The role of TNFα in the periaqueductal gray during naloxone-precipitated morphine withdrawal in rats.
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.
Department of Neurology, University of Michigan, Ann Arbor, MI, USA. shao@med.miami.edu
Shuanglin
S
Hao
Shue
S
Liu
Xuexing
X
Zheng
Wenwen
W
Zheng
Handong
H
Ouyang
Marina
M
Mata
David J
DJ
Fink
D000818:Animals; D001522:Behavior, Animal; D050882:CREB-Binding Protein / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000235:genetics; D008297:Male; D008845:Microinjections / Q000379:methods; D009020:Morphine / Q000009:adverse effects*; D009270:Naloxone / Q000627:therapeutic use*; D009292:Narcotic Antagonists / Q000627:therapeutic use*; D016761:Oncogene Proteins v-fos / Q000378:metabolism; D010487:Periaqueductal Gray / Q000187:drug effects* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013375:Substance Withdrawal Syndrome / Q000188:drug therapy / Q000209:etiology / Q000473:pathology; D014161:Transduction, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D005904:Glial Fibrillary Acidic Protein; D009292:Narcotic Antagonists; D016761:Oncogene Proteins v-fos; D014409:Tumor Necrosis Factor-alpha; D049452:Green Fluorescent Proteins; D009270:Naloxone; D009020:Morphine; D050882:CREB-Binding Protein; D048049:Extracellular Signal-Regulated MAP Kinases