In a paper published online Thursday by the Journal of Neuroinflammation, a team led by Fletcher A. White, Ph.D., Vergil K. Stoelting Professor of Anesthesia and professor of pharmacology & toxicology, reported that the increased sensitivity to pain following morphine administration was due to the activation of a immune system receptor designed to detect the presence of bacterial invaders. The receptor, called TLR4, was found, and determined to be active, in the neurons that transmit pain sensations to the central nervous system.
When morphine is given to a patient, the body breaks down – metabolizes – the drug into two primary compounds, or metabolites. One metabolite, M6G, can enter the central nervous system and produce the intended pain-relieving effects. More of the other metabolite, M3G, is produced but M3G has no pain-relieving role and cannot cross the blood-brain barrier that protects the central nervous system from many foreign substances.
What M3G can do, Dr. White and colleagues determined, is activate TLR4, one of a family of toll-like receptors used by the immune system to detect and mount a defense against bacterial infections.
Morphine had been shown in other research to activate TLR4 receptors in microglial cells, which are found only in the central nervous system, when the morphine was injected directly into the central nervous system.
That work raised the question of whether similar activity could be found outside the central nervous system given that morphine generally is not delivered directly into the central nervous system, and because the M3G metabolite cannot enter the central nervous system.
In experiments using nerve cell tissue, the researchers determined that TLR4 proteins were being produced by sensory neurons and the TLR4 receptors were being activated by the presence of M3G. In experiments with rats that had no other injuries, administering M3G resulted in more sensitivity to pain, while rats that had been genetically modified to not produce TLR4 were not more sensitive. In other experiments, administering a compound that inhibits the activity of TLR4 blocked the increased pain sensitivity that had been produced by M3G.
“What this suggests is that if we could administer morphine along with a small molecule that inhibits TLR4 we could have the desired effect of reducing the unwanted pain effects, called opioid-induced hyperalgesia,” said Dr. White.
In addition to Dr. White, researchers included first authors Michael R. Due, Ph.D., post-doctoral fellow in anesthesia, and Andrew D. Piekarz, Ph.D., post-doctoral scientist, pharmacology and toxicology. Other contributors were Natalie Wilson, Ph.D., fellow in the Department of Anesthesia; Polina Feldman, Medical Neuroscience Program; Rajesh Khanna, Ph.D., assistant professor of pharmacology and toxicology and Matthew S. Ripsch, Department of Anesthesia, all Indiana University School of Medicine; and Sherry Chavez, Ph.D., and Hang Yin, Ph.D., assistant professor, Department of Chemistry and Biochemistry, University of Colorado at Boulder.
The research was supported by a Indiana Spinal Cord & Brain Injury Research Grant, and the National Institutes of Health awards NS049136, DA026040, NS067425 and DA026950, the National Scientist Development from the American Heart Association SDG5280023, and the Neurofibromatosis New Investigator Award from the Department of Defense/CDMRP NF1000099.