Lori N. Eidson is a Ph.D. candidate in Dr. Anne Murphy’s lab. Lori’s dissertation project examines how glial cells within the midbrain periaqueductal gray region of the brain contribute to the development of morphine tolerance.
Over 90% of the 50 million Americans suffering from chronic pain each year are treated with opioids, including morphine. Although morphine is one of the most effective pain relievers available, chronic morphine treatment leads to a myriad of negative side effects, including tolerance and thus increasingly inadequate pain relief.
There is extensive research supporting a critical role for glial cell activation in the development of morphine tolerance. Glial cells (i.e., microglia and astrocytes) are the immune cells of the central nervous system. In response to morphine, glial cells become activated and release a number of substances that decrease the pain relieving effects of morphine. Until relatively recently, however, the way opioids activate glia was unknown. Recent studies have demonstrated that an immune receptor located on glial cells, called Toll-like receptor 4 (TLR4) responds to morphine. Whether or not TLR4 plays a role in the development of tolerance to morphine, however, had not been investigated.
The midbrain periaqueductal gray (PAG) is a key brain region for the development of morphine tolerance. Lori’s dissertation research tests the hypothesis that morphine binds to TLR4 within the PAG, thereby activating glia and initiating the development of morphine tolerance. In her Journal of Neuroscience paper, Lori shows that blocking glia or TLR4 within the PAG eliminates the development of morphine tolerance. Interestingly, activating TLR4 within the PAG in the absence of morphine produces a naïve tolerance to subsequent morphine administration. Finally, Lori also demonstrated that blocking TLR4 within the PAG enhances the ability of morphine to block pain sensation. These results support the hypothesis that activated PAG glial cells contribute to morphine tolerance development.
Together, Lori’s data demonstrate that the glial receptor TLR4 plays a significant role in the development of morphine tolerance. Collectively, these data provide novel information about how glial cells regulate morphine analgesia and tolerance, and have exciting implications for how management of chronic pain can be improved in humans suffering from this all-too-common disorder.