Brain, behavior, and immunity
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Brain Behav. Immun. · May 2010
Dynamic regulation of spinal pro-inflammatory cytokine release in the rat in vivo following peripheral nerve injury.
Spinal release of cytokines may play a critical role in the maladapted nociceptive signaling underlying chronic pain states. In order to investigate this biology, we have developed a novel 'high flux' intrathecal microdialysis approach in combination with multiplex bead-based immunoassay technology to concurrently monitor the spinal release of interleukin (IL)-1beta, IL-6 and tumour necrosis factor (TNF)alpha in rats with unilateral sciatic nerve chronic constriction injury (CCI). Intrathecal microdialysis was performed under isoflurane/N(2)O anaesthesia in rats with confirmed mechanical hypersensitivity. ⋯ In the same animals, this treatment also significantly reduced intrathecal IL-1beta, IL-6 and TNFalpha and prevented afferent stimulation-evoked cytokine release of both IL-1beta and IL-6. These results provide support for glia as the source of the majority of intrathecal IL-1beta, IL-6 and TNFalpha that accompanies mechanical hypersensitivity in the CCI rat. Moreover, our studies demonstrate the ability of a neurone-glia signaling mechanism to dynamically modulate this release and support a role of spinal IL-1beta in the phasic transmission of abnormal pain signals.
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Brain Behav. Immun. · Mar 2010
Spinally applied ketamine or morphine attenuate peripheral inflammation and hyperalgesia in acute and chronic phases of experimental arthritis.
Inflammation causes sensitization of peripheral and central nociceptive neurons. Pharmacological modulation of the latter has successfully been used for clinical pain relief. In particular, inhibitors of the NMDA glutamate receptor such as ketamine and agonists at the mu-opioid receptor such as morphine are broadly used. ⋯ Morphine showed strong antinociceptive effects in the acute phase only, while the newly established effective dose for ketamine in a continuous application design reduced hyperalgesia in the acute and the chronic stage. In conclusion, both compounds exhibit anti-inflammatory effects during induction and maintenance of arthritis when applied intrathecally. These data thus propose a role of spinal NMDA- and opioid-receptors in the neuronal control of immune-mediated inflammation.
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Brain Behav. Immun. · Mar 2010
The effect of non-steroidal anti-inflammatory agents on behavioural changes and cytokine production following systemic inflammation: Implications for a role of COX-1.
Systemic inflammation gives rise to metabolic and behavioural changes, largely mediated by pro-inflammatory cytokines and prostaglandin production (PGE(2)) at the blood-brain barrier. Despite numerous studies, the exact biological pathways that give rise to these changes remains elusive. This study investigated the mechanisms underlying immune-to-brain communication following systemic inflammation using various anti-inflammatory agents. ⋯ Our results suggest that the acute LPS-induced changes in burrowing and open-field activity depend on COX-1. We further show that COX-1 is not responsible for the induction of brain IL-6, IL-1beta and TNF-alpha synthesis or LPS-induced hypothermia. Our results may have implications for novel therapeutic strategies to treat or prevent neurological diseases with an inflammatory component.
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Brain Behav. Immun. · Mar 2010
Self-reported experiences of everyday discrimination are associated with elevated C-reactive protein levels in older African-American adults.
Self-reported experiences of "everyday" discrimination have been linked to indices of cardiovascular disease and overall mortality and findings have been particularly pronounced for African-American populations. However, the biological mechanisms underlying these associations remain unclear. C-reactive protein (CRP), a marker of inflammation, is a known correlate of cardiovascular and other health outcomes and has also been linked to several psychosocial processes. ⋯ This association remained significant after additional adjustments for depressive symptoms (B=.10, p=.04), smoking, and chronic health conditions (heart disease, diabetes, hypertension) that might influence inflammation (B=.11, p=.02). However, results were attenuated when body mass index (BMI) was added to the model (B=.09, p=.07). In conclusion, self-reported experiences of everyday discrimination are associated with higher levels of CRP in older African-American adults, although this association is not completely independent of BMI.
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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.