ArticleThe Journal of neuroscience : the official journal of the Society for Neuroscience2010
Spinal matrix metalloproteinase-9 contributes to physical dependence on morphine in mice.
Article in The Journal of neuroscience : the official journal of the Society for Neuroscience, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 37 papers.
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Who cites it
37 citing papers in PubMed, 68 citations in OpenAlex.
- Amyloid Precursor Protein Processing Links Female Urgency Urinary Incontinence with Alzheimer's Disease: Implications for Treatment.International journal of molecular sciences · 2026Article
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- Diabetic Neuropathic Pain: Directions for Exploring Treatments.Biomedicines · 2024Review
- Hydrogen attenuates postoperative pain through Trx1/ASK1/MMP9 signaling pathway.Journal of neuroinflammation · 2023Article
- Dynamic regulation of the extracellular matrix in reward memory processes: a question of time.Frontiers in cellular neuroscience · 2023Review
- A Glitch in the Matrix: The Role of Extracellular Matrix Remodeling in Opioid Use Disorder.Frontiers in integrative neuroscience · 2022Review
- Role of Matrix Metalloproteinases in Myelin Abnormalities and Mechanical Allodynia in Rodents with Diabetic Neuropathy.Aging and disease · 2021Article
- Opioid and neuroHIV Comorbidity - Current and Future Perspectives.Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology · 2020Review
- Sphingosine-1-phosphate receptor subtype 1 activation in the central nervous system contributes to morphine withdrawal in rodents.Journal of neuroinflammation · 2020Article
- High Estrogen Level Modifies Postoperative Hyperalgesia via GPR30 and MMP-9 in Dorsal Root Ganglia Neurons.Neurochemical research · 2020Article
- In Vitro and In Vivo Effects of Flavonoids on Peripheral Neuropathic Pain.Molecules (Basel, Switzerland) · 2020Review
- Article
- The Opioid-Addicted Tetrapartite Synapse.Biological psychiatry · 2020Review
- Murine Models for the Study of Fetal Alcohol Spectrum Disorders: An Overview.Frontiers in pediatrics · 2020Review
- Chronic Intermittent Ethanol Exposure Induces Upregulation of Matrix Metalloproteinase-9 in the Rat Medial Prefrontal Cortex and Hippocampus.Neurochemical research · 2019Article
- Yokukansan Alleviates Cancer Pain by Suppressing Matrix Metalloproteinase-9 in a Mouse Bone Metastasis Model.Evidence-based complementary and alternative medicine : eCAM · 2019Article
- The Attenuating Effect of Curcumin on Morphine Dependence in Rats: The Involvement of Spinal Microglial Cells and Inflammatory Cytokines.Iranian journal of pharmaceutical research : IJPR · 2019Article
- Astroglial correlates of neuropsychiatric disease: From astrocytopathy to astrogliosis.Progress in neuro-psychopharmacology & biological psychiatry · 2018Review
- Procyanidins attenuate neuropathic pain by suppressing matrix metalloproteinase-9/2.Journal of neuroinflammation · 2018Article
- Morphine alters the circulating proteolytic profile in mice: functional consequences on cellular migration and invasion.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2017Article
Corrections and comments
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Authors and funding
6 authors at 2 institutions in 2 countries.
Funding
Abstract
Preventing and reversing opioid dependence continues to be a clinical challenge and underlying mechanisms of opioid actions remain elusive. We report that matrix metalloproteinase-9 (MMP-9) in the spinal cord contributes to development of physical dependence on morphine. Chronic morphine exposure and naloxone-precipitated withdrawal increase activity of spinal MMP-9. Spinal inhibition or targeted mutation of MMP-9 suppresses behavioral signs of morphine withdrawal and the associated neurochemical alterations. The increased MMP-9 activity is mainly distributed in the superficial dorsal horn and colocalized primarily with neurons and small numbers of astrocytes and microglia. Morphine exposure and withdrawal increase phosphorylation of NR1 and NR2B receptors, ERK1/2, calmodulin-dependent kinase II, and cAMP response element binding proteins; and such phosphorylation is suppressed by either spinal inhibition or targeted mutation of MMP-9. Further, spinal administration of exogenous MMP-9 induces morphine withdrawal-like behavioral signs and mechanical allodynia, activates NR1 and NR2 receptors, and downregulates integrin-beta1, while a function-neutralizing antibody against integrin-beta1 suppresses MMP-9-induced phosphorylation of NR1 and NR2B. Morphine withdrawal-induced MMP-9 activity is also reduced by an nNOS inhibitor. Thus, we hypothesize that spinal MMP-9 may contribute to the development of morphine dependence primarily through neuronal activation and interaction with NR1 and NR2B receptors via integrin-beta1 and NO pathways. The other gelatinase, MMP-2, is not involved in morphine dependence. Inhibiting spinal MMP-9 or MMP-2 reduces chronic and/or acute morphine tolerance. This study suggests a novel therapeutic approach for preventing, minimizing, or reversing opioid dependence and tolerance.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.