New Drug Target Could Prevent Tolerance and Addiction to Opioids

Summary: A new study reports researchers have discovered a brain mechanism that could be a suitable target to prevent addiction and tolerance to opioids.

Source: Georgia State University.

Researchers have identified a brain mechanism that could be a drug target to help prevent tolerance and addiction to opioid pain medication, such as morphine, according to a study by Georgia State University and Emory University.

The findings, published in the Nature journal Neuropsychopharmacology in August, show for the first time that morphine tolerance is due to an inflammatory response produced in the brain. This brain inflammation is caused by the release of cytokines, chemical messengers in the body that trigger an immune response, similar to a viral infection.

Researchers’ results show blocking a particular cytokine eliminated morphine tolerance, and they were able to reduce the dose of morphine required to alleviate pain by half.

“These results have important clinical implications for the treatment of pain and also addiction,” said Lori Eidson, lead author and a graduate student in the laboratory of Dr. Anne Murphy in the Neuroscience Institute of Georgia State. “Until now, the precise underlying mechanism for opioid tolerance and its prevention have remained unknown.”

Over 67 percent of the United States population will experience chronic pain at some point in their lives. Morphine is the primary drug used to manage severe and chronic pain, with 3 to 4 percent of adults in the U.S. receiving long-term opioid therapy. However, tolerance to morphine, defined as a decrease in pain relief over time, significantly impedes treatment for about 60 percent of patients. Long-term treatment with opioids is associated with increased risk of abuse, dependence and fatal overdoses.

Image shows pill bottles.

Researchers’ results show blocking a particular cytokine eliminated morphine tolerance, and they were able to reduce the dose of morphine required to alleviate pain by half. Neurosciencenews image is adapted from the Georgia State University press release.

In the absence of pain, morphine interferes with the body’s ability to maintain normal function, referred to as homeostasis. Anything that interferes with homeostasis is viewed by the body as a pathogen, resulting in an immune response to rid the body of the pathogen. When Eidson gave rats drugs that blocked the immune response, the rats no longer became tolerant to morphine.

The study also found that tolerance to morphine develops rapidly. Administering one dose of morphine to rats for three days was sufficient to induce tolerance.

About this neurology research article

Co-authors of the study include Murphy and Drs. Kiyoshi Inoue, Larry Young and Malu Tansey of Emory University.

Funding: The study was funded by the National Institutes of Health and awards from Georgia State and Emory.

Source: LaTina Emerson – Georgia State University
Image Source: This NeuroscienceNews.com image is adapted from the Georgia State University press release.
Original Research: Abstract for “Toll-like Receptor 4 Mediates Morphine-Induced Neuroinflammation and Tolerance via Soluble Tumor Necrosis Factor Signaling” by Lori N Eidson, Kiyoshi Inoue, Larry J Young, Malu G Tansey and Anne Z Murphy in Neuropsychopharmacology. Published online July 27 2016 doi:10.1038/npp.2016.131

Cite This NeuroscienceNews.com Article
Georgia State University. “New Drug Target Could Prevent Tolerance and Addiction to Opioids.” NeuroscienceNews. NeuroscienceNews, 22 August 2016.
<http://neurosciencenews.com/opioid-addiction-tolerance-target-4882/>.
Georgia State University. (2016, August 22). New Drug Target Could Prevent Tolerance and Addiction to Opioids. NeuroscienceNews. Retrieved August 22, 2016 from http://neurosciencenews.com/opioid-addiction-tolerance-target-4882/
Georgia State University. “New Drug Target Could Prevent Tolerance and Addiction to Opioids.” http://neurosciencenews.com/opioid-addiction-tolerance-target-4882/ (accessed August 22, 2016).

Abstract

Toll-like Receptor 4 Mediates Morphine-Induced Neuroinflammation and Tolerance via Soluble Tumor Necrosis Factor Signaling

Opioid tolerance and the potential for addiction is a significant burden associated with pain management, yet its precise underlying mechanism and prevention remain elusive. Immune signaling contributes to the decreased efficacy of opioids, and we recently demonstrated that Toll-like receptor 4 (TLR4)-mediated neuroinflammation in the periaqueductal gray (PAG) drives tolerance. Tumor necrosis factor (TNF), a product of TLR4 signaling, promotes inflammation and facilitates glutamatergic signaling, key components of opioid tolerance. Therefore, we hypothesize that TLR4-mediated opioid tolerance requires TNF signaling. By expression of a dominant-negative TNF peptide via lentiviral vector injection in rat PAG to sequester soluble TNF (solTNF), we demonstrate that solTNF mediates morphine tolerance induced by TLR4 signaling, stimulates neuroinflammation (increased IL-1β and TLR4 mRNA), and disrupts glutamate reuptake (decreased GLT-1 and GLAST mRNA). We further demonstrate the efficacy of the brain-permeant PEGylated version of the anti-solTNF peptide, XPro1595, injected systemically, to normalize morphine-induced CNS neuroinflammation and morphine- and endotoxin-induced changes in glutamate transport, effectively preserving the efficacy of morphine analgesia and eliminating tolerance. Our findings provide a novel pharmacological target for the prevention of opioid-induced immune signaling, tolerance, and addiction.

“Toll-like Receptor 4 Mediates Morphine-Induced Neuroinflammation and Tolerance via Soluble Tumor Necrosis Factor Signaling” by Lori N Eidson, Kiyoshi Inoue, Larry J Young, Malu G Tansey and Anne Z Murphy in Neuropsychopharmacology. Published online July 27 2016 doi:10.1038/npp.2016.131

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