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August 16, 2012: by Bill Sardi
Scientists report today that heroin and morphine addiction can be blocked by inhibition of an immune cell receptor called toll-like receptor-4 (TLR-4). It has been reported that resveratrol specifically inhibits TLR-4. See reports below.
ScienceDaily (Aug. 14, 2012) — In a major breakthrough, an international team of scientists has proven that addiction to morphine and heroin can be blocked, while at the same time increasing pain relief.
The team from the University of Adelaide and University of Colorado has discovered the key mechanism in the body’s immune system that amplifies addiction to opioid drugs.
Laboratory studies have shown that the drug (+)-naloxone (pronounced: PLUS nal-OX-own) will selectively block the immune-addiction response.
The results — which could eventually lead to new co-formulated drugs that assist patients with severe pain, as well as helping heroin users to kick the habit — will be published August 16 in the Journal of Neuroscience.
“Our studies have shown conclusively that we can block addiction via the immune system of the brain, without targeting the brain’s wiring,” says the lead author of the study, Dr Mark Hutchinson, ARC Research Fellow in the University of Adelaide’s School of Medical Sciences.
“Both the central nervous system and the immune system play important roles in creating addiction, but our studies have shown we only need to block the immune response in the brain to prevent cravings for opioid drugs.”
The team has focused its research efforts on the immune receptor known as Toll-Like receptor 4 (TLR4).
“Opioid drugs such as morphine and heroin bind to TLR4 in a similar way to the normal immune response to bacteria. The problem is that TLR4 then acts as an amplifier for addiction,” Dr Hutchinson says.
“The drug (+)-naloxone automatically shuts down the addiction. It shuts down the need to take opioids, it cuts out behaviours associated with addiction, and the neurochemistry in the brain changes — dopamine, which is the chemical important for providing that sense of ‘reward’ from the drug, is no longer produced.”
Senior author Professor Linda Watkins, from the Center for Neuroscience at the University of Colorado Boulder, says: “This work fundamentally changes what we understand about opioids, reward and addiction. We’ve suspected for some years that TLR4 may be the key to blocking opioid addiction, but now we have the proof.
“The drug that we’ve used to block addiction, (+)-naloxone, is a non-opioid mirror image drug that was created by Dr Kenner Rice in the 1970s. We believe this will prove extremely useful as a co-formulated drug with morphine, so that patients who require relief for severe pain will not become addicted but still receive pain relief. This has the potential to lead to major advances in patient and palliative care,” Professor Watkins says.
The researchers say clinical trials may be possible within the next 18 months.
This study has been funded by the National Institute on Drug Abuse (NIDA) in the United States and the Australian Research Council (ARC).
J Immunol. 2005 Sep 1;175(5):3339-46.
Western Human Nutrition Research Center, Agricultural Research Service, US Department of Agriculture, University of California, Davis, CA 95616, USA
TLRs can activate two distinct branches of downstream signaling pathways. MyD88 and Toll/IL-1R domain-containing adaptor inducing IFN-beta (TRIF) pathways lead to the expression of proinflammatory cytokines and type I IFN genes, respectively. Numerous reports have demonstrated thatresveratrol, a phytoalexin with anti-inflammatory effects, inhibits NF-kappaB activation and other downstream signaling pathways leading to the suppression of target gene expression. However, the direct targets of resveratrol have not been identified. In this study, we attempted to identify the molecular target for resveratrol in TLR-mediated signaling pathways. Resveratrol suppressed NF-kappaB activation and cyclooxygenase-2 expression in RAW264.7 cells following TLR3 and TLR4 stimulation, but not TLR2 or TLR9. Further, resveratrol inhibited NF-kappaB activation induced by TRIF, but not by MyD88. The activation of IFN regulatory factor 3 and the expression of IFN-beta induced by LPS, poly(I:C), or TRIF were also suppressed by resveratrol. The suppressive effect of resveratrol on LPS-induced NF-kappaB activation was abolished in TRIF-deficient mouse embryonic fibroblasts, whereas LPS-induced degradation of IkappaBalpha and expression of cyclooxygenase-2 and inducible NO synthase were still inhibited in MyD88-deficient macrophages. Furthermore, resveratrol inhibited the kinase activity of TANK-binding kinase 1 and the NF-kappaB activation induced by RIP1 in RAW264.7 cells. Together, these results demonstrate that resveratrol specifically inhibits TRIF signaling in the TLR3 and TLR4 pathway by targeting TANK-binding kinase 1 and RIP1 in TRIF complex. The results raise the possibility that certain dietary phytochemicals can modulate TLR-derived signaling and inflammatory target gene expression and can alter susceptibility to microbial infection and chronic inflammatory diseases.