Brain, behavior, and immunity
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Brain Behav. Immun. · Jan 2010
Evidence that opioids may have toll-like receptor 4 and MD-2 effects.
Opioid-induced proinflammatory glial activation modulates wide-ranging aspects of opioid pharmacology including: opposition of acute and chronic opioid analgesia, opioid analgesic tolerance, opioid-induced hyperalgesia, development of opioid dependence, opioid reward, and opioid respiratory depression. However, the mechanism(s) contributing to opioid-induced proinflammatory actions remains unresolved. The potential involvement of toll-like receptor 4 (TLR4) was examined using in vitro, in vivo, and in silico techniques. ⋯ In silico docking simulations revealed ligands bound preferentially to the LPS binding pocket of MD-2 rather than TLR4. An in silico to in vitro prediction model was built and tested with substantial accuracy. These data provide evidence that select opioids may non-stereoselectively influence TLR4 signaling and have behavioral consequences resulting, in part, via TLR4 signaling.
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Brain Behav. Immun. · Jan 2010
Glial cell line-derived neurotrophic factor acutely modulates the excitability of rat small-diameter trigeminal ganglion neurons innervating facial skin.
Glial cell line-derived neurotrophic factor (GDNF) plays an important role in adult sensory neuron function. However, the acute effects of GDNF on primary sensory neuron excitability remain to be elucidated. The aim of the present study was to investigate whether GDNF acutely modulates the excitability of adult rat trigeminal ganglion (TRG) neurons that innervate the facial skin by using perforated-patch clamping, retrograde-labeling and immunohistochemistry techniques. ⋯ GDNF application also increased the duration of the repolarization phase and decreased the duration of the depolarization phase of the action potential, and these characteristic effects were also abolished by co-application of K252b. These results suggest that acute application of GDNF enhances the neuronal excitability of adult rat small-diameter TRG neurons innervating the facial skin, via activation of GDNF-induced intracellular signaling pathway. We therefore conclude that a local release of GDNF from TRG neuronal soma and/or nerve terminals may regulate normal sensory function, including nociception.
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Brain Behav. Immun. · Jan 2010
Regulation of cytokine signaling and T-cell recruitment in the aging mouse brain in response to central inflammatory challenge.
Aging is often accompanied by increased levels of inflammatory molecules in the organism, but age-related changes in the brain response to inflammatory challenges still require clarification. We here investigated in mice whether cytokine signaling and T-cell neuroinvasion undergo age-related changes. We first analyzed the expression of molecules involved in T-cell infiltration and cytokine signaling regulation in the septum and hippocampus of 2-3 months and 20- to 24-month-old mice at 4h after intracerebroventricular injections of tumor necrosis factor (TNF)-alpha or interferon-gammaversus saline injections. ⋯ CD3(+), CD4(+) and CD8(+) T-cells exhibited progressive age-related increases in brain parenchyma and choroid plexus after cytokine exposure. The findings indicate that the brain responses to inflammatory challenges are not only preserved with advancing age, but also include gradual amplification of ICAM-1 expression and T-cell recruitment. The data highlight molecular and cellular correlates of age-related increase of brain sensitivity to inflammatory stimuli, which could be involved in altered brain vulnerability during aging.