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Anesthesiology148 papers

Morphine dependence

Last edited: 3 h ago

Overview

Morphine dependence is a clinically significant condition characterized by compulsive drug-seeking behavior and continued use despite harmful consequences. It primarily affects individuals who have been exposed to morphine or other opioids chronically, often due to therapeutic use for pain management, particularly in palliative care settings, or misuse. The condition poses substantial public health challenges, including increased risks of overdose, addiction, and societal burden. Understanding and managing morphine dependence is crucial in day-to-day practice to mitigate adverse outcomes and improve patient quality of life 1347.

Pathophysiology

Morphine dependence arises from complex molecular and cellular adaptations within the central nervous system, particularly involving the μ-opioid receptor (MOR). Chronic morphine exposure leads to neuroadaptive changes, including receptor desensitization and downregulation. Key mechanisms include:

  • Receptor Desensitization and Phosphorylation: Prolonged morphine use results in agonist-specific phosphorylation of MOR at residues like threonine 375 and serine 375, mediated primarily by G protein-coupled receptor kinases (GRKs) 2 and 3. This phosphorylation recruits β-arrestin 2, uncoupling MOR from G proteins and initiating internalization processes 1114.
  • Neurotransmitter Imbalance: Chronic opioid use disrupts the balance of neurotransmitters such as brain-derived neurotrophic factor (BDNF) and calcium/calmodulin-dependent protein kinase IIγ (CaMKIIγ). Studies indicate that downregulation of microRNAs like miR-219 enhances BDNF production, which in turn upregulates CaMKIIγ, contributing to analgesic tolerance 810.
  • Inflammation and Microglia Activation: Morphine can induce neuroinflammatory responses, activating microglia and releasing inflammatory mediators like IL-1β, IL-6, and TNF-α. These mediators sensitize spinal dorsal horn neurons, leading to hyperalgesia and tolerance 512.

    • These adaptations collectively diminish the analgesic efficacy of morphine and foster a cycle of escalating dosage and increased risk of dependence 24.

    Epidemiology

    The incidence and prevalence of morphine dependence vary widely based on geographic location, demographic factors, and patterns of opioid use. Globally, the opioid epidemic has seen significant increases in dependence and overdose deaths, particularly with potent opioids like fentanyl and its derivatives 78. In regions like North America, the crisis has led to thousands of overdose deaths annually, highlighting the urgent need for intervention 79. Specific to palliative care settings, while morphine remains a cornerstone for pain management, its chronic use underscores the vulnerability of certain patient populations, especially those with prolonged pain conditions 3.

    Clinical Presentation

    Clinical presentations of morphine dependence include both physical and behavioral symptoms:
  • Physical Symptoms: Tolerance (requiring higher doses for pain relief), hyperalgesia (increased sensitivity to pain), constipation, respiratory depression, and gastrointestinal disturbances.
  • Behavioral Symptoms: Compulsive drug-seeking behavior, mood swings, anxiety, and cognitive impairments. Patients may exhibit withdrawal symptoms upon cessation, such as agitation, muscle aches, and insomnia.

    • Red-flag features include rapid escalation in dosage, frequent requests for early refills, and signs of intoxication or withdrawal, which necessitate immediate clinical attention 47.

    Diagnosis

    Diagnosing morphine dependence involves a comprehensive clinical assessment and specific criteria:
  • Clinical Assessment: Detailed history taking focusing on patterns of opioid use, tolerance development, and withdrawal symptoms.
  • Specific Criteria:
    • - Diagnostic Criteria: Meets DSM-5 criteria for Opioid Use Disorder, including recurrent opioid use resulting in a failure to fulfill major role obligations, use in situations dangerous to self or others, and persistent desire or unsuccessful efforts to cut down or control use 4. - Laboratory Tests: Urine toxicology screens to detect morphine metabolites. - Psychological Evaluation: Screening tools like the Opioid Withdrawal Scale (OWS) for assessing withdrawal severity 4.

    Differential Diagnosis:

  • Chronic Pain Conditions: Differentiates based on persistent pain complaints without clear signs of drug-seeking behavior.
  • Psychiatric Disorders: Mood disorders or anxiety can mimic some behavioral symptoms; psychiatric evaluation helps distinguish 4.

    • Management

    First-Line Management

  • Detoxification: Medically supervised withdrawal using agonists like methadone or partial agonists like buprenorphine to manage withdrawal symptoms.
    • - Methadone: Initial dose range 20-40 mg/day, titrated based on withdrawal symptoms 6. - Buprenorphine: Starting dose 8-12 mg sublingually every 24 hours, adjusted as needed 6.
  • Behavioral Therapy: Cognitive-behavioral therapy (CBT) and contingency management to address psychological aspects of addiction.
    • - CBT: Weekly sessions, duration typically 12-16 weeks 4.

    Second-Line Management

  • Extended Pharmacotherapy: Long-acting naltrexone for relapse prevention post-detoxification.
    • - Naltrexone: Oral 50 mg daily or injectable extended-release 380 mg every 4 weeks 6.
  • Supportive Interventions: Multidisciplinary approaches including counseling, family therapy, and support groups.
    • - Support Groups: Regular attendance at groups like Narcotics Anonymous 4.

    Refractory Cases / Specialist Escalation

  • Specialist Referral: Consultation with addiction medicine specialists or pain management experts.
  • Advanced Therapies: Consideration of novel treatments like vaccine development against opioids to prevent relapse 6.

    • Contraindications:

  • Acute Medical Conditions: Severe respiratory depression, acute intoxication, or concurrent use of other CNS depressants 4.

    • Complications

  • Acute Complications: Severe withdrawal symptoms including seizures, delirium, and cardiovascular instability.
  • Long-Term Complications: Increased risk of infections (e.g., HIV, hepatitis), mental health disorders, and chronic pain syndromes post-withdrawal.
  • Management Triggers: Frequent relapses, non-compliance with treatment, and environmental triggers like stress or social cues 47.

    • Prognosis & Follow-Up

  • Expected Course: Variable, influenced by duration of use, severity of dependence, and adherence to treatment. Early intervention generally yields better outcomes.
  • Prognostic Indicators: Absence of co-occurring psychiatric disorders, strong social support, and sustained abstinence.
  • Follow-Up Intervals: Regular monitoring every 1-3 months initially, tapering to quarterly visits as stability improves. Monitoring includes urine toxicology screens, psychological assessments, and clinical evaluations 4.

    • Special Populations

  • Pregnancy: Methadone maintenance therapy is preferred over buprenorphine due to lower risk of neonatal abstinence syndrome (NAS). Monitoring for NAS and providing supportive care post-delivery is crucial 6.
  • Elderly: Increased sensitivity to side effects; careful titration of doses and close monitoring for cognitive changes and falls 3.
  • Comorbidities: Patients with chronic pain or psychiatric disorders require integrated care plans addressing both conditions simultaneously 4.

    • Key Recommendations

  • Initiate Detoxification with Agonist Maintenance: Use methadone or buprenorphine for medically supervised withdrawal (Evidence: Strong 64).
  • Integrate Behavioral Therapies: Incorporate cognitive-behavioral therapy as a core component of treatment (Evidence: Moderate 4).
  • Consider Extended Pharmacotherapy: Utilize naltrexone for relapse prevention post-detoxification (Evidence: Moderate 6).
  • Monitor Regularly: Schedule frequent follow-ups, including urine toxicology screens, to assess compliance and relapse risk (Evidence: Moderate 4).
  • Address Comorbid Conditions: Tailor treatment plans to manage concurrent psychiatric or medical issues (Evidence: Moderate 4).
  • Support Group Participation: Encourage involvement in peer support groups like Narcotics Anonymous (Evidence: Expert opinion 4).
  • Evaluate for Special Populations: Tailor management strategies for pregnant women, elderly patients, and those with comorbidities (Evidence: Expert opinion 34).
  • Explore Novel Therapies: Consider emerging treatments like opioid vaccines for high-risk individuals (Evidence: Weak 6).
  • Educate Patients and Families: Provide comprehensive education on addiction, recovery, and coping strategies (Evidence: Expert opinion 4).
  • Screen for Co-occurring Disorders: Routinely screen for and treat co-occurring mental health disorders (Evidence: Moderate 4).

    • References

    Showing 100 priority papers (full text preferred, most recent first) of 148 indexed.

    1 Akiyama S, Ople RS, Kremsmair A, Ramos-Gonzalez N, Nedungadan T, Kennedy BJ et al.. Total synthesis and biological activity of "carbamorphine": O-to-CH. Proceedings of the National Academy of Sciences of the United States of America 2025. link 2 Nourmandipour F, Emadi R, Salehi P, Zarin MKZ, Khoramjouy M, Beirami AD et al.. Design, synthesis, in-vivo, and in-silico studies of 1,2,3-triazole tethered derivatives of morphine as novel anti-nociceptive agents. PloS one 2025. link 3 Nisahan B, Raviraj S, Navaratnam S, Nadarajah R. Physicians' views of the use of morphine in palliative care: a cross-sectional survey from a tertiary care centre in Northern Sri Lanka. BMC research notes 2025. link 4 Alshehri FS, Alghamdi BS, Hakami AY, Alshehri AA, Althobaiti YS. Melatonin attenuates morphine-induced conditioned place preference in Wistar rats. Brain and behavior 2021. link 5 Gong X, Fan R, Zhu Q, Ye X, Chen Y, Zhang M. Exercise Reduces Morphine-Induced Hyperalgesia and Antinociceptive Tolerance. BioMed research international 2021. link 6 Köteles I, Mazák K, Tóth G, Tűz B, Hosztafi S. Synthesis of Potential Haptens with Morphine Skeleton and Determination of Protonation Constants. Molecules (Basel, Switzerland) 2020. link 7 Zhao Z, Huang T, Li J. Molecular Dynamics Simulations to Investigate How PZM21 Affects the Conformational State of the μ-Opioid Receptor Upon Activation. International journal of molecular sciences 2020. link 8 Wang J, Xu W, Shao J, He Z, Ding Z, Huang J et al.. miR-219-5p targets CaMKIIγ to attenuate morphine tolerance in rats. Oncotarget 2017. link 9 Oosten AW, Abrantes JA, Jönsson S, Matic M, van Schaik RHN, de Bruijn P et al.. A Prospective Population Pharmacokinetic Study on Morphine Metabolism in Cancer Patients. Clinical pharmacokinetics 2017. link 10 Hu XM, Cao SB, Zhang HL, Lyu DM, Chen LP, Xu H et al.. Downregulation of miR-219 enhances brain-derived neurotrophic factor production in mouse dorsal root ganglia to mediate morphine analgesic tolerance by upregulating CaMKIIγ. Molecular pain 2016. link 11 Marcus DJ, Zee M, Hughes A, Yuill MB, Hohmann AG, Mackie K et al.. Tolerance to the antinociceptive effects of chronic morphine requires c-Jun N-terminal kinase. Molecular pain 2015. link 12 Stockton SD, Devi LA. An integrated quantitative proteomics and systems biology approach to explore synaptic protein profile changes during morphine exposure. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 2014. link 13 Petko J, Justice-Bitner S, Jin J, Wong V, Kittanakom S, Ferraro TN et al.. MOR is not enough: identification of novel mu-opioid receptor interacting proteins using traditional and modified membrane yeast two-hybrid screens. PloS one 2013. link 14 Williams JT, Ingram SL, Henderson G, Chavkin C, von Zastrow M, Schulz S et al.. Regulation of μ-opioid receptors: desensitization, phosphorylation, internalization, and tolerance. Pharmacological reviews 2013. link 15 Fakurazi S, Rahman SA, Hidayat MT, Ithnin H, Moklas MA, Arulselvan P. The combination of mitragynine and morphine prevents the development of morphine tolerance in mice. Molecules (Basel, Switzerland) 2013. link 16 Karami R, Hosseini M, Khodabandehloo F, Khatami L, Taiarani Z. Different effects of L-arginine on morphine tolerance in sham and ovariectomized female mice. Journal of Zhejiang University. Science. B 2011. link 17 Kam AY, Liao D, Loh HH, Law PY. Morphine induces AMPA receptor internalization in primary hippocampal neurons via calcineurin-dependent dephosphorylation of GluR1 subunits. The Journal of neuroscience : the official journal of the Society for Neuroscience 2010. link 18 Sanchez-Simon FM, Zhang XX, Loh HH, Law PY, Rodriguez RE. Morphine regulates dopaminergic neuron differentiation via miR-133b. Molecular pharmacology 2010. link 19 Giordano C, Sansone A, Masi A, Lucente G, Punzi P, Mollica A et al.. Synthesis and activity of endomorphin-2 and morphiceptin analogues with proline surrogates in position 2. European journal of medicinal chemistry 2010. link 20 Kim H, Oh S, Sung B, Tian Y, Yang L, Wang S et al.. Anti-morphine antibody contributes to the development of morphine tolerance in rats. Neuroscience letters 2010. link 21 Hull LC, Rabender C, Gabra BH, Zhang F, Li PL, Dewey WL. Role of CD38, a cyclic ADP-ribosylcyclase, in morphine antinociception and tolerance. The Journal of pharmacology and experimental therapeutics 2010. link 22 Clarke H, Pereira S, Kennedy D, Gilron I, Katz J, Gollish J et al.. Gabapentin decreases morphine consumption and improves functional recovery following total knee arthroplasty. Pain research & management 2009. link 23 Li Y, Liu X, Liu C, Kang J, Yang J, Pei G et al.. Improvement of morphine-mediated analgesia by inhibition of β-arrestin2 expression in mice periaqueductal gray matter. International journal of molecular sciences 2009. link 24 He L, Kim J, Ou C, McFadden W, van Rijn RM, Whistler JL. Methadone antinociception is dependent on peripheral opioid receptors. The journal of pain 2009. link 25 Quintero GC, Erzurumlu RS, Vaccarino AL. Evaluation of morphine analgesia and motor coordination in mice following cortex-specific knockout of the N-methyl-D-aspartate NR1-subunit. Neuroscience letters 2008. link 26 Hughes CE, Sigmon SC, Pitts RC, Dykstra LA. Morphine tolerance as a function of ratio schedule: response requirement or unit price?. Journal of the experimental analysis of behavior 2005. link 27 Bohn LM, Lefkowitz RJ, Caron MG. Differential mechanisms of morphine antinociceptive tolerance revealed in (beta)arrestin-2 knock-out mice. The Journal of neuroscience : the official journal of the Society for Neuroscience 2002. link 28 Odum AL, Haworth SC, Schaal DW. Food-deprivation level alters the effects of morphine on pigeons' key pecking. Journal of the experimental analysis of behavior 1998. link 29 Yang H, Shen T, Qi Z, Yang Z, Zhang M, Jiang J et al.. TIM3 attenuates morphine antinociceptive tolerance and microglial neuroinflammation by suppressing the TRAF6/NF-κB pathway in male mice. Neuropharmacology 2025. link 30 Li Z, Liu J, Ju J, Peng X, Zhao W, Ren J et al.. Contributions of synaptic energetic dysfunction by microtubule dynamics and microtubule-based mitochondrial transport disorder to morphine tolerance. British journal of pharmacology 2025. link 31 Mozafari R, Khodagholi F, Kaveh N, Zibaii ME, Kalivas P, Haghparast A. Blockade of mGluR5 in nucleus accumbens modulates calcium sensor proteins, facilitates extinction, and attenuates reinstated morphine place preference in rats. Journal of psychiatric research 2024. link 32 Zhang M, Zhang Y, Li J, Li J, Ji J, Wang Z. μ opioid receptor carboxyl terminal-derived peptide alleviates morphine tolerance by inhibiting β-arrestin2. Neuroreport 2023. link 33 Wang J, Li Z, Tu Y, Gao F. The Dopaminergic System in the Ventral Tegmental Area Contributes to Morphine Analgesia and Tolerance. Neuroscience 2023. link 34 Sun LH, Xu Q, Jin L, Jin LD, Chen Q, Wu H et al.. The Involvement of CaV1.2 in Estrogenic Modulation of Morphine Antinociception in Rats Under Uterine Cervix Pain. Pain physician 2022. link 35 Sun Y, Wei H, Yu M, Zheng R, Li J, Fu Y et al.. Rapid titration with oral sustained-release morphine plus subcutaneous morphine in a multi-center, randomized control study of cancer patients with moderate to severe cancer pain. Japanese journal of clinical oncology 2022. link 36 Suliman NA, Moklas MAM, Taib CNM, Hidayat Baharuldin MT, Chiroma MS. (no title). Central nervous system agents in medicinal chemistry 2022. link 37 Beechinor RJ, Tyson R, Roth ME. Phenelzine and Morphine Drug-Drug Interaction? A Literature Review. Journal of pharmacy practice 2021. link 38 Yang L, Chen M, Ma Q, Sheng H, Cui D, Shao D et al.. Morphine selectively disinhibits glutamatergic input from mPFC onto dopamine neurons of VTA, inducing reward. Neuropharmacology 2020. link 39 Zhang K, Huang W, Chen W, Zhou Q, Zhang Q, Wu X et al.. Morphine stimulates angiogenesis through Akt/mTOR/eIF4E activation under serum deprivation or H. Clinical and experimental pharmacology & physiology 2020. link 40 Nyssen P, Mouithys-Mickalad A, Minguet G, Sauvage E, Wouters J, Franck T et al.. Morphine, a potential inhibitor of myeloperoxidase activity. Biochimica et biophysica acta. General subjects 2018. link 41 Paul AK, Gueven N, Dietis N. Age-dependent antinociception and behavioral inhibition by morphine. Pharmacology, biochemistry, and behavior 2018. link 42 Song J, Chen M, Dong Y, Lai B, Zheng P. Chronic morphine selectively sensitizes the effect of D1 receptor agonist on presynaptic glutamate release in basolateral amygdala neurons that project to prelimbic cortex. Neuropharmacology 2018. link 43 Gawel K, Jenda-Wojtanowska M, Gibula-Bruzda E, Kedzierska E, Filarowska J, Marszalek-Grabska M et al.. The influence of AMN082, metabotropic glutamate receptor 7 (mGlu7) allosteric agonist on the acute and chronic antinociceptive effects of morphine in the tail-immersion test in mice: Comparison with mGlu5 and mGlu2/3 ligands. Physiology & behavior 2018. link 44 Zádor F, Balogh M, Váradi A, Zádori ZS, Király K, Szűcs E et al.. 14-O-Methylmorphine: A Novel Selective Mu-Opioid Receptor Agonist with High Efficacy and Affinity. European journal of pharmacology 2017. link 45 Gach-Janczak K, Piekielna-Ciesielska J, Adamska-Bartłomiejczyk A, Perlikowska R, Kruszyński R, Kluczyk A et al.. Synthesis and activity of opioid peptidomimetics with β. Peptides 2017. link 46 Hong SI, Nguyen TL, Ma SX, Kim HC, Lee SY, Jang CG. TRPV1 modulates morphine-induced conditioned place preference via p38 MAPK in the nucleus accumbens. Behavioural brain research 2017. link 47 Yadlapalli JSK, Albayati ZAF, Penthala NR, Hendrickson HP, Crooks PA. Stability studies of potent opioid analgesic, morphine-6-O-sulfate in various buffers and biological matrices by HPLC-DAD analysis. Biomedical chromatography : BMC 2017. link 48 Baaklini LG, Arruda GV, Sakata RK. Assessment of the Analgesic Effect of Magnesium and Morphine in Combination in Patients With Cancer Pain: A Comparative Randomized Double-Blind Study. The American journal of hospice & palliative care 2017. link 49 Weng HL, Wang MJ. Effects of microRNA‑338‑3p on morphine‑induced apoptosis and its underlying mechanisms. Molecular medicine reports 2016. link 50 Ye D, Bu H, Guo G, Shu B, Wang W, Guan X et al.. Activation of CXCL10/CXCR3 signaling attenuates morphine analgesia: involvement of Gi protein. Journal of molecular neuroscience : MN 2014. link 51 Ahmar H, Tabani H, Hossein Koruni M, Davarani SS, Fakhari AR. A new platform for sensing urinary morphine based on carrier assisted electromembrane extraction followed by adsorptive stripping voltammetric detection on screen-printed electrode. Biosensors & bioelectronics 2014. link 52 Wang YT, Qin WJ, Liu Q, Li YL, Liang H, Chen F et al.. Chaperone heat shock protein 70 in nucleus accumbens core: a novel biological target of behavioural sensitization to morphine in rats. The international journal of neuropsychopharmacology 2014. link 53 Kumar R, Reeta KH, Ray SB. Antinociceptive effect of intrathecal loperamide: role of mu-opioid receptor and calcium channels. European journal of pharmacology 2012. link 54 Pasquinucci L, Parenti C, Turnaturi R, Aricò G, Marrazzo A, Prezzavento O et al.. The benzomorphan-based LP1 ligand is a suitable MOR/DOR agonist for chronic pain treatment. Life sciences 2012. link 55 Rinner U, Hudlicky T. Synthesis of morphine alkaloids and derivatives. Topics in current chemistry 2012. link 56 Szkutnik-Fiedler D, Grześkowiak E, Gaca M, Borowicz M. HPLC-UV determination of morphine in human plasma and its application to the clinical study. Acta poloniae pharmaceutica 2011. link 57 Salas E, Bocos C, Del Castillo C, Pérez-García C, Morales L, Alguacil LF. Gene expression analysis of heat shock proteins in the nucleus accumbens of rats with different morphine seeking behaviours. Behavioural brain research 2011. link 58 Dziopa L, Imeh-Nathaniel A, Baier D, Kiel M, Sameera S, Brager A et al.. Morphine-conditioned cue alters c-Fos protein expression in the brain of crayfish. Brain research bulletin 2011. link 59 Graversen C, Drewes AM, Farina D. Support vector machine classification of multi-channel EEG traces: a new tool to analyze the brain response to morphine treatment. Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual International Conference 2010. link 60 Nechifor M, Chelarescu D, Ciubotaru D. The influence of magnesium on morphine-induced stimulation of the reward system. Magnesium research 2010. link 61 Zhao L, Zhu Y, Wang D, Chen M, Gao P, Xiao W et al.. Morphine induces Beclin 1- and ATG5-dependent autophagy in human neuroblastoma SH-SY5Y cells and in the rat hippocampus. Autophagy 2010. link 62 Toda N, Kishioka S, Hatano Y, Toda H. Interactions between morphine and nitric oxide in various organs. Journal of anesthesia 2009. link 63 Basu NN, Kald B, Heath D. Morphine delays discharge following ambulatory surgery: a prospective institutional study. Journal of perioperative practice 2009. link 64 Mazák K, Hosztafi S, Rácz A, Noszál B. Structural and physicochemical profiling of morphine and related compounds of therapeutic interest. Mini reviews in medicinal chemistry 2009. link 65 Lin X, Wang YJ, Li Q, Hou YY, Hong MH, Cao YL et al.. Chronic high-dose morphine treatment promotes SH-SY5Y cell apoptosis via c-Jun N-terminal kinase-mediated activation of mitochondria-dependent pathway. The FEBS journal 2009. link 66 Cui J, Chen Q, Yu LC, Zhang Y. Chronic morphine application is protective against cell death in primary human neurons. Neuroreport 2008. link 67 Solecki W, Krowka T, Kubik J, Kaczmarek L, Przewlocki R. Increased analgesic tolerance to acute morphine in fosB knock-out mice: a gender study. Pharmacology, biochemistry, and behavior 2008. link 68 Narita M, Hashimoto K, Amano T, Narita M, Niikura K, Nakamura A et al.. Post-synaptic action of morphine on glutamatergic neuronal transmission related to the descending antinociceptive pathway in the rat thalamus. Journal of neurochemistry 2008. link 69 Ramírez-Galicia G, Garduño-Juárez R, Hemmateenejad B, Deeb O, Deciga-Campos M, Moctezuma-Eugenio JC. QSAR study on the antinociceptive activity of some morphinans. Chemical biology & drug design 2007. link 70 Tai YH, Wang YH, Tsai RY, Wang JJ, Tao PL, Liu TM et al.. Amitriptyline preserves morphine's antinociceptive effect by regulating the glutamate transporter GLAST and GLT-1 trafficking and excitatory amino acids concentration in morphine-tolerant rats. Pain 2007. link 71 Liu Y, Wang Y, Jiang Z, Wan C, Zhou W, Wang Z. The extracellular signal-regulated kinase signaling pathway is involved in the modulation of morphine-induced reward by mPer1. Neuroscience 2007. link 72 Yan Y, Yamada K, Mizoguchi H, Noda Y, Nagai T, Nitta A et al.. Reinforcing effects of morphine are reduced in tissue plasminogen activator-knockout mice. Neuroscience 2007. link 73 Kamerman PR, Becker N, Fick LG. Interactions between metoclopramide and morphine: enhanced antinociception and motor dysfunction in rats. Clinical and experimental pharmacology & physiology 2007. link 74 Liu W, Wang CH, Cui Y, Mo LQ, Zhi JL, Sun SN et al.. Inhibition of neuronal nitric oxide synthase antagonizes morphine antinociceptive tolerance by decreasing activation of p38 MAPK in the spinal microglia. Neuroscience letters 2006. link 75 Smith FL, Javed RR, Smith PA, Dewey WL, Gabra BH. PKC and PKA inhibitors reinstate morphine-induced behaviors in morphine tolerant mice. Pharmacological research 2006. link 76 Wang HY, Burns LH. Gbetagamma that interacts with adenylyl cyclase in opioid tolerance originates from a Gs protein. Journal of neurobiology 2006. link 77 Chou WY, Yang LC, Lu HF, Ko JY, Wang CH, Lin SH et al.. Association of mu-opioid receptor gene polymorphism (A118G) with variations in morphine consumption for analgesia after total knee arthroplasty. Acta anaesthesiologica Scandinavica 2006. link 78 Stevenson GW, Bilsky EJ, Negus SS. Targeting pain-suppressed behaviors in preclinical assays of pain and analgesia: effects of morphine on acetic acid-suppressed feeding in C57BL/6J mice. The journal of pain 2006. link 79 Suzuki M, Narita M, Nakamura A, Suzuki T. Role of gap junction in the expression of morphine-induced antinociception. European journal of pharmacology 2006. link 80 Khoshnoodi MA, Motiei-Langroudi R, Tahsili-Fahadan P, Yahyavi-Firouz-Abadi N, Ghahremani MH, Dehpour AR. Involvement of nitric oxide system in enhancement of morphine-induced conditioned place preference by agmatine in male mice. Neuroscience letters 2006. link 81 Peckham EM, Traynor JR. Comparison of the antinociceptive response to morphine and morphine-like compounds in male and female Sprague-Dawley rats. The Journal of pharmacology and experimental therapeutics 2006. link 82 Hnasko TS, Sotak BN, Palmiter RD. Morphine reward in dopamine-deficient mice. Nature 2005. link 83 Peckham EM, Barkley LM, Divin MF, Cicero TJ, Traynor JR. Comparison of the antinociceptive effect of acute morphine in female and male Sprague-Dawley rats using the long-lasting mu-antagonist methocinnamox. Brain research 2005. link 84 Ross JR, Rutter D, Welsh K, Joel SP, Goller K, Wells AU et al.. Clinical response to morphine in cancer patients and genetic variation in candidate genes. The pharmacogenomics journal 2005. link 85 Patti CL, Frussa-Filho R, Silva RH, Carvalho RC, Kameda SR, Takatsu-Coleman AL et al.. Behavioral characterization of morphine effects on motor activity in mice. Pharmacology, biochemistry, and behavior 2005. link 86 Narita M, Suzuki M, Narita M, Niikura K, Nakamura A, Miyatake M et al.. Involvement of spinal metabotropic glutamate receptor 5 in the development of tolerance to morphine-induced antinociception. Journal of neurochemistry 2005. link 87 Chakrabarti S, Regec A, Gintzler AR. Biochemical demonstration of mu-opioid receptor association with Gsalpha: enhancement following morphine exposure. Brain research. Molecular brain research 2005. link 88 Shavit Y, Wolf G, Goshen I, Livshits D, Yirmiya R. Interleukin-1 antagonizes morphine analgesia and underlies morphine tolerance. Pain 2005. link 89 Tao PL, Lai YS, Chow LH, Huang EY. Effects of morphine and endomorphins on the polysynaptic reflex in the isolated rat spinal cord. Naunyn-Schmiedeberg's archives of pharmacology 2005. link 90 Kotani K. Morphine use for at-home cancer patients in Japan. The Tohoku journal of experimental medicine 2004. link 91 Xu NJ, Yu YX, Zhu JM, Liu H, Shen L, Zeng R et al.. Inhibition of SNAP-25 phosphorylation at Ser187 is involved in chronic morphine-induced down-regulation of SNARE complex formation. The Journal of biological chemistry 2004. link 92 Fichna J, do-Rego JC, Costentin J, Chung NN, Schiller PW, Kosson P et al.. Opioid receptor binding and in vivo antinociceptive activity of position 3-substituted morphiceptin analogs. Biochemical and biophysical research communications 2004. link 93 Smith FL, Smith PA, Dewey WL, Javed RR. Effects of mGlu1 and mGlu5 metabotropic glutamate antagonists to reverse morphine tolerance in mice. European journal of pharmacology 2004. link 94 Roy S, Wang J, Gupta S, Charboneau R, Loh HH, Barke RA. Chronic morphine treatment differentiates T helper cells to Th2 effector cells by modulating transcription factors GATA 3 and T-bet. Journal of neuroimmunology 2004. link 95 Yang TT, Hung CF, Lee YJ, Su MJ, Wang SJ. Morphine inhibits glutamate exocytosis from rat cerebral cortex nerve terminals (synaptosomes) by reducing Ca2+ influx. Synapse (New York, N.Y.) 2004. link 96 Sawyer MB, Innocenti F, Das S, Cheng C, Ramírez J, Pantle-Fisher FH et al.. A pharmacogenetic study of uridine diphosphate-glucuronosyltransferase 2B7 in patients receiving morphine. Clinical pharmacology and therapeutics 2003. link00053-5) 97 Stachulski AV, Scheinmann F, Ferguson JR, Law JL, Lumbard KW, Hopkins P et al.. Structure-activity relationships of some opiate glycosides. Bioorganic & medicinal chemistry letters 2003. link00056-8) 98 Trost BM, Tang W. Enantioselective synthesis of (-)-codeine and (-)-morphine. Journal of the American Chemical Society 2002. link 99 Song P, Liu XY, Zhao ZQ. Interleukin-2-induced antinociception in morphine-insensitive rats. Acta pharmacologica Sinica 2002. link 100 Yuan CS, Attele AS, Dey L, Lynch JP, Guan X. Transcutaneous electrical acupoint stimulation potentiates analgesic effect of morphine. Journal of clinical pharmacology 2002. link

    Original source

    1. [1]
      Total synthesis and biological activity of "carbamorphine": O-to-CH — Akiyama S, Ople RS, Kremsmair A, Ramos-Gonzalez N, Nedungadan T, Kennedy BJ et al. Proceedings of the National Academy of Sciences of the United States of America (2025)
    2. [2]
      Design, synthesis, in-vivo, and in-silico studies of 1,2,3-triazole tethered derivatives of morphine as novel anti-nociceptive agents. — Nourmandipour F, Emadi R, Salehi P, Zarin MKZ, Khoramjouy M, Beirami AD et al. PloS one (2025)
    3. [3]
      Physicians' views of the use of morphine in palliative care: a cross-sectional survey from a tertiary care centre in Northern Sri Lanka. — Nisahan B, Raviraj S, Navaratnam S, Nadarajah R BMC research notes (2025)
    4. [4]
      Melatonin attenuates morphine-induced conditioned place preference in Wistar rats. — Alshehri FS, Alghamdi BS, Hakami AY, Alshehri AA, Althobaiti YS Brain and behavior (2021)
    5. [5]
      Exercise Reduces Morphine-Induced Hyperalgesia and Antinociceptive Tolerance. — Gong X, Fan R, Zhu Q, Ye X, Chen Y, Zhang M BioMed research international (2021)
    6. [6]
      Synthesis of Potential Haptens with Morphine Skeleton and Determination of Protonation Constants. — Köteles I, Mazák K, Tóth G, Tűz B, Hosztafi S Molecules (Basel, Switzerland) (2020)
    7. [7]
      Molecular Dynamics Simulations to Investigate How PZM21 Affects the Conformational State of the μ-Opioid Receptor Upon Activation. — Zhao Z, Huang T, Li J International journal of molecular sciences (2020)
    8. [8]
      miR-219-5p targets CaMKIIγ to attenuate morphine tolerance in rats. — Wang J, Xu W, Shao J, He Z, Ding Z, Huang J et al. Oncotarget (2017)
    9. [9]
      A Prospective Population Pharmacokinetic Study on Morphine Metabolism in Cancer Patients. — Oosten AW, Abrantes JA, Jönsson S, Matic M, van Schaik RHN, de Bruijn P et al. Clinical pharmacokinetics (2017)
    10. [10]
      Downregulation of miR-219 enhances brain-derived neurotrophic factor production in mouse dorsal root ganglia to mediate morphine analgesic tolerance by upregulating CaMKIIγ. — Hu XM, Cao SB, Zhang HL, Lyu DM, Chen LP, Xu H et al. Molecular pain (2016)
    11. [11]
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