The Role of TNFα in the Periaqueductal Gray During Naloxone-Precipitated Morphine Withdrawal in Rats

• Published in: Neuropsychopharmacology (New York, N.Y.) Vol. 36; no. 3; pp. 664 - 676
• Main Authors: SHUANGLIN HAO, SHUE LIU, XUEXING ZHENG, WENWEN ZHENG, OUYANG, Handong, MATA, Marina, FINK, David J
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing Group 01.02.2011
• Subjects: Animals; Astrocytes; Behavior, Animal; Biological and medical sciences; CREB-Binding Protein - metabolism; Cyclic AMP response element-binding protein; Cytokines; Drug tolerance; Enzyme-Linked Immunosorbent Assay - methods; Extracellular signal-regulated kinase; Extracellular Signal-Regulated MAP Kinases - metabolism; Fos protein; Gene Expression Regulation - drug effects; Glial fibrillary acidic protein; Glial Fibrillary Acidic Protein - metabolism; Green Fluorescent Proteins - genetics; Herpes simplex virus; Immunoreactivity; Inflammation; Male; Medical sciences; Mesencephalon; Microinjection; Microinjections - methods; Morphine; Morphine - adverse effects; Naloxone; Naloxone - therapeutic use; Narcotic Antagonists - therapeutic use; Oncogene Proteins v-fos - metabolism; Opioids; Original; Periaqueductal Gray - drug effects; Periaqueductal Gray - metabolism; Periaqueductal gray area; Phosphorylation; Phosphorylation - drug effects; Rats; Rats, Sprague-Dawley; Regulatory sequences; Substance Withdrawal Syndrome - drug therapy; Substance Withdrawal Syndrome - etiology; Substance Withdrawal Syndrome - pathology; Transduction, Genetic; Tumor necrosis factor receptors; Tumor necrosis factor- alpha; Tumor Necrosis Factor-alpha - metabolism; Morphinan derivatives; Narcotic antagonist; TNFα; Rat; Cytokine; Rodentia; Central nervous system; morphine withdrawal; Opiates; Morphine; Narcotic analgesic; Encephalon; soluble TNF receptor; Vertebrata; Mammalia; Naloxone; Periaqueductal gray matter; Tumor necrosis factor; Animal; PAG; Drug of abuse; Gene therapy; Tumor necrosis factor α; Biological receptor
• ISSN: 0893-133X; 1740-634X
• DOI: 10.1038/npp.2010.197

Tolerance and dependence are common complications of long-term treatment of pain with opioids, which substantially limit the long-term use of these drugs. The mechanisms underlying these phenomena are poorly understood. Studies have implicated the midbrain periaqueductal gray (PAG) in the pathogenesis of morphine withdrawal, and recent evidence suggests that proinflammatory cytokines in the PAG may play an important role in morphine withdrawal. Here we report that chronic morphine withdrawal-induced upregulation of glial fibrillary acidic protein (GFAP), tumor necrosis factor alpha (TNFα) and phosphorylation of ERK1/2 (pERK1/2) in the caudal ventrolateral PAG (vlPAG). Microinjection of recombinant TNFα into the vlPAG followed by intraperitoneal naloxone resulted in morphine withdrawal-like behavioral signs, and upregulation of pERK1/2, expression of Fos, and phosphorylation of cAMP response element binding (pCREB) protein. We used a herpes simplex virus (HSV)-based vector expressing p55 soluble TNF receptor (sTNFR) microinjected into the PAG to examine the role of the proinflammatory cytokine TNFα in the PAG in the naloxone-precipitated withdrawal response. Microinjection of HSV vector expressing sTNFR into the PAG before the start of morphine treatment significantly reduced the naloxone-precipitated withdrawal behavioral response and downregulated the expression of GFAP and TNFα in astrocytes of the PAG. TNFR type I colocalized with neuronal pERK1/2. Microinjection of HSV vector expressing sTNFR into the PAG also significantly reduced the phosphorylation of both ERK1/2 and CREB, and reduced Fos immunoreactivity in neurons of the PAG following naloxone-precipitated withdrawal. These results support the concept that proinflammatory cytokines expressed in astrocytes in the PAG may play an important role in the pathogenesis of morphine withdrawal response.