-
Brain and Nerve = Shinkei Kenkyu No... Dec 2023Christie's Sad Cypress features an impressive trick with morphine and apomorphine. I read the book as if I were this killer, and also thought about the effects of...
Christie's Sad Cypress features an impressive trick with morphine and apomorphine. I read the book as if I were this killer, and also thought about the effects of morphine and apomorphine.
Topics: Humans; Morphine; Apomorphine; Cupressus
PubMed: 38097220
DOI: 10.11477/mf.1416202530 -
Central Nervous System Agents in... 2022Chronic morphine stimulates prolonged stimulation of opioid receptors, especially μ-opioid subtype (MOR), which in turn signals cellular adaptation. However, the sudden...
BACKGROUND
Chronic morphine stimulates prolonged stimulation of opioid receptors, especially μ-opioid subtype (MOR), which in turn signals cellular adaptation. However, the sudden termination of the use of morphine after chronic intake causes the withdrawal syndrome.
OBJECTIVES
Hence, this study was designed to find an alternative treatment for morphine withdrawal using the alkaloid leaf extract of Erythroxylum cuneatum (E. cuneatum) for the treatment of morphine-exposed neuroblastoma cell lines.
METHODS
SK-N-SH, a commercialised neuroblastoma cell line, was used in two separate study designs; the antagonistic and pre-treatment of morphine. The antagonistic treatment was conducted through concurrent exposure of the cells to morphine and E. cuneatum or morphine and methadone for 24 hrs. The pre-treatment design was carried out by exposing the cells to morphine for 24 hrs, followed by 24 hrs exposure to E. cuneatum or methadone. The cytosolic fraction was collected and assessed for proteins expression involved in cellular adaptation, including mitogen-activated protein (MAP)/extracellular signal-regulated (ERK) kinase 1/2 (MEK 1/2), extracellular signalregulated kinase 2 (ERK 2), cAMP-dependent protein kinase (PKA) and protein kinases C (PKC).
RESULTS
The antagonistic treatment showed the normal level of MEK 1/2, ERK 2, PKA and PKC by the combination treatment of morphine and E. cuneatum, comparable to the combination of morphine and methadone. Neuroblastoma cells exposed to morphine pre-treatment expressed a high level of MEK 1/2, ERK 2, PKA and PKC, while the treatments with E. cuneatum and methadone normalised the expression of the cellular adaptation proteins.
CONCLUSION
E. cuneatum exerted anti-addiction properties by lowering the levels of cellular adaptation proteins it's effects is comparable to that of methadone (an established anti-addiction drug).
Topics: Analgesics, Opioid; Humans; Methadone; Morphine; Neuroblastoma
PubMed: 35578883
DOI: 10.2174/1871524922666220516151121 -
Brain, Behavior, and Immunity Jan 2023Severe pain in patients can be alleviated by morphine treatment. However, long-term morphine treatment induces analgesic tolerance and the molecular mechanism of...
BACKGROUND
Severe pain in patients can be alleviated by morphine treatment. However, long-term morphine treatment induces analgesic tolerance and the molecular mechanism of morphine analgesic intolerance is still not fully elucidated. Therefore, a novel target for improving morphine analgesic tolerance is required. Whole-genome sequencing showed that circNf1 is highly expressed in the dorsal horns of morphine-treated rats. Circular RNAs (circRNAs) are known to be unique and conserved cellular molecules that are mostly present in cytoplasm and participate in various biochemical processes with different functions. Therefore, we focused on exploring the molecular mechanism by which circNf1 contributes to morphine analgesic tolerance.
METHODS
CircRNA sequencing revealed differential expression of circRNAs after morphine treatment, and bioinformatics software programs (miRNAda, PicTar, and RNAhybrid) were used to predict possible mRNAs and binding sites. RNA binding protein immunoprecipitation (RIP), chromatin isolation by RNA purification (ChIRP), fluorescence in situ hybridization (FISH), western blotting, biotin-coupled probe pull-down assay, luciferase assay, and quantitative real-time polymerase chain reaction (qRT-PCR) were conducted to detect and measure the expression levels of circRNAs, mRNAs, and proteins. Intrathecal injections of small interfering RNAs (siRNAs), microRNA (miRNA) agomirs, and functional virus microinjections were administered to artificially mediate the expression of molecules. Tail immersion and hotplate tests were performed to evaluate morphine analgesic tolerance.
RESULTS
Morphine-induced circNf1 expression was high in the spinal cord. RIP-PCR and luciferase assay data showed that circNf1 could combine with both miR-330-3p and miR-665, and FISH showed that circNf1 co-localized with miR-330-3p and miR-665. qRT-PCR assay showed downregulation of miR-330-3p and miR-665 in morphine-treated rats; western blotting results showed that CXCL12 increased after morphine treatment, however, the upregulation of CXCL12 could be alleviated after the intrathecal injection of miR-330-3p as well as miR-665 agomir. qRT-PCR indicated that circNf1 can bind to CXCL12 promoter, the increased circNf1 can enhance CXCL12 mRNA in naïve rats, and inhibition of circNf1 can alleviate the upregulation of CXCL12 mRNA in morphine-treated rats. Behavioral tests revealed that inhibition of circNf1 and CXCL12 and the enhancement of miR-330-3p and miR-665 can alleviate morphine analgesic tolerance.
CONCLUSIONS
Our study indicates a novel pathway that can contribute to morphine analgesic tolerance, the circRNA to cytokine pathway, in which circNf1 functions as a sponge for miR-330-3p and miR-665 and induces the upregulation of CXCL12 at both transcriptional and translational levels in morphine-treated rats.
Topics: Rats; Animals; Morphine; In Situ Hybridization, Fluorescence; Spinal Cord; RNA, Messenger; Chemokine CXCL12; MicroRNAs
PubMed: 36202171
DOI: 10.1016/j.bbi.2022.09.018 -
Revue Medicale Suisse Jan 2024
Topics: Humans; Palliative Care; Family Practice; Morphine Derivatives
PubMed: 38268379
DOI: 10.53738/REVMED.2024.20.858.185 -
Blocking Palmitoylation of Apelin Receptor Alleviates Morphine Tolerance in Neuropathic Cancer Pain.International Journal of Biological... 2024Neuropathic cancer pain (NCP) is an important symptom in patients with cancer. However, significant analgesic tolerance and other side effects critically hamper the...
Neuropathic cancer pain (NCP) is an important symptom in patients with cancer. However, significant analgesic tolerance and other side effects critically hamper the administration of morphine. Protein palmitoylation mediated by the DHHC family may be involved in the glial activation and inflammatory responses underlying organ failure. In this study, we investigated the key role of protein palmitoylation in cancer pain and sought to target palmitoylation to suppress morphine tolerance. We found that long-term use of morphine led to the accumulation of the morphine metabolite, morphine-3-glucuronide, and activated ERK1/2 and microglia to release inflammatory factors through the apelin receptor APLNR. Palmitoyltransferase ZDHHC9 was upregulated in NCP, and APLNR was palmitylated to protect it from lysosomal degradation and to maintain its stability. We also designed competitive inhibitors of APLNR palmitoylation to inhibit the development of NCP, release of inflammatory factors, and attenuation of morphine tolerance. Therefore, targeting APLNR palmitoylation in combination with morphine is a potent method for cancer pain treatment. Our data provide a basis for the future clinical use of related drugs combined with morphine for the treatment of cancer-related pain.
Topics: Humans; Morphine; Apelin Receptors; Cancer Pain; Lipoylation; Neuralgia; Neoplasms
PubMed: 38164190
DOI: 10.7150/ijbs.86888 -
Pain Physician Dec 2021Numerous combination intrathecal drug therapy (CIDT) strategies exist and are utilized for varying pain syndromes, typically when monotherapy dose escalation or... (Review)
Review
BACKGROUND
Numerous combination intrathecal drug therapy (CIDT) strategies exist and are utilized for varying pain syndromes, typically when monotherapy dose escalation or medication alternation is deemed untenable or unfeasible. Unfortunately, the supportive evidence basis for the use of these strategies and specific drug combinations is generally lacking and unclear, with many medications being used for off-label indications.
OBJECTIVE
In this manuscript, we provide a robust exploration and analysis of the literature to provide an evidence-based narrative for the use of CIDT strategies in regard to clinical indications, pharmacologic parameters, specific drug combinations, safety profiles, and future directions.
STUDY DESIGN
Narrative review.
METHODS
This was an evidence based narrative performed after extensive review of the literature.
RESULTS
Variances in intrathecal pharmacokinetics and pharmacodynamics are utilized advantageously with CIDT strategies to achieve improved analgesic benefit; however, appropriate use may be limited by increased or compounded risk of adverse effects. The supportive evidence for CIDT use for chronic pain conditions is largely lacking and limited to small, uncontrolled, observational studies, with many having various confounding factors, including a lack of standardized dosing. The most evidenced CIDT strategies include polyanalgesia with morphine-ziconotide, opioid-clonidine, and morphine-bupivacaine. Notably, in addition to pain relief, morphine-bupivacaine has been shown to decrease early opioid escalation requirements.
LIMITATIONS
The supportive evidence for CIDT use for chronic pain conditions is largely lacking and limited to small, uncontrolled, observational studies, with many having various confounding factors including a lack of standardized dosing.
CONCLUSIONS
CIDT strategies and polyanalgesia combinations can be effective for treating various patient populations with chronic pain. The appropriate use of these strategies may be limited by increased or compounded risk of adverse effects, both of which are highly patient and scenario dependent. Therefore, practitioners should maintain a particularly low threshold of suspicion for adverse effects in patients with CIDT such that safety profiles associated with this therapy can be favorably maintained.
Topics: Analgesics, Opioid; Chronic Pain; Drug Therapy, Combination; Humans; Injections, Spinal; Morphine; Pain Management
PubMed: 34793643
DOI: No ID Found -
Brain and Behavior Dec 2021Morphine is the predominantly used drug for postoperative and cancer pain management. However, the abuse potential of morphine is the primary disadvantage of using...
PURPOSE
Morphine is the predominantly used drug for postoperative and cancer pain management. However, the abuse potential of morphine is the primary disadvantage of using opioids in pain management. Melatonin is a neurohormone synthesized in the pineal gland and is involved in circadian rhythms in mammals, as well as other physiological functions. Melatonin provenly attenuates alcohol-seeking and relapse behaviors in rats. Therefore, we aimed to investigate the involvement of the melatonergic system in attenuating morphine dependence.
MATERIALS AND METHODS
Male Wistar rats were divided into three groups: control, morphine, and morphine + melatonin. Animals were habituated for 3 days, and the initial preference was evaluated. Following the initial preference, the control group received the vehicle and was placed for a 45-min session in the assigned chamber every day, alternating between the two chambers, for 8 days. The morphine group received a morphine injection (5 mg/kg, IP) and was placed for a 45-min session in the white chamber, for a total of four sessions. The morphine + melatonin group received the morphine injection (5 mg/kg, IP) for a total of four sessions over an 8-day period. In the posttest session, the control and morphine groups received a vehicle injection 30 min before placement in the conditioned place preference (CPP). The morphine + melatonin group received a single injection of melatonin (50 mg/kg, IP) 30 min before the preference test.
RESULTS
Statistical analysis revealed that repeated administration of morphine for four sessions produced a significant increase in the CPP score in the morphine group compared to the control group. However, a single melatonin injection administered 30 min before the posttest attenuated morphine-seeking behavior and reduced morphine-induced place preference.
CONCLUSION
These findings provide novel evidence for the role of the melatonergic system as a potential target in modulating morphine-seeking behavior.
Topics: Analgesics, Opioid; Animals; Conditioning, Classical; Male; Melatonin; Morphine; Rats; Rats, Wistar
PubMed: 34710287
DOI: 10.1002/brb3.2397 -
The Pharmacogenomics Journal Jun 2024The aim was to determine if opioid neuroimmunopharmacology pathway gene polymorphisms alter serum morphine, morphine-3-glucuronide and morphine-6-glucuronide...
The aim was to determine if opioid neuroimmunopharmacology pathway gene polymorphisms alter serum morphine, morphine-3-glucuronide and morphine-6-glucuronide concentration-response relationships in 506 cancer patients receiving controlled-release oral morphine. Morphine-3-glucuronide concentrations (standardised to 11 h post-dose) were higher in patients without pain control (median (interquartile range) 1.2 (0.7-2.3) versus 1.0 (0.5-1.9) μM, P = 0.006), whereas morphine concentrations were higher in patients with cognitive dysfunction (40 (20-81) versus 29 (14-60) nM, P = 0.02). TLR2 rs3804100 variant carriers had reduced odds (adjusted odds ratio (95% confidence interval) 0.42 (0.22-0.82), P = 0.01) of opioid adverse events. IL2 rs2069762 G/G (0.20 (0.06-0.52)), BDNF rs6265 A/A (0.15 (0.02-0.63)) and IL6R rs8192284 carrier (0.55 (0.34-0.90)) genotypes had decreased, and IL6 rs10499563 C/C increased (3.3 (1.2-9.3)), odds of sickness response (P ≤ 0.02). The study has limitations in heterogeneity in doses, sampling times and diagnoses but still suggests that pharmacokinetics and immune genetics co-contribute to morphine pain control and adverse effects in cancer patients.
Topics: Humans; Morphine; Male; Female; Cancer Pain; Middle Aged; Analgesics, Opioid; Delayed-Action Preparations; Aged; Pharmacogenetics; Polymorphism, Single Nucleotide; Morphine Derivatives; Adult; Pharmacogenomic Variants; Toll-Like Receptor 2
PubMed: 38824169
DOI: 10.1038/s41397-024-00339-w -
International Journal of Developmental... May 2023Maternal morphine exposure reduces motivation for basic cognitive tasks, followed by executive function deficits in attention and accuracy. It also induces...
Maternal morphine exposure reduces motivation for basic cognitive tasks, followed by executive function deficits in attention and accuracy. It also induces depression-like behaviors and has negative consequences for learning and memory in offspring. Interaction between mothers and pups has a crucial effect on the mammal's development. Maternal separation (MS) can originate behavioral and neuropsychiatric abnormalities later in life. It seems that adolescents are more susceptible to the effects of early-life stress; Therefore, this study aimed to evaluate the effects of chronic morphine consumption (21 days before and after mating and gestation) and MS (180 min/day from postnatal day [PND] 1-21) on the cognitive and behavioral performance of male offspring in mid-adolescence. Six groups, including control, MS, V (vehicle), morphine, V+MS, and morphine+MS, were tested for open field (OF), novel object recognition (NOR), and the Morris water maze (MWM). The results of the OF test showed that MS increased locomotor activity and movement velocity. Inner and outer zone durations did not differ among groups. The body stretching of the morphine+MS rats was significantly more than the MS rats. Moreover, the MS and morphine+MS groups showed significantly less sniffing behavior in the OF test. The MS group showed deficits in spatial learning in the MWM test, but recognition memory in the NOR and spatial memory in the MWM tests were not significantly different among groups. We concluded that MS could induce impairments in spatial learning and locomotor activity that could be worsened by maternal morphine exposure in adolescent male rats.
Topics: Rats; Animals; Male; Morphine; Rats, Wistar; Maze Learning; Maternal Deprivation; Cognition; Locomotion; Mammals
PubMed: 36794284
DOI: 10.1002/jdn.10251 -
Indian Journal of Pharmacology 2023
Topics: Ketamine; Morphine; Analgesics, Opioid
PubMed: 38174540
DOI: 10.4103/ijp.ijp_230_23