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

Department of Neurology, University of Michigan, Ann Arbor, MI, USA.
Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology (Impact Factor: 7.05). 11/2010; 36(3):664-76. DOI: 10.1038/npp.2010.197
Source: PubMed


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.

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Available from: Xianguo Liu, Apr 06, 2014
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    • "It has been documented that chronic morphine activates astrocytes and microglia cells and increases pro-inflammatory cytokine gene expression.26,27 Once activated, microglia can release cytokines, chemokines, ROS, and complement proteins which start progressive cycle of neuroinflammation and cause synaptic plasticity.28,29 "
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    • "While opioid receptor-effector uncoupling has been implicated in physical dependence, this phenomenon cannot fully account for withdrawal signs and symptoms or rebound responses in neurons after the administration of opioid receptor antagonists [5]. Recently, the importance of glial activation and the release of proinflammatory cytokines within the PAG acting on neuronal receptor in withdrawal responses has been reported [6]. This topical report will review "
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    The Scientific World Journal 08/2012; 2012(24):940613. DOI:10.1100/2012/940613 · 1.73 Impact Factor
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    • "Immunohistochemical expression of GFAP, TNFα and NeuN in the spinal cord and the L4/5 DRG in rats with ddC treatment was investigated as described previously (Hao et al., 2011). For immunofluorescence detection, cryosections were probed overnight with rabbit anti- GFAP polyclonal antibody (1: 2000, DakoCytomation, Glostrup, Denmark), goat anti-rat TNFα antibody (1: 100; R&D systems, Minneapolis, MN), and mouse anti-NeuN monoclonal antibody (A60) (1: 5000, Millipore, Billerica, MA). "
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