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Journal articles on the topic 'Morphine'

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Author: Grafiati

Published: 4 June 2021

Last updated: 30 July 2024

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1

Ninkovic, Jana, and Sabita Roy. "Chronic morphine modulates actin polymerization leading to inhibition of Fc-gamma receptor mediated phagocytosis (111.29)." Journal of Immunology 186, no. 1_Supplement (April 1, 2011): 111.29. http://dx.doi.org/10.4049/jimmunol.186.supp.111.29.

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Abstract Morphine has been known to modulate innate immune functions, by inhibiting macrophage phagocytosis. However, mechanisms by which morphine inhibits macrophage phagocytic ability remain to be explained. Our results indicate that chronic morphine treatment in vitro and in vivo inhibited Fcγ receptor mediated phagocytosis in murine macrophages by inhibiting actin polymerization. Using fluorescence microscopy and fluorometry, we showed that chronic morphine treatment led to inhibition of actin polymerization resulting in impaired internalization of opsonized dextran beads. Chronic morphine treatment inhibited activation of Rac1-GTPase, therefore inhibiting formation of lamellipodia and membrane ruffling. Morphine’s inhibition of Rac1-GTPase activation was abolished in J774 macrophages transfected with constitutively active Rac1. In addition, chronic morphine treatment led to an increase in intracellular cAMP, which resulted in inhibition of actin polymerization through a PKA dependant pathway. DB-cAMP, by increasing intracellular cAMP, led to suppression of actin polymerization while H89 treatment induced inhibition of PKA and abolished morphine’s inhibitory effect implicating cAMP as the key effector in morphine’s modulation of actin. Together these data indicate that chronic morphine by increasing cAMP, activating PKA which inhibits Rac1 GTP-ase, leads to inhibition of actin polymerization and phagocytosis.

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2

Bouaziz, Herve, Chuanyao Tong, Young Yoon, David D. Hood, and James C. Eisenach. "Intravenous Opioids Stimulate Norepinephrine and Acetylcholine Release in Spinal Cord Dorsal Horn." Anesthesiology 84, no. 1 (January 1, 1996): 143–54. http://dx.doi.org/10.1097/00000542-199601000-00017.

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Background Opioids produce analgesia by direct effects as well as by activating neural pathways that release nonopioid transmitters. This study tested whether systematically administered opioids activate descending spinal noradrenergic and cholinergic pathways. Methods The effect of intravenous morphine on cerebrospinal fluid and dorsal horn microdialysate concentrations of norepinephrine and acetylcholine was examined in 20 sheep. Animals received either intravenous morphine or fentanyl alone, or morphine plus intravenous naloxone or intrathecal idazoxan. Results Intravenous morphine (0, 0.5, 1 mg/kg, intravenous) produced dose-dependent increases in cerebrospinal fluid norepinephrine and acetylcholine, but not epinephrine or dopamine. Morphine's effect was blocked by intravenous naloxone and by intrathecal idazoxan. In microdialysis experiments, intravenous morphine increased the concentration of norepinephrine and acetylcholine, but not epinephrine or dopamine, in the dorsal horn. In contrast, intravenous morphine exerted no effect on any of these monoamines in the ventral horn. Intravenous naloxone and cervical cord transection each blocked morphine's effect on dorsal horn norepinephrine. Conclusions These results support functional studies that indicate that systematically administered opioids cause spinal norepinephrine and acetylcholine release by a naloxone-sensitive mechanism. Idazoxan blockade of morphine's effects on cerebrospinal fluid norepinephrine was unexpected, and suggests that both norepinephrine and acetylcholine release in the spinal cord may be regulated by alpha 2-adrenoceptors. Microdialysis experiments suggest increased norepinephrine and acetylcholine levels in cerebrospinal fluid resulted from intravenous morphine-induced activation of bulbospinal pathways.

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3

Møllendal, Harald, David Balcells, Odile Eisenstein, Linda Syversen, and Michal Rachel Suissa. "Conformational complexity of morphine and morphinum in the gas phase and in water. A DFT and MP2 study." RSC Adv. 4, no. 47 (2014): 24729–35. http://dx.doi.org/10.1039/c4ra02992e.

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4

Zhang, Li, Jingjing Meng, Yuguang Ban, Richa Jalodia, Irina Chupikova, Irina Fernandez, Nivis Brito, et al. "Morphine tolerance is attenuated in germfree mice and reversed by probiotics, implicating the role of gut microbiome." Proceedings of the National Academy of Sciences 116, no. 27 (June 17, 2019): 13523–32. http://dx.doi.org/10.1073/pnas.1901182116.

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Prolonged exposure to opioids results in analgesic tolerance, drug overdose, and death. The mechanism underlying morphine analgesic tolerance still remains unresolved. We show that morphine analgesic tolerance was significantly attenuated in germfree (GF) and in pan-antibiotic−treated mice. Reconstitution of GF mice with naïve fecal microbiota reinstated morphine analgesic tolerance. We further demonstrated that tolerance was associated with microbial dysbiosis with selective depletion in Bifidobacteria and Lactobacillaeae. Probiotics, enriched with these bacterial communities, attenuated analgesic tolerance in morphine-treated mice. These results suggest that probiotic therapy during morphine administration may be a promising, safe, and inexpensive treatment to prolong morphine’s efficacy and attenuate analgesic tolerance. We hypothesize a vicious cycle of chronic morphine tolerance: morphine-induced gut dysbiosis leads to gut barrier disruption and bacterial translocation, initiating local gut inflammation through TLR2/4 activation, resulting in the activation of proinflammatory cytokines, which drives morphine tolerance.

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Bimonte, Sabrina, Antonio Barbieri, Domenica Rea, Giuseppe Palma, Antonio Luciano, Arturo Cuomo, Claudio Arra, and Francesco Izzo. "Morphine Promotes Tumor Angiogenesis and Increases Breast Cancer Progression." BioMed Research International 2015 (2015): 1–8. http://dx.doi.org/10.1155/2015/161508.

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Morphine is considered a highly potent analgesic agent used to relieve suffering of patients with cancer. Severalin vitroandin vivostudies showed that morphine also modulates angiogenesis and regulates tumour cell growth. Unfortunately, the results obtained by these studies are still contradictory. In order to better dissect the role of morphine in cancer cell growth and angiogenesis we performedin vitrostudies on ER-negative human breast carcinoma cells, MDA.MB231 andin vivostudies on heterotopic mouse model of human triple negative breast cancer, TNBC. We demonstrated that morphinein vitroenhanced the proliferation and inhibited the apoptosis of MDA.MB231 cells.In vivostudies performed on xenograft mouse model of TNBC revealed that tumours of mice treated with morphine were larger than those observed in other groups. Moreover, morphine was able to enhance the neoangiogenesis. Our data showed that morphine at clinical relevant doses promotes angiogenesis and increases breast cancer progression.

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6

Bosshart, MD, Herbert. "Morphine and cancer progression: Hydrogen peroxide points to need for more research." Journal of Opioid Management 7, no. 2 (January 15, 2018): 93–96. http://dx.doi.org/10.5055/jom.2011.0051.

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Background: Morphine is widely used in the management of intractable cancer pain. However, conflicting views exist on two suspected nonanalgesic properties of morphine: suppression of immune function and inhibition of cancer progression.Methods: In vitro measurement of the tumor growth-inhibiting signaling molecule, hydrogen peroxide (H2O2), released from the cultured acute monocytic leukemia cell line, THP-1, in the presence or absence of morphine.Results: Morphine at concentrations of 10−8 M significantly reduced H2O2 release from THP-1 cells.Conclusions: These results provide a proof of concept for morphine’s ability to inhibit H2O2 production and release in a leukemia cell system and point to a possible and as yet unrecognized tumor-promoting effect of morphine. More research is needed to systematically examine this suspected morphine-associated tumor-promoting effect.

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7

Bruce, N. C., C. J. Wilmot, K. N. Jordan, L. D. G. Stephens, and C. R. Lowe. "Microbial degradation of the morphine alkaloids. Purification and characterization of morphine dehydrogenase from Pseudomonas putida M10." Biochemical Journal 274, no. 3 (March 15, 1991): 875–80. http://dx.doi.org/10.1042/bj2740875.

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The NADP(+)-dependent morphine dehydrogenase that catalyses the oxidation of morphine to morphinone was detected in glucose-grown cells of Pseudomonas putida M10. A rapid and reliable purification procedure involving two consecutive affinity chromatography steps on immobilized dyes was developed for purifying the enzyme 1216-fold to electrophoretic homogeneity from P. putida M10. Morphine dehydrogenase was found to be a monomer of Mr 32,000 and highly specific with regard to substrates, oxidizing only the C-6 hydroxy group of morphine and codeine. The pH optimum of morphine dehydrogenase was 9.5, and at pH 6.5 in the presence of NADPH the enzyme catalyses the reduction of codeinone to codeine. The Km values for morphine and codeine were 0.46 mM and 0.044 mM respectively. The enzyme was inhibited by thiol-blocking reagents and the metal-complexing reagents 1,10-phenanthroline and 2,2′-dipyridyl, suggesting that a metal centre may be necessary for activity of the enzyme.

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8

Tai, Yueh-Hua, Ru-Yin Tsai, Shinn-Long Lin, Chun-Chang Yeh, Jhi-Joung Wang, Pao-Luh Tao, and Chih-Shung Wong. "Amitriptyline Suppresses Neuroinflammation-dependent Interleukin-10-p38 Mitogen-activated Protein Kinase-Heme Oxygenase-1 Signaling Pathway in Chronic Morphine-infused Rats." Anesthesiology 110, no. 6 (June 1, 2009): 1379–89. http://dx.doi.org/10.1097/aln.0b013e31819fccd5.

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Background This study explores the underlying mechanism of the antiinflammatory effect of amitriptyline in chronic morphine-infused rats. Methods Male Wistar rats were implanted with two intrathecal catheters. One catheter was for the continuous infusion of saline, amitriptyline (15 microg/h), morphine (15 microg/h), p38 mitogen-activated protein kinase inhibitor SB203580 (0.5 microg/h), morphine plus amitriptyline, or morphine plus amitriptyline plus SB203580 for 5 days. The other catheter was used for daily intrathecal injection of anti-interleukin-10 (IL-10) antibody or heme oxygenase-1 inhibitor zinc protoporphyrin for 5 days. Results Amitriptyline/morphine coinfusion upregulated IL-10 protein expression in microglia; this was not observed in morphine-infused rats. Anti-IL-10 antibody effectively neutralized the amitriptyline-induced IL-10 expression in chronic morphine-infused rats. In addition, coinfusion of amitriptyline restored the antinociceptive effect of morphine (a 4.8-fold right-shift of the morphine dose-response curve compared to a 77.8-fold right-shift in its absence), and the injection of anti-IL-10 antibody or coinfusion of SB203580 partially reversed the effect of amitriptyline on the antinociceptive effect of morphine in morphine-infused rats (a 17.9-fold and 15.1-fold right-shift in morphine dose-response curves). Anti-IL-10 antibody and SB203580 significantly inhibited the amitriptyline-induced p38 mitogen-activated protein kinase and heme oxygenase-1 expression and the associated antiinflammatory effect of amitriptyline. Daily injection of zinc protoporphyrin also demonstrated that it reverses the effect of amitriptyline in morphine's antinociception and antiinflammation in chronic morphine-infused rats. Conclusions These results suggest that the antiinflammatory effect of amitriptyline on morphine tolerance, probably acting by increasing IL-10 expression, is mediated by p38 mitogen-activated protein kinase heme oxygenase-1 signal transduction cascade.

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Kutchy, Naseer A., Amelia Palermo, Rong Ma, Zhong Li, Alexandria Ulanov, Shannon Callen, Gary Siuzdak, Sabita Roy, Shilpa Buch, and Guoku Hu. "Changes in Plasma Metabolic Signature upon Acute and Chronic Morphine Administration in Morphine-Tolerant Mice." Metabolites 13, no. 3 (March 16, 2023): 434. http://dx.doi.org/10.3390/metabo13030434.

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Morphine administration causes system-level metabolic changes. Here, we show that morphine-tolerant mice exhibited distinct plasma metabolic signatures upon acute and chronic administration. We utilized a mouse model of morphine tolerance by exposing mice to increasing doses of the drug over 4 days. We collected plasma samples from mice undergoing acute or chronic morphine or saline injections and analyzed them using targeted GC–MS-based metabolomics to profile approximately 80 metabolites involved in the central carbon, amino acid, nucleotide, and lipid metabolism. Our findings reveal distinct alterations in plasma metabolite concentrations in response to acute or chronic morphine intake, and these changes were linked to the development of tolerance to morphine’s analgesic effects. We identified several metabolites that had been differentially affected by acute versus chronic morphine use, suggesting that metabolic changes may be mitigated by prolonged exposure to the drug. Morphine-tolerant mice showed a restoration of amino acid and glycolytic metabolites. Additionally, we conducted reconstructed metabolic network analysis on the first 30 VIP-ranked metabolites from the PLSDA of the saline, acute, and morphine-tolerant mice groups, which uncovered four interaction networks involving the amino acid metabolism, the TCA cycle, the glutamine-phenylalanine-tyrosine pathway, and glycolysis. These pathways were responsible for the metabolic differences observed following distinct morphine administration regimens. Overall, this study provides a valuable resource for future investigations into the role of metabolites in morphine-induced analgesia and associated effects following acute or chronic use in mice.

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Fecho, K., K. A. Maslonek, M. E. Coussons-Read, L. A. Dykstra, and D. T. Lysle. "Macrophage-derived nitric oxide is involved in the depressed concanavalin A responsiveness of splenic lymphocytes from rats administered morphine in vivo." Journal of Immunology 152, no. 12 (June 15, 1994): 5845–52. http://dx.doi.org/10.4049/jimmunol.152.12.5845.

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Abstract The present study examined the role of macrophage-derived nitric oxide in the suppressive effect of in vivo morphine administration on Con A-stimulated proliferation of splenic lymphocytes in rats. The results showed that concentrations of nitrite are significantly greater in Con A-stimulated splenocyte cultures from morphine-treated rats than in cultures from saline-treated rats, and that the depletion of macrophages from splenocyte cultures abolishes the suppressive effect of morphine on Con A-stimulated proliferation. Moreover, the addition of NG-monomethyl-L-arginine (NMMA) to Con A-stimulated splenocyte cultures attenuates the suppressive effect of morphine on mitogenic responsiveness. The addition of excess L-arginine to splenocyte cultures containing NMMA reverses the effect of NMMA and restores morphine's suppressive effect on Con A-stimulated proliferation, but the addition of D-arginine to splenocyte cultures containing NMMA does not restore the suppressive effect of morphine. Taken together, these findings demonstrate that the suppressive effect of in vivo morphine administration on Con A-stimulated proliferation of splenic lymphocytes involves macrophage-derived nitric oxide.

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11

Song, Ho-Kyung, Hui-Lin Pan, and James C. Eisenach. "Spinal Nitric Oxide Mediates Antinociception from Intravenous Morphine." Anesthesiology 89, no. 1 (July 1, 1998): 215–21. http://dx.doi.org/10.1097/00000542-199807000-00028.

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Introduction Spinal nitric oxide (NO) is thought in many circumstances to play a pronociceptive role, because spinal injection of NO synthase inhibitors block hypersensitivity after nerve injury and enhance antinociception from spinal opioids. Conversely, intravenous injection of morphine has been demonstrated to activate descending noradrenergic pathways and to increase spinal synthesis of NO. This study examined the role of spinal NO in antinociception produced by intravenously administered morphine. Methods Polyethylene catheters were inserted with tips in the lumbar intrathecal space and in a jugular vein in male rats. Antinociception in response to intravenous injection of morphine was determined by latency to withdrawal of the hind paw from a heat source. Animals received an intrathecal injection of saline, an alpha2-adrenergic antagonist (idazoxan), a muscarinic antagonist (atropine), two NO synthase inhibitors, or an NO scavenger after intravenously administered morphine. Results Intravenously administered morphine produced dose-dependent antinociception, which was stable for 45 min and unaffected by intrathecally administered saline or atropine injection. In contrast, idazoxan, each of the NO synthase inhibitors, and the NO scavenger produced dose-dependent attenuation of intravenously administered morphine-induced antinociception. Discussion These results confirm a spinal alpha2-adrenergic mechanism of antinociception from intravenously administered morphine, consistent with morphine's activation of descending noradrenergic pathways. Further, these data suggest that spinal NO mediates antinociception produced by intravenous morphine.

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12

Yu, Yinghao, Alan Bohan He, Michelle Liou, Chenyin Ou, Anna Kozłowska, Pingwen Chen, and Andrew Chihwei Huang. "The Paradoxical Effect Hypothesis of Abused Drugs in a Rat Model of Chronic Morphine Administration." Journal of Clinical Medicine 10, no. 15 (July 21, 2021): 3197. http://dx.doi.org/10.3390/jcm10153197.

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A growing body of studies has recently shown that abused drugs could simultaneously induce the paradoxical effect in reward and aversion to influence drug addiction. However, whether morphine induces reward and aversion, and which neural substrates are involved in morphine’s reward and aversion remains unclear. The present study first examined which doses of morphine can simultaneously produce reward in conditioned place preference (CPP) and aversion in conditioned taste aversion (CTA) in rats. Furthermore, the aversive dose of morphine was determined. Moreover, using the aversive dose of 10 mg/kg morphine tested plasma corticosterone (CORT) levels and examined which neural substrates were involved in the aversive morphine-induced CTA on conditioning, extinction, and reinstatement. Further, we analyzed c-Fos and p-ERK expression to demonstrate the paradoxical effect—reward and aversion and nonhomeostasis or disturbance by morphine-induced CTA. The results showed that a dose of more than 20 mg/kg morphine simultaneously induced reward in CPP and aversion in CTA. A dose of 10 mg/kg morphine only induced the aversive CTA, and it produced higher plasma CORT levels in conditioning and reacquisition but not extinction. High plasma CORT secretions by 10 mg/kg morphine-induced CTA most likely resulted from stress-related aversion but were not a rewarding property of morphine. For assessments of c-Fos and p-ERK expression, the cingulate cortex 1 (Cg1), prelimbic cortex (PrL), infralimbic cortex (IL), basolateral amygdala (BLA), nucleus accumbens (NAc), and dentate gyrus (DG) were involved in the morphine-induced CTA, and resulted from the aversive effect of morphine on conditioning and reinstatement. The c-Fos data showed fewer neural substrates (e.g., PrL, IL, and LH) on extinction to be hyperactive. In the context of previous drug addiction data, the evidence suggests that morphine injections may induce hyperactivity in many neural substrates, which mediate reward and/or aversion due to disturbance and nonhomeostasis in the brain. The results support the paradoxical effect hypothesis of abused drugs. Insight from the findings could be used in the clinical treatment of drug addiction.

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Chen, Ing-Jung, Chih-Ping Yang, Sheng-Hsiung Lin, Chang-Mei Lai, and Chih-Shung Wong. "The Circadian Hormone Melatonin Inhibits Morphine-Induced Tolerance and Inflammation via the Activation of Antioxidative Enzymes." Antioxidants 9, no. 9 (August 22, 2020): 780. http://dx.doi.org/10.3390/antiox9090780.

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Opioids are commonly prescribed for clinical pain management; however, dose-escalation, tolerance, dependence, and addiction limit their usability for long-term chronic pain. The associated poor sleep pattern alters the circadian neurobiology, and further compromises the pain management. Here, we aim to determine the correlation between constant light exposure and morphine tolerance and explore the potential of melatonin as an adjuvant of morphine for neuropathic pain treatment. Methods: Wistar rats were preconditioned under constant light (LL) or a regular light/dark (LD) cycle before neuropathic pain induction by chronic constriction injury. An intrathecal (i.t.) osmotic pump was used for continued drug delivery to induce morphine tolerance. Pain assessments, including the plantar test, static weight-bearing symmetry, and tail-flick latency, were used to determine the impact of the light disruption or exogenous melatonin on the morphine tolerance progression. Results: constant light exposure significantly aggravates morphine tolerance in neuropathic rats. Continued infusion of low-dose melatonin (3 μg/h) attenuated morphine tolerance in both neuropathic and naïve rats. This protective effect was independent of melatonin receptors, as shown by the neutral effect of melatonin receptors inhibitors. The transcriptional profiling demonstrated a significant enhancement of proinflammatory and pain-related receptor genes in morphine-tolerant rats. In contrast, this transcriptional pattern was abolished by melatonin coinfusion along with the upregulation of the Kcnip3 gene. Moreover, melatonin increased the antioxidative enzymes SOD2, HO-1, and GPx1 in the spinal cord of morphine-tolerant rats. Conclusion: Dysregulated circadian light exposure significantly compromises the efficacy of morphine’s antinociceptive effect, while the cotreatment with melatonin attenuates morphine tolerance/hyperalgesia development. Our results suggest the potential of melatonin as an adjuvant of morphine in clinical pain management, particularly in patients who need long-term opioid treatment.

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Canonico, Dalton, Sadie Casale, Tristan Look, and Ling Cao. "Effects of Morphine on Behavioral and CNS Inflammatory Responses in GP120 Mice Under Immunocompetent vs. Immunodeficient Conditions." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 225.13. http://dx.doi.org/10.4049/jimmunol.204.supp.225.13.

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Abstract HIV-associated neurocognitive disorder is a common complication of HIV infection, whose development is known to be facilitated by inflammation and exacerbated by morphine. In this study, we infected HIV gp120tg mice with LP-BM5 (a murine retrovirus that can cause systemic immunodeficiency in susceptible mouse strains) to examine morphine’s effect on gp120 in both immunocompetent and immunodeficient conditions. Specifically, we examined the expression of a series of inflammation-related molecules in the brain via qRT-PCR as well as the animals’ learning/memory function using spontaneous alternation T-maze. Morphine treatment (2×25mg pellets) did not significantly affect the development of immunodeficiency induced by LP-BM5 and all brain regions examined (hippocampus, striatum, and frontal lobe) had detectable LP-BM5 viral gag genes. Morphine notably reduced the performance of gp120tg+ mice in the T-maze assay when 2-minute retention was used, regardless of LP-BM5 treatment. Without LP-BM5 treatment, morphine increased hippocampal expression of CCL2, CCL5, CXCL10, IL-12 p40, TNFα, and IFNγ, while it decreased the expression of IL-6, arginase-1, IFNα and IFNβ. For mice who were subjected to LP-BM5 treatment, hippocampal expression of CCL2, CCL5, CXCL10, IL-12p40, and IL-1β were decreased by morphine, while CCL4, TNFα, IFNγ, iNOS, arginase-1 and IFNβ were increased by morphine. Further, expression of the mu opioid receptor was upregulated by morphine without LP-BM5, yet down-regulated by morphine with LP-BM5 treatment. Altogether, the effects of morphine are complex and dependent on the immune status of the host, which will be further elucidated in the future studies. (Supported by NIH/NIDA R21DA044886 (PI, Cao))

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Inagaki, Masanao, Toshiyuki Kanemasa, and Takaaki Yokota. "Naldemedine: Peripherally Acting Opioid Receptor Antagonist for Treating Opioid-induced Adverse Effects." Current Topics in Medicinal Chemistry 20, no. 31 (December 3, 2020): 2830–42. http://dx.doi.org/10.2174/1568026620666200710105953.

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Opioids are widely used for pain management in moderate-to-severe pain. However, opioids are associated with adverse events, such as constipation and emesis/vomiting. To reduce these undesired effects, a structure–activity relationship study of morphinan derivatives was conducted, and a promising lead compound with inhibitory effects on opioid receptors was obtained. Further improvement in the potency and pharmacokinetic profiles of the lead compound led to the discovery of naldemedine, which showed anti-constipation and anti-emetic effects against these adverse events that were induced by morphine without influencing morphine’s analgesic effect. Naldemedine was launched in Japan and the USA in 2017 and in the EU in 2019, for treating opioid-induced constipation.

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Teppema, Luc J., Eveline van Dorp, Babak Mousavi Gourabi, Jack W. van Kleef, and Albert Dahan. "Differential Effect of Morphine and Morphine-6-glucuronide on the Control of Breathing in the Anesthetized Cat." Anesthesiology 109, no. 4 (October 1, 2008): 689–97. http://dx.doi.org/10.1097/aln.0b013e31818631bd.

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Background Morphine's metabolite, morphine-6-glucuronide (M6G), activates the mu-opioid receptor. Previous data suggest that M6G activates a unique M6G receptor that is selectively antagonized by 3-methoxynaltrexome (3mNTX). The authors compared the effects of M6G and morphine on breathing in the anesthetized cat and assessed whether 3mNTX reversal was selective for M6G. Methods Step changes in end-tidal carbon dioxide concentration were applied in cats anesthetized with alpha-chloralose-urethane. In study 1, the effect of the 0.15 mg/kg morphine followed by 0.2 mg/kg 3mNTX and next 0.8 mg/kg M6G was assessed in six cats. In study 2, the effect of 0.8 mg/kg M6G followed by 0.2 mg/kg 3mNTX and 0.15 mg/kg morphine was tested in another six cats. The ventilatory carbon dioxide responses were analyzed with a two-compartment model of the ventilatory controller, which consists of a fast peripheral and a slow central component. Results Both opioids shifted the ventilatory carbon dioxide responses to higher end-tidal carbon dioxide levels. Morphine had a preferential depressant effect within the central chemoreflex loop. In contrast, M6G had a preferential depressant effect within the peripheral chemoreflex loop. Irrespective of the opioid, 3mNTX caused full reversal of and prevented respiratory depression. Conclusions In anesthetized cats, the mu-opioids morphine and M6G induce respiratory depression at different sites within the ventilatory control system. Because 3mNTX caused full reversal of the respiratory depressant effects of both opioids, it is unlikely that a 3mNTX-sensitive unique M6G receptor is the cause of the differential respiratory behavior of morphine and M6G.

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&NA;. "Morphine see Meptazinol/morphine." Reactions Weekly &NA;, no. 285 (January 1990): 8. http://dx.doi.org/10.2165/00128415-199002850-00031.

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&NA;. "Morphine see Hydromorphone/morphine." Reactions Weekly &NA;, no. 308 (July 1990): 9. http://dx.doi.org/10.2165/00128415-199003080-00037.

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Bergum, Nikolas, Casey-Tyler Berezin, Connie M. King, and Jozsef Vigh. "µ-Opioid Receptors Expressed by Intrinsically Photosensitive Retinal Ganglion Cells Contribute to Morphine-Induced Behavioral Sensitization." International Journal of Molecular Sciences 23, no. 24 (December 14, 2022): 15870. http://dx.doi.org/10.3390/ijms232415870.

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Opioid drugs are the most effective tools for treating moderate to severe pain. Despite their analgesic efficacy, long-term opioid use can lead to drug tolerance, addiction, and sleep/wake disturbances. While the link between opioids and sleep/wake problems is well-documented, the mechanism underlying opioid-related sleep/wake problems remains largely unresolved. Importantly, intrinsically photosensitive retinal ganglion cells (ipRGCs), the cells that transmit environmental light/dark information to the brain’s sleep/circadian centers to regulate sleep/wake behavior, express μ-opioid receptors (MORs). In this study, we explored the potential contribution of ipRGCs to opioid-related sleep/circadian disruptions. Using implanted telemetry transmitters, we measured changes in horizontal locomotor activity and body temperature in mice over the course of a chronic morphine paradigm. Mice lacking MORs expressed by ipRGCs (McKO) exhibited reduced morphine-induced behavioral activation/sensitization compared with control littermates with normal patterns of MOR expression. Contrastingly, mice lacking MORs globally (MKO) did not acquire morphine-induced locomotor activation/sensitization. Control mice also showed morphine-induced hypothermia in both the light and dark phases, while McKO littermates only exhibited morphine-induced hypothermia in the dark. Interestingly, only control animals appeared to acquire tolerance to morphine’s hypothermic effect. Morphine, however, did not acutely decrease the body temperature of MKO mice. These findings support the idea that MORs expressed by ipRGCs could contribute to opioid-related sleep/wake problems and thermoregulatory changes.

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Altree, T., K. Loffler, B. Toson, D. Currow, and D. Eckert. "P009 The effects of low-dose morphine on sleep and breathlessness in chronic obstructive pulmonary disease." SLEEP Advances 3, Supplement_1 (October 1, 2022): A34. http://dx.doi.org/10.1093/sleepadvances/zpac029.082.

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Abstract Introduction Low-dose morphine is prescribed for refractory breathlessness in chronic obstructive pulmonary disease (COPD). Preliminary investigations suggest improved perceived sleep quality, although concerns exist regarding opioid-induced sedation. This study assessed the effects of morphine on subjective sleep quality and alertness, and potential links between sleep quality and breathlessness. Methods Analysis of sleep questionnaire and breathlessness data at baseline and after one week of low-dose slow-release morphine versus placebo according to a double-blind randomised controlled design was performed. Participants were randomised to placebo, 8mg or 16mg/day oral morphine for one week (before further dose escalation). Epworth Sleepiness Scale (ESS), Karolinska Sleep Score (KSS), Leeds Sleep Evaluation Questionnaire (LSEQ) and breathlessness severity scores were assessed. Dose effects on sleep measures were assessed via linear regression (including baseline sleep measures). Drug effects on the relationship between sleep quality and breathlessness were assessed via linear mixed models with random effects and three-way interaction between sleep measures, dose, and visit. Results 156 patients were randomised as follows: 8mg, n=55; 16mg, n=51; placebo n=50. Overall, there was a neutral effect of morphine on ESS, KSS, and LSEQ (all p>0.05). Morphine did not modify the relationship between sleep measures and breathlessness. Discussion Despite safety concerns, one week of morphine did not negatively impact subjective sleep or daytime alertness measures. There was no clear relationship between morphine’s effects on sleep and next-day breathlessness perception. Objective data assessing sleep and next-day alertness are required to further explore potential links between sleep and breathlessness in people with COPD.

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Goldberg, Joel S. "Stereochemical Basis for a Unified Structure Activity Theory of Aromatic and Heterocyclic Rings in Selected Opioids and Opioid Peptides." Perspectives in Medicinal Chemistry 4 (January 2010): PMC.S3898. http://dx.doi.org/10.4137/pmc.s3898.

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This paper presents a novel unified theory of the structure activity relationship of opioids and opioid peptides. It is hypothesized that a virtual or known heterocyclic ring exists in all opioids which have activity in humans, and this ring occupies relative to the aromatic ring of the drug, approximately the same plane in space as the piperidine ring of morphine. Since the rings of morphine are rigid, and the aromatic and piperidine rings are critical structural components for morphine's analgesic properties, the rigid morphine molecule allows for approximations of the aromatic and heterocyclic relationships in subsequent drug models where bond rotations are common. This hypothesis and five propositions are supported by stereochemistry and experimental observations. Proposition #1 The structure of morphine provides a template. Proposition #2 Steric hindrance of some centric portion of the piperidine ring explains antagonist properties of naloxone, naltrexone and alvimopam. Proposition #3 Methadone has an active conformation which contains a virtual heterocyclic ring which explains its analgesic activity and racemic properties. Proposition #4 The piperidine ring of fentanyl can assume the morphine position under conditions of nitrogen inversion. Proposition #5 The first 3 amino acid sequences of beta endorphin (l-try-gly-gly) and the active opioid dipeptide, l-tyr-pro, (as a result of a peptide turn and zwitterion bonding) form a virtual piperazine-like ring which is similar in size, shape and location to the heterocyclic rings of morphine, meperidine, and methadone. Potential flaws in this theory are discussed. This theory could be important for future analgesic drug design.

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Mai, Jie-Zhen, Chong Liu, Zhuo Huang, Chun-Lin Mai, Xin Zhou, Jun Zhang, and Xian-Guo Liu. "Oral application of bulleyaconitine A attenuates morphine tolerance in neuropathic rats by inhibiting long-term potentiation at C-fiber synapses and protein kinase C gamma in spinal dorsal horn." Molecular Pain 16 (January 2020): 174480692091724. http://dx.doi.org/10.1177/1744806920917242.

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Morphine is frequently used for the treatment of chronic pain, while long-term use of the drug leads to analgesic tolerance. At present, the prevention of the side effect remains a big challenge. Bulleyaconitine A, a diterpenoid alkaloid from Aconitum bulleyanum plants, has been used to treat chronic pain in China for more than 30 years. In the present study, we tested the effect of bulleyaconitine A on analgesic tolerance induced by morphine injections (10 mg/kg s.c., b.i.d.) in the lumbar 5 spinal nerve ligation model of neuropathic pain. We found that intragastrical application of bulleyaconitine A (0.4 mg/kg) 30 min before each morphine injection substantially inhibited the decrease in morphine’s inhibitory effect on mechanical allodynia and thermal hyperalgesia. Mechanistically, morphine injections further potentiated the lumbar 5 spinal nerve ligation induced long-term potentiation at C-fiber synapses in the spinal dorsal horn, a synaptic model of chronic pain. This effect was completely blocked by intragastrical bulleyaconitine A. It has been well established that activation of protein kinase C gamma and of glial cells in the spinal dorsal horn are critical for the development of opioid tolerance and neuropathic pain. We found that morphine injections exacerbated the upregulation of phospho-protein kinase C gamma (an active form of protein kinase C gamma), and the activation of microglia and astrocytes in the spinal dorsal horn induced by lumbar 5 spinal nerve ligation, and the effects were considerably prohibited by intragastrical bulleyaconitine A. Thus, spinal long-term potentiation at C-fiber synapses may underlie morphine tolerance. Oral administration of bulleyaconitine A may be a novel and simple approach for treating of opioid tolerance.

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Boyle, R. K. "A Review of Anatomical and Immunological Links between Epidural Morphine and Herpes Simplex Labialis in Obstetric Patients." Anaesthesia and Intensive Care 23, no. 4 (August 1995): 425–32. http://dx.doi.org/10.1177/0310057x9502300402.

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The anatomical basis for facial itch after epidural morphone is outlined. CNS nuclear events which reactivate latent herpes simplex and immune inhibition resulting in maternal mouth vesicles or neonatal infections are described. Morphine is hypothesized to affect these processes and facial itch is only a marker, not a trigger of this trigeminal opioid activity.

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Chung, James H., Raymond S. Sinatra, Ferne B. Sevarino, and Leonda Fermo. "Subarachnoid Meperidine-Morphine Combination: An Effective Perioperative Analgesic Adjunct for Cesarean Delivery." Regional Anesthesia: The Journal of Neural Blockade in Obstetrics, Surgery, & Pain Control 22, no. 2 (March 1997): 119–24. http://dx.doi.org/10.1136/rapm-00115550-199722020-00003.

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Background and ObjectivesLow-dose subarachnoid morphine provides effective perioperative analgesia but may be associated with a transient period of inadequate pain relief between the regression of local anesthetic block and the onset of morphine's analgesic effect. We hypothesized that this period of suboptimal analgesia could be avoided by adding meperidine, a rapid-acting, intermediate-duration opioid.MethodsIn a double-blind, randomized trial, 49 patients scheduled for elective cesarean delivery received subarachnoid 0.75% bupivacaine, 12 mg in 8.25% dextrose, with either meperidine 10 mg, morphine 0.15 mg, or meperidine 10 mg plus morphine 0.15 mg. Visual analog scale scores for pain and satisfaction were obtained at skin incision, delivery, uterine exteriorization, on arrival in the postanesthesia care unit, and 2, 4, 6, 12, and 24 hours after drug administration. Neonatal Apgar scores and adverse effects were also noted. Postoperative intravenous patient-controlled analgesia (PCA) requirements were recorded for 24 hours. The data were analyzed by chi-square analysis Fisher's exact test, the Wilcoxon rank sum test, and analysis of variance with Tukey's adjustment for multiple comparisons.ResultsThere were no significant differences in the incidence and severity of side effects, including nausea, vomiting, pruritus, and sedation. Respiratory depression was not observed. Patients treated with morphine alone were least comfortable (P < .006), expressed the lowest satisfaction scores at early observations (P < .002), and required more PCA meperidine (P < .001) than any other group. Patients treated with meperidine alone were comfortable at early observations but required the greatest total amount of PCA meperidine over the first 24 hours (P < .05). Patients in the meperidine-morphine combination group reported the lowest pain scores and highest satisfaction scores at 4-hour and 6-hour observations (P < .03) and required the least total amount of PCA meperidine.ConclusionThe subarachnoid combination of meperidine-morphine provided more uniform analgesia, higher satisfaction, and a lower requirement for intravenous narcotic supplementation than either morphine or meperidine alone in patients recovering from cesarean delivery.

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Romberg, Raymonda, Erik Olofsen, Elise Sarton, Luc Teppema, and Albert Dahan. "Pharmacodynamic Effect of Morphine-6-glucuronide versus Morphine on Hypoxic and Hypercapnic Breathing in Healthy Volunteers." Anesthesiology 99, no. 4 (October 1, 2003): 788–98. http://dx.doi.org/10.1097/00000542-200310000-00008.

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Background Morphine-6-glucuronide (M6G) is an active metabolite of morphine that is generally associated with less respiratory depression than morphine. Because M6G will be on the market in the near future, the authors assessed the time profile and relative potency of M6G's effect versus morphine's effect on carbon dioxide-driven and hypoxic breathing. Methods In nine healthy female volunteers, the effects of 0.2 mg/kg intravenous M6G, 0.13 mg/kg intravenous morphine, and intravenous placebo were tested on ventilation at a fixed end-tidal pressure of carbon dioxide (Petco2) of 45 mmHg (Vi45) and on the acute hypoxic ventilatory response (AHR). All subjects participated in all three arms of the study. Respiratory studies were performed at 1-h intervals for 7 h after drug infusion. The data were analyzed using a population dose-driven approach, which uses a dose rate in function of time as input function driving the pharmacodynamics, and a population pharmacokinetic-pharmacodynamic (PK/PD) approach in which fixed pharmacokinetic parameter values from the literature were used as input function to the respiratory model. From the latter analysis, the authors obtained the blood effect-site equilibration half-life (t1/2ke0) and the effect-site concentration producing 25% depression of Vi45 and AHR (C25). Values reported are mean +/- SE. Results Placebo had no effect on Vi45 or AHR over time. Both analysis approaches yielded good descriptions of the data with comparable model parameters. M6G PK/PD model parameters for Vi45 were t1/2ke0 2.1 +/- 0.2 h and C25 528 +/- 88 nm and for AHR were t1/2ke0 1.0 +/- 0.1 h and C25 873 +/- 81 nm. Morphine PK/PD model parameters for Vi45 were t1/2ke0 3.8 +/- 0.9 h and C25 28 +/- 6 nm and for AHR were t1/2ke0 4.3 +/- 0.6 h and C25 16 +/- 2 nm. Conclusions Morphine is more potent in affecting hypoxic ventilatory control than M6G, with a potency ratio ranging from 1:19 for Vi45 to 1:50 for AHR. At drug concentrations causing 25% depression of Vi45, M6G caused only 15% depression of AHR, whereas morphine caused greater than 50% depression of AHR. Furthermore, the speed of onset/offset of M6G is faster than morphine by a factor of approximately 2. The authors discuss some of the possible mechanisms for the observed differences in opioid behavior.

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Kalman, Sigga, Kerstin Metcalf, and Christina Eintrei. "Morphine, Morphine-6-Glucuronide, and Morphine-3-Glucuronide in Cerebrospinal Fluid and Plasma After Epidural Administration of Morphine." Regional Anesthesia: The Journal of Neural Blockade in Obstetrics, Surgery, & Pain Control 22, no. 2 (March 1997): 131–36. http://dx.doi.org/10.1136/rapm-00115550-199722020-00005.

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Background and ObjectivesIt has been suggested that the potency of epidural morphine might be explained by spinal metabolism to the active and potent metabolite morphine-6-glucuronide (M6G). The main objective of this study was to describe the early pharmacokinetics of epidurally administered, morphine with special attention to the appearance of the glucuronated metabolites in cerebrospinal fluid (CSF).MethodsMorphine was administered epidurally to eight patients scheduled for major abdominal surgery. The concentrations of morphine and its 6-glucuronide and 3-glucuronide metabolites were monitored in blood and CSF at 10, 30, 60, and 120 minutes and 10 and 24 hours. Postoperative pain was estimated on a visual analog scale, and analgesia requirements (administered by a patient-controlled techique) were recorded.ResultsOnly traces of the metabolites were found in CSF and in only two patients throughout the 24 hours. Both metabolites appeared rapidly (within 30 minutes) in plasma in all patients and were found in plasma throughout the study period. Morphine concentration peaked in CSF within 30 minutes at a very high level; in plasma, it peaked at 10 minutes. No correlation was seen between initial or later concentrations of morphine in CSF and postoperative pain or morphine requirements.ConclusionsNo evidence of spinal metabolism of morphine could be found. Rapid distribution of morphine to CSF and plasma occurred after epidural administration. No value of initial CSF morphine concentrations for prediction of analgesic requirements could be demonstrated.

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&NA;. "Morphine." Reactions Weekly &NA;, no. 1377 (November 2011): 28. http://dx.doi.org/10.2165/00128415-201113770-00094.

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&NA;. "Morphine." Reactions Weekly &NA;, no. 1381 (December 2011): 20–21. http://dx.doi.org/10.2165/00128415-201113810-00071.

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&NA;. "Morphine." Reactions Weekly &NA;, no. 1394 (March 2012): 32. http://dx.doi.org/10.2165/00128415-201213940-00117.

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&NA;. "Morphine." Reactions Weekly &NA;, no. 703 (May 1998): 9. http://dx.doi.org/10.2165/00128415-199807030-00029.

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&NA;. "Morphine." Reactions Weekly &NA;, no. 768 (September 1999): 9. http://dx.doi.org/10.2165/00128415-199907680-00031.

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&NA;. "Morphine." Reactions Weekly &NA;, no. 1167 (September 2007): 20. http://dx.doi.org/10.2165/00128415-200711670-00061.

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&NA;. "Morphine." Reactions Weekly &NA;, no. 1181 (December 2007): 26–27. http://dx.doi.org/10.2165/00128415-200711810-00076.

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&NA;. "Morphine." Reactions Weekly &NA;, no. 1182 (December 2007): 27. http://dx.doi.org/10.2165/00128415-200711820-00082.

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&NA;. "Morphine." Reactions Weekly &NA;, no. 1183 (January 2008): 22. http://dx.doi.org/10.2165/00128415-200811830-00070.

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&NA;. "Morphine." Reactions Weekly &NA;, no. 1184 (January 2008): 27. http://dx.doi.org/10.2165/00128415-200811840-00082.

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&NA;. "Morphine." Reactions Weekly &NA;, no. 1185 (January 2008): 22. http://dx.doi.org/10.2165/00128415-200811850-00065.

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&NA;. "Morphine." Reactions Weekly &NA;, no. 1191 (March 2008): 18. http://dx.doi.org/10.2165/00128415-200811910-00059.

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&NA;. "Morphine." Reactions Weekly &NA;, no. 1122 (October 2006): 16. http://dx.doi.org/10.2165/00128415-200611220-00046.

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&NA;. "Morphine." Reactions Weekly &NA;, no. 1127 (November 2006): 18–19. http://dx.doi.org/10.2165/00128415-200611270-00060.

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&NA;. "Morphine." Reactions Weekly &NA;, no. 1144 (March 2007): 19. http://dx.doi.org/10.2165/00128415-200711440-00055.

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&NA;. "Morphine." Reactions Weekly &NA;, no. 1146-1147 (April 2007): 21. http://dx.doi.org/10.2165/00128415-200711460-00064.

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&NA;. "Morphine." Reactions Weekly &NA;, no. 1153 (May 2007): 20–21. http://dx.doi.org/10.2165/00128415-200711530-00066.

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&NA;. "Morphine." Reactions Weekly &NA;, no. 1362 (July 2011): 23. http://dx.doi.org/10.2165/00128415-201113620-00084.

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&NA;. "Morphine." Reactions Weekly &NA;, no. 1369 (September 2011): 29. http://dx.doi.org/10.2165/00128415-201113690-00104.

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&NA;. "Morphine." Reactions Weekly &NA;, no. 1371 (October 2011): 26–27. http://dx.doi.org/10.2165/00128415-201113710-00098.

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&NA;. "Morphine." Reactions Weekly &NA;, no. 1373 (October 2011): 23. http://dx.doi.org/10.2165/00128415-201113730-00077.

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&NA;. "Morphine." Reactions Weekly &NA;, no. 1375 (October 2011): 22. http://dx.doi.org/10.2165/00128415-201113750-00074.

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&NA;. "Morphine." Reactions Weekly &NA;, no. 540 (March 1995): 10. http://dx.doi.org/10.2165/00128415-199505400-00034.

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&NA;. "Morphine." Reactions Weekly &NA;, no. 543 (March 1995): 10. http://dx.doi.org/10.2165/00128415-199505430-00020.

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