or 1.2 mg/kg codeine or 0.2 mg/kg morphine IV (positive control) in a randomized balanced 5-way cross-over design. Blood samples were collected up to 72 hours post administration, codeine, codeine 6-glucuronide, norcodeine morphine, morphine 3-glucuronide and M6G concentrations determined by liquid chromatography- mass spectrometry and pharmacokinetic analysis performed. Pre- and post-drug related behavior, locomotor activity, heart rate and gastrointestinal borborygmi were recorded. Response to noxious stimuli was evaluated by determining thermal threshold latency.ResultsMorphine concentrations were highest in the morphine dose group at all times post administration, however, M6G concentrations were significantly higher in all the codeine dose groups compared to the morphine group starting at 1 hour post drug administration and up to 72-hours in the 1.2 mg/kg group. With the exception of one horse that exhibited signs of colic following administration of 0.3 and 0.6 mg/kg, codeine administration was well tolerated. Morphine administration, led to signs of agitation, tremors and excitation. There was not a significant effect on thermal nociception in any of the dose groups studied.ConclusionsThe current study describes the metabolic profile and pharmacokinetics of codeine in horses and provides information that can be utilized in the design of future studies to understand the anti-nociceptive and analgesic effects of opioids in this species with the goal of promoting judicious and safe use of this important class of drugs.

Effect of electrical stimulation of central nucleus of the amygdala on morphine conditioned place preference in male rats.

Objective(s):The central nucleus of the amygdala (CeA) is one of the most important areas for the morphine reward system. This study investigated the effect of electrical stimulation of CeA on morphine conditioned place preference (CPP) in male rats. Materials and Methods:After anesthetizing male Wistar rats, both electrode and cannula were implanted into CeA for stimulating (low intensity: 25 μA, and high intensity: 150 μA) and injecting (lidocaine and dopamine D2 receptor antagonist), respectively. Then, CPP induced by effective (5 mg/kg) and ineffective (0.5 mg/kg) doses of morphine was evaluated for five consecutive days (n = 6 / group).Results:The low electrical stimulation intensity of 25 μA suppressed both acquisition and expression phases, but the high intensity of 150 µA attenuated only the expression phase. On the other hand, intra-CeA administration of dopamine D2 receptor antagonist, eticlopride (2 µg/rat), with the effective dose of morphine, decreased CPP. In addition, infusion of lidocaine into the CeA inhibited morphine-induced CPP in both acquisition and expression phases with the effective dose of morphine.Conclusion:Electrical stimulation of the CeA may play an important role in attenuating morphine induced CPP via possible changes in neurotransmitters involved in the reward system such as dopamine (DA) and gamma-aminobutyric acid (GABA).

Feasibility study of morphine-induced rat pica model by tail vein injection to replace vomiting model

Objective： To explore the feasibility of the morphine-induced rat pica model by tail vein injection to replace the vomiting model，and the effective dose of morphine with less severe complications when the model was developed.Methods： Fifty SD rats were randomly divided into the blank control group and the M1，M2，M3 and M4 groups，each consisting of 10 animals. The rats in the blank control group were injected with 10 ml/kg normal saline（NS） via tail vein，while the animals in the M1，M2，M3 and M4 groups were injected with morphine hydrochloride injection at a dosage of 5，10，20 and 30 mg/kg via tail vein.Heart rate，blood oxygen saturation and activities of the animals were closely observed and recorded at 5，10 and 15 minutes after medication.Then，changes in the intake of kaolin，feed and water of the rats in each group were recorded and compared between the groups for 4 successive days after medication.Results： The blood oxygen saturation in the morphine treatment groups all reduced significantly，and statistical significance could be seen，when it was compared with that of the blank control group（P<0.05）.On the first day after medication，the intake of kaolin in the M3 and M4 groups increased significantly，as compared with that of the blank control group（P<0.05）.On the third day after medication，the intake of kaolin in the M1 group significantly increased，as compared with that of the blank control group（P<0.05）.Conclusion： The rat pica model was established by tail vein injection of morphine，which could be used to replace the vomiting model.The effective dose of morphine was 20 mg/kg with less severe complications.

Effects of Isoniazid on Tolerance and Sensitization to the Rewarding Properties of Morphine: A Conditioned Place Preference Procedure Investigation in Mice.

Introduction:The GABAergic system of the brain plays a key role in morphine tolerance and sensitization. As isoniazid is a modulator of the GABAergic system, the present study aims to understand whether isoniazid can influence the induction of tolerance and sensitization to the rewarding effects of morphine.Methods:The rewarding effects of morphine and isoniazid were assessed using a Conditioned Place Preference (CPP) procedure in female mice. Tolerance to the rewarding effects of morphine was induced with high-dose morphine (25 mg/kg, SC), twice a day, for four days. Also, the sensitization was induced with an effective dose of morphine (5 mg/kg, SC), once a day, for three days. During the induction of tolerance or sensitization, the different groups of mice received saline or isoniazid (25, 50, and 75 mg/kg, IP) one hour before each morphine injection.Results:Morphine (0.5–10 mg/kg, SC) produced a significant CPP, but isoniazid (25, 50, and 75 mg/kg, IP) did not induce place preference or place aversion in mice. Although an effective dose of morphine (5 mg/kg, SC) did not induce CPP in morphine tolerated mice, an ineffective dose (0.5 mg/kg, SC) could produce a significant CPP in morphine-sensitized animals. The administration of isoniazid before morphine (on the days of tolerance or sensitization induction) inhibited the development of tolerance or sensitization to the rewarding effect of morphine in the CPP paradigm.Conclusion:Isoniazid can be a useful drug for the prevention of tolerance and sensitization to the rewarding effects of morphine.

The dorsal hippocampal group III metabotropic glutamate receptors are involved in morphine effect on memory formation in male mice

This study investigated the role of dorsal hippocampal (CA1) group III metabotropic glutamate (mGlu) receptors in impairment of memory formation and state-dependent memory induced by morphine. For this purpose, the CA1 area was cannulated and one-trial passive avoidance task was selected to assess the memory function. Morphine was administrated subcutaneously (s.c.) and mGlu receptors agonist or antagonist were microinjected into CA1 regions. The obtained results indicated that pre-training administration of morphine (5 mg/kg; s.c.) decreased memory retention. Moreover, pre-test administration of morphine (5 mg/kg; s.c.) induced morphine state–dependent memory retention under pre-training morphine effect (5 mg/kg; s.c.). Although, intra-CA1 microinjection of lower doses of group III mGlu receptors agonist, L-AP4, (10 and 20 mmol/mouse) and antagonist, CPPG, (10 and 15 mmol/mouse) did not affect memory retention, but higher dose of the drugs (30 mmol/mouse) decreased memory retention. Pre-test microinjection of L-AP4 (10, 20 and 30 mmol/mouse; intra-CA1) had no effect on morphine-induced amnesia, but same doses of L-AP4 plus an effective dose of morphine (1 mg/kg; s.c.) reversed morphine-induced amnesia. Interestingly, amnesia induced by pre-training morphine (5 mg/kg; s.c.) was significantly reversed by pre-test administration of CPPG (30 mmol/mouse; intra-CA1). On the other hand, pre-test co-administration of CPPG (10 and 15 mmol/mouse; intra-CA1) and morphine (5 mg/kg; s.c.) following pre-training morphine (5 mg/kg; s.c.) decreased memory retention. Taken together, our results suggested that morphine effects on memory formation might be mediated via the activity of dorsal hippocampal metabotropic glutamate receptors.

The influence of electrical stimulation on dorsal raphe nucleus with different current intensities on morphine-induced conditioned place preference in male rats.

The dorsal raphe nucleus (DRN) influences a wide range of behavioral and physiological processes. The purpose of the present study was to test the effects of electrical stimulation of the DRN with different current intensities on morphine-induced conditioned place preference (CPP). Male Wistar rats were divided for experimental groups (n=7). Stimulating electrodes were stereotaxically implanted into the DRN in anesthetized rats. We investigated the influences of electrical stimulation of the DRN with different current intensities with ineffective and effective dose of morphine (0.5 and 2.5mg/kg, respectively) on morphine-induced CPP. Subcutaneous administration of morphine 2.5mg/kg produced significant CPP in comparison with saline group. The stimulation of the DRN with different current intensities (10, 25, 50 and 100μA) in combination with an effective dose of morphine did not show significant differences on acquisition phases, whereas there were significant decreases on expression phases versus to the morphine group on CPP only in current intensity 100μA. The stimulation of the DRN with different current intensities in combination with an ineffective dose of morphine showed significant increases in current intensities (50 and 100μA) on acquisition phases of CPP, but did not show significant differences on expression phases versus to the morphine group on CPP. It is possible that electrical stimulation of the DRN with changes in concentration of serotonin or involving other transmitters such as glutamate and GABA would be involved with these changes of CPP.

Persistent Pain Facilitates Response to Morphine Reward by Downregulation of Central Amygdala GABAergic Function

Opioid-based analgesics are widely used for treating chronic pain, but opioids are highly addictive when repeatedly used because of their strong rewarding effects. In recent years, abuse of prescription opioids has dramatically increased, including incidences of misuse of opioid drugs prescribed for pain control. Despite this issue in current clinical pain management, it remains unknown how pain influences the abuse liability of prescription opioids. Pain as aversive experience may affect opioid reward of positive emotion through common brain sites involved in emotion processing. In this study, on a rat model of chronic pain, we determined how persistent pain altered behavioral responses to morphine reward measured by the paradigm of unbiased conditioned place preference (CPP), focusing on GABAergic synaptic activity in neurons of the central nucleus of the amygdala (CeA), an important brain region for emotional processing of both pain and reward. We found that pain reduced the minimum number of morphine-conditioning sessions required for inducing CPP behavior. Both pain and morphine conditioning that elicited CPP inhibited GABA synaptic transmission in CeA neurons. Pharmacological activation of CeA GABAA receptors reduced the pain and inhibited CPP induced both by an effective dose of morphine and by a sub-threshold dose of morphine under pain condition. Furthermore, inhibition of CeA GABAA receptors mimicked the pain effect, rendering the sub-threshold dose of morphine effective in CPP induction. These findings suggest that pain facilitates behavioral responses to morphine reward by predisposing the inhibitory GABA function in the CeA circuitry involved in the behavior of opioid reward.

Effect of electrical stimulation of nucleus accumbens with low, median and high currents intensities on conditioned place preference induced by morphine in rats.

Background:Some investigators indicated the effect of electrical or chemical stimulation on different parts of the brain and its effect on animal's behaviors. Furthermore, drug addiction is known to be associated with dysfunction of memory and motivational systems. In this study, we aimed to evaluate the effect of electrical stimulation of nucleus accumbens (NAc) with different currents intensities on conditioned place preference (CPP) induced by morphine.Materials and Methods:Male Wistar rats were randomly divided for experimental groups (n = 8). We investigated the influence of electrical stimulation with different current intensities (low: 15 μA, median: 50 μA and high: 100 μA) on NAc with ineffective and effective dose of morphine (0.5 and 5 mg/kg, respectively) on acquisition and expression of morphine-induced place conditioning in male rats.Results:The doses of subcutaneous administration morphine (2.5 and 5 mg/kg, P < 0.05 and P < 0.001; respectively) induced CPP compared with saline group. Furthermore, our findings are showed that electrical stimulation (100 μA) of NAc suppressed morphine-induced CPP. It revealed impairment of learning and memory formation in conditioning process due to morphine administration.Conclusion:It is possible that high current intensity (100 μA) had an accompanied effect by a reversal of the increased tissue contents of dopamine and its metabolites in the NAc of morphine-induced CPP rats. Furthermore, high current intensity in combination with ineffective dose of morphine (0.5 mg/kg) increased morphine-induced CPP probability via the prove reward system.

Involvement of opioidergic and nitrergic systems in memory acquisition and exploratory behaviors in cholestatic mice

Bile duct ligation (BDL) is an animal model used in cholestatic disease research. Both opioidergic and nitrergic systems are known to be involved in cholestasis. The aim of this study was to investigate the possible interaction between these two systems in BDL-induced memory formation and exploratory behaviors in mice. Male mice weighing 25-30 g were divided into nonoperated controls, sham-operated, and BDL groups. One-trial step-down and hole-board paradigms were used to assess memory acquisition and exploratory behaviors, respectively. Cholestasis did not alter memory acquisition while increasing exploratory behaviors 7 days after BDL. A pretraining intraperitoneal injection of L-arginine (50, 100, and 200 mg/kg), L-NG-nitroarginine methyl ester (L-NAME) (5, 10, 20, and 40 mg/kg), or naloxone (0.125, 0.25, and 0.5 mg/kg) did not alter memory acquisition or exploratory behaviors, whereas morphine (5 and 7.5 mg/kg) decreased memory acquisition in sham-operated animals. Moreover, although injection of L-NAME and naloxone exerted no effect on memory acquisition in the 7 days post-BDL mice, L-arginine (100 and 200 mg/kg) and morphine (2.5, 5, and 7.5 mg/kg) injection reduced it. In contrast, L-NAME and naloxone, but not morphine or L-arginine, reduced the BDL-induced exploratory behaviors. Coadministration of subthreshold doses of morphine (1.25 mg/kg) and L-arginine (50 mg/kg) caused a memory deficit in 7 days post-BDL mice. However, the memory deficit induced by the effective doses of morphine (2.5 mg/kg) or L-arginine (200 mg/kg) in these mice was restored by the administration of either naloxone (0.5 mg/kg) or L-NAME (40 mg/kg). In addition, naloxone and L-NAME reduced the exploratory behaviors in L-arginine-pretreated mice but not in morphine-pretreated mice. We conclude that there appears to be a synergistic effect between opioidergic and nitrergic systems on memory acquisition and exploratory behaviors in cholestatic mice.

Different current intensities electrical stimulation of prelimbic cortex of mPFC produces different effects on morphine-induced conditioned place preference in rats

The medial prefrontal cortex (mPFC) is a part of brain reward system involved in higher cognitive functions such as learning and memory. The mPFC receives strong dopaminergic innervations from ventral tegmental area (VTA) that comprises a portion of the mesolimbic dopaminergic system (MLDS), and in turn sends glutamate projection to both the VTA and nucleus accumbens (NAc). In the present study, we investigated the influence of electrical stimulation with different current intensities on prelimbic cortex (PL, subdivision of mPFC) (25, 50, 100, and 150μA) with and without an effective dose of morphine (0.5 and 5mg/kg) on CPP during conditioning and post-conditioning phases. Subcutaneous administration of morphine 5mg/kg produced significant CPP in comparison with saline group. Our findings also showed that electrical stimulation of PL (100μA) suppressed morphine-induced CPP that reveals impaired learning and memory formation in the process of conditioning through the blocking connection from the hippocampus to the prelimbic cortex of mPFC. A lowest current intensity (25μA) in combination with ineffective dose of morphine (0.5mg/kg) increased morphine-induced CPP probability via the prove reward system.

Time of Admission, Gender and Age: Challenging Factors in Emergency Renal Colic - A Preliminary Study

BackgroundNephrolithiasis is a relatively common problem and a frequent Emergency Department (ED) diagnosis in patients who present with acute flank/abdominal pain. The pain management in these patients is often challenging.ObjectivesTo investigate the most effective dose of morphine with the least side effects in emergency renal colic patients.Materials and Methods150 renal colic patients who experienced a pain level of 4 or greater, based on visual analog scale (VAS) at admission time were included. Pain was scored on a 100 mm VAS (0 = no pain, 100 = the worst pain imagined). When patients arrived at ED, a physician would examine the patients and assessed initial pain score, then filled a questionnaire according to the patient information. Patients were assigned to receive 2.5 mg morphine sulfate intravenously. We monitored patients’ visual analog scale (VAS), and adverse events at different time points (every 15 minutes) for 90 minutes. Additional doses of intravenous morphine (2.5 mg) were administered if the patient still had pain. (Max dose: 10 mg). The cumulative dose of morphine, defined as the total amount of morphine prescribed to each patient during the 90 minutes of the study, was recorded. Patients were not permitted to use any nonsteroidal anti-inflammatory drugs as coadjuvant analgesics during the study period. Subjects with inadequate pain relief at 90 minutes received rescue morphine and were excluded from the study. The primary end point in this study was pain relief at 90 minutes, defined as either VAS<40 or decrease of 50% or more as compared to the initial VAS. The secondary objective was to detect the occurrence of adverse effects at any time points in ED.ResultsThe studied patients consisted of 104 men and 46 women with the mean age of 43 ±14 years (range, 18 to 75 years). There was no statistically significant difference between the mean age and gender differences in pain response. Rescue analgesia at 30 minutes were given in 54.5% receiving morphine. The average time to painless was 35 minutes. But there were no statistically significant differences between the mean age and gender differences in pain response (P > 0.05). Older patients responded sooner to morphine than the young. Most of the patients had a pain score of 90 -100 (77.3 %) at the beginning that was reduced to 29.4% during the 30 minutes follow up. During the first hour, we found that 94.7% of the patients had no pain or significant pain reduction and only 2.1% of the patients still had pain.ConclusionsWe conclude that there were no significant differences among the gender, time of admission and side - effects in renal colic patients in response to morphine.

Electrolytic lesion of the nucleus raphe magnus reduced the antinociceptive effects of bilateral morphine microinjected into the nucleus cuneiformis in rats

Several lines of investigation show that the rostral ventromedial medulla is a critical relay for midbrain regions, including the nucleus cuneiformis (CnF), which control nociception at the spinal cord. There is some evidence that local stimulation or morphine administration into the CnF produces the effective analgesia through the nucleus raphe magnus (NRM). The present study tries to determine the effect of morphine-induced analgesia following microinjection into the CnF in the absence of NRM. Seven days after the cannulae implantation, morphine was microinjected bilaterally into the CnF at the doses of 0.25, 1, 2.5, 5, 7.5 and 10 microg/0.3 microl saline per side. The morphine-induced antinociceptive effect measured by tail-flick test at 30, 60, 90 and 120 min after microinjection. The results showed that bilateral microinjection of morphine into the CnF dose-dependently causes increase in tail-flick latency (TFL). The 50% effective dose of morphine was determined and microinjected into the CnF (2.5 microg/0.3 microl saline per side) in rats after NRM electrolytic lesion (1 mA, 30 s). Lesion of the NRM significantly decreased TFLs, 30 (P<0.01) and 60 (P<0.05) but not 90-120 min after morphine microinjection into the CnF, compared with sham-lesion group. We concluded that morphine induces the analgesic effects through the opioid receptors in the CnF. It is also appeared that morphine-induced antinociception decreases following the NRM lesion but it seems that there are some other descending pain modulatory pathways that activate in the absence of NRM.

The interaction of morphine and selective serotonin reuptake inhibitors on mechanical allodynia in rats with a spinal nerve ligation

Nerve injury may produce a tactile allodynia. However, there are few reports regarding the interaction of morphine and selective serotonin reuptake inhibitors (SSRIs) during a neuropathic pain state. Therefore, we investigated the antiallodynic interaction between morphine and SSRIs in a rat model of neuropathic pain. Methods: Rats were prepared with a tight ligation of the left fifth and sixth lumbar spinal nerves and chronic intrathecal catheter implantation. Mechanical allodynia was then measured by application of von Frey filaments. Morphine, citalopram and paroxetine were administered intrathecally to obtain the dose-response curves. The 50% effective dose of morphine and citalopram or paroxetine were then coadministered to evaluate the drug interaction. In addition, naloxone and methysergide were administered to examine the reversal of the antiallodynic effect. Results: Intrathecal morphine produced a dose-dependent antagonism of the tactile allodynia, but intrathecal citalopram or paroxetine showed no antiallodynic effects. In addition, a morphine-citalopram or paroxetine combination produced an increase in the withdrawal threshold, but naloxone and methysergide reversed the antiallodynic effect. In addition, no interactions were observed between naloxone and citalopram or paroxetine, or morphine and methysergide. Conclusions: These results suggest that activation of both μ-opioid and serotonin receptors is required for the increased interaction to occur between morphine and SSRIs administered to reduce tactile allodynia. Thus, serotonin receptors take part in the antiallodynic action of morphine at the spinal level.

Activation of central opioid receptors determines the timing of hypotension during acute hemorrhage-induced hypovolemia in conscious sheep

After an initial compensatory phase, hemorrhage reduces blood pressure due to a widespread reduction of sympathetic nerve activity (decompensatory phase). Here, we investigate the influence of intracerebroventricular naloxone (opioid-receptor antagonist) and morphine (opioid-receptor agonist) on the two phases of hemorrhage, central and peripheral hemodynamics, and release of vasopressin and renin in chronically instrumented conscious sheep. Adult ewes were bled (0.7 ml x kg(-1) x min(-1)) from a jugular vein until mean arterial blood pressure (MAP) reached 50 mmHg. Starting 30 min before and continuing until 60 min after hemorrhage, either artificial cerebrospinal fluid (aCSF), naloxone, or morphine was infused intracerebroventricularly. Naloxone (200 microg/min but not 20 or 2.0 microg/min) significantly increased the hemorrhage volume compared with aCSF (19.5 +/- 3.2 vs. 13.9 +/- 1.1 ml/kg). Naloxone also increased heart rate and cardiac index. Morphine (2.0 microg/min) increased femoral blood flow and decreased hemorrhage volume needed to reduce MAP to 50 mmHg (8.9 +/- 1.5 vs. 13.9 +/- 1.1 ml/kg). The effects of morphine were abolished by naloxone at 20 microg/min. It is concluded that the commencement of the decompensatory phase of hemorrhage in conscious sheep involves endogenous activation of central opioid receptors. The effective dose of morphine most likely activated mu-opioid receptors, but they appear not to have been responsible for initiating decompensation as 1) naloxone only inhibited an endogenous mechanism at a dose much higher than the effective dose of morphine, and 2) the effects of morphine were blocked by a dose of naloxone, which, by itself, did not delay the decompensatory phase.

Intraoperative and postoperative analgesic efficacy and adverse effects of intrathecal opioids in patients undergoing cesarean section with spinal anesthesia: a qualitative and quantitative systematic review of randomized controlled trials.

SPINAL anesthesia is commonly used for cesarean section, and it has become a popular practice to add opioids to spinal solutions to enhance and prolong intraoperative and postoperative analgesia. Morphine and fentanyl are the opioids most often used for this purpose, but there is not a general consensus about the benefits of the various regimens, and the incidence of side effects with different opioids and doses is controversial. Recently, a number of systematic reviews have been published in the field of pain and perioperative medicine. The aim of a systematic review is to summarize available information from controlled clinical trials to produce evidence-based estimates of the true clinical effect of an intervention. The purpose of this systematic review was to investigate the effect of intrathecal opioids added to spinal anesthesia on intraoperative and postoperative pain and to evaluate adverse effects in patients scheduled for cesarean section, using evidence from all relevant randomized controlled and blinded trials.

Differential effects of morphine and clonidine on visceral and cutaneous spinal nociceptive transmission in the rat

1. The effect of morphine or clonidine administered systemically on visceral and cutaneous spinal nociceptive transmission was examined in 45 dorsal horn neurons in spinalized, decerebrate rats: 17 "cutaneous" dorsal horn neurons located in the L3-L5 spinal segments were excited by heating the glabrous skin of the hindpaw (48 degrees C, 15 s) and 28 "visceral" dorsal horn neurons located in the T13-L2 spinal segments were excited by colorectal distension (80 mmHg, 20 s). The 28 visceral dorsal horn neurons were subclassified as 18 short-latency abrupt neurons (SL-A), which were excited by colorectal distension at short latency (less than 1 s) and whose activity abruptly returned to base line following termination of the distending stimulus, and as 10 short-latency-sustained (SL-S) neurons, which also were excited at short latency (less than 1 s) by colorectal distension, but whose activity was sustained above base line for 4-31 s following termination of the distending stimulus. 2. Morphine produced a dose-dependent, naloxone-reversible inhibition of both spontaneous activity and/or neuronal responses during heating or colorectal distension of 8 SL-A, 7 SL-S, and 11 cutaneous dorsal horn neurons. Comparison of the effective doses of morphine to produce a 50% reduction in the response of the neurons (ED50s) during colorectal distension or heating demonstrated that, at the intensities of distension and heating employed, SL-S neurons were affected at the least dosage (ED50 = 0.46 mumol/kg), followed by SL-A neurons (ED50 = 1.95 mumol/kg) and cutaneous neurons (ED50 = 6.12 mumol/kg). Effects on spontaneous activity were variable: at low doses morphine produced an increase in the spontaneous activity of 2 SL-A and 5 cutaneous neurons; greater doses (up to 42 mumol/kg) inhibited in all of the SL-A and SL-S neurons, but not three cutaneous neurons studied. With the exclusion of these three neurons, the ED50s for inhibition of spontaneous activity were comparable to the ED50s for inhibition of neuronal responses during colorectal distension or heating of the hindpaw in all three neuronal groups. 3. Clonidine produced a dose-dependent, yohimbine- or phentolamine-reversible inhibition of both spontaneous activity and neuronal responses during heating or colorectal distension of 10 SL-A, 3 SL-S, and 6 cutaneous dorsal horn neurons.(ABSTRACT TRUNCATED AT 400 WORDS)

Effect of propranolol on antinociceptive, tolerance- and dependence-producing properties of morphine in rodents and monkeys

Since an abstinence syndrome may accompony the injection of opioids in addicts pretreated with propranolol the morphine antagonistic properties of this compound were investigated. Racemic propranolol did not significantly affect the antinociceptive ED 50 of morphine in rodents and neither precipitated abstinence in morphine-dependent monkeys nor exacerbated the syndrome in 24 hr withdrawn monkeys. Multiple doses of propranolol did not alter the development of physical dependence on morphine in monkeys. Clinical narcotic antagonism would not be predicted from this profile. Evidence for a possible propranolol-morphine interaction came from studies using the mouse tail flick test. Thus, after 8 injections of propranolol (over 4 days) mice were tolerant to normally effective doses of morphine. Concurrent injections of naloxone antagonised this effect. When propranolol and morphine were administered concurrently the morphine ED 50 (on day 5) was twice that of the group receiving morphine alone. Similar results were obtained with d-propranolol; practolol had a neutral effect.