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.

Download full-text


Available from: Xianguo Liu, Apr 06, 2014
  • Source
    • "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 "
    [Show abstract] [Hide abstract]
    ABSTRACT: Consumption of chronic morphine induces neuro-inflammation and addictive seeking behavior. Ginger (Zingiber officinale Roscoe), a well-known spice plant, has been used traditionally in the treatment of a wide variety of ailments. It has been shown that ginger has anti-inflammatory, anti-oxidative and antinociceptive properties. However, its influences on morphine-induced addictive behaviors have not yet been clarified. For conditioning to the morphine, the male Wistar rats received morphine (12 mg/kg i.p.) for 6 consecutive days and treatment groups were given different doses of ginger (25, 50 and 100 mg/kg i.g.) 30 min before morphine injection. For investigating addictive seeking behavior, conditioned place preference test (CPP) was used. Our result demonstrated that injection of morphine for 6 days induces dependency to morphine and creates addictive seeking behavior and ginger (100 mg/kg) could decrease time spend in conditioning box (addictive seeking behavior). In conclusion, the data indicate that ginger extract has a potential anti-addictive property against chronic usage of morphine.
    Full-text · Article · Oct 2013
  • Source
    • "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 "
    [Show abstract] [Hide abstract]
    ABSTRACT: The chronic use of opiates (i.e., narcotics such as the natural derivatives of opium including morphine or codeine) or opioids (i.e., semisynthetic derivatives of opium and other molecules that activate opioid receptors) induces dependence, which is associated with various specific behavioral and somatic signs after their withdrawal or after the administration of an opioid antagonist. Among the brain regions implicated in opiate dependence and withdrawal, the periaqueductal gray area (PAG) appears to be critical in regulating the complex signs and symptoms of opioid withdrawal. Numerous neurochemical mechanisms in the PAG have been identified that may contribute to the opioid withdrawal syndrome. Accumulating evidence suggests that glial activation leading to the release of proinflammatory molecules acting on neurons is important in the complex syndrome of opioid dependence and withdrawal. This paper focuses on the recent advances in our understanding of the vital role that glia-neuron interactions play in opioid dependence and withdrawal within the PAG. We summarize those neurochemical mechanisms associated with opioid withdrawal including the recently defined importance of TNFα release from activated glial cells that communicate with TNF receptors on PAG neurons.
    Full-text · Article · Aug 2012 · The Scientific World Journal
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    ABSTRACT: In patients with HIV/AIDS, neuropathic pain is a common neurological complication. Infection with the HIV itself may lead to neuropathic pain, and painful symptoms are enhanced when patients are treated with nucleoside reverse transcriptase inhibitors (NRTIs). The mechanisms by which NRTIs contribute to the development of neuropathic pain are not known. In the current studies, we tested the role of TNFα in antiretroviral drug-induced neuropathic pain. We administered 2',3'-dideoxycytidine (ddC, one of the NRTIs) systemically to induce mechanical allodynia. We found that ddC induced overexpression of both mRNA and proteins of GFAP and TNFα in the spinal dorsal horn. TNFα was colocalized with GFAP in the spinal dorsal horn and with NeuN in the DRG. Knockdown of TNFα with siRNA blocked the mechanical allodynia induced by ddC. Intrathecal administration of glial inhibitor or recombinant TNF soluble receptor, reversed mechanical allodynia induced by ddC. These results suggest that TNFα is involved in NRTI-induced neuropathic pain.
    Full-text · Article · Jun 2011 · Brain Behavior and Immunity
Show more