The role of TNFalpha in the periaqueductal gray during naloxone-precipitated morphine withdrawal in rats.

Authors: Hao, S  Liu, S  Zheng, X  Zheng, W  Ouyang, H  Mata, M  Fink, DJ 
Citation: Hao S, etal., Neuropsychopharmacology. 2011 Feb;36(3):664-76. Epub 2010 Nov 10.
Pubmed: (View Article at PubMed) PMID:21068718
DOI: Full-text: 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 (TNFalpha) and phosphorylation of ERK1/2 (pERK1/2) in the caudal ventrolateral PAG (vlPAG). Microinjection of recombinant TNFalpha 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 TNFalpha 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 TNFalpha 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.

Annotation

Objects referenced in this article

Additional Information

 
CRRD Object Information
CRRD ID: 5131155
Created: 2011-04-20
Species: All species
Last Modified: 2011-04-20
Status: ACTIVE



NHLBI Logo

RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.