Spinal matrix metalloproteinase-9 contributes to physical dependence on morphine in mice.
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.
Liu
Wen-Tao
WT
Department of Neurobiology, Parker University Research Institute, Dallas, Texas 75229, USA.
Han
Yuan
Y
Liu
Yue-Peng
YP
Song
Angela A
AA
Barnes
Beth
B
Song
Xue-Jun
XJ
D000818:Animals; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004361:Drug Tolerance / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D006930:Hyperalgesia / Q000503:physiopathology; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000172:deficiency / Q000378:metabolism* / Q000493:pharmacokinetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009020:Morphine / Q000009:adverse effects; D009021:Morphine Dependence / Q000188:drug therapy / Q000473:pathology* / Q000503:physiopathology*; D009270:Naloxone / Q000627:therapeutic use; D009292:Narcotic Antagonists / Q000627:therapeutic use; D009294:Narcotics / Q000009:adverse effects; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D017288:Pain Threshold / Q000187:drug effects / Q000502:physiology; D013116:Spinal Cord / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D013997:Time Factors
D004791:Enzyme Inhibitors; D009292:Narcotic Antagonists; D009294:Narcotics; D009419:Nerve Tissue Proteins; D009270:Naloxone; D009020:Morphine; D020780:Matrix Metalloproteinase 9