Periodically, we highlight one paper that was recently published by a Ph.D. student in the Neuroscience Institute.

Neuroscience Institute Highlighted Paper:

Eidson, Lori N. and Anne Z. Murphy
Journal of Pain (2013) in press. doi: 10.1016/j.jpain.2012.12.010.
Persistent Peripheral Inflammation Attenuates Morphine-Induced Periaqueductal Gray Glial Cell Activation and Analgesic Tolerance in the Male Rat.

Lori N. Eidson is a Ph.D. student 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.
Recent statistics from the American Pain Society indicate that over 50 million Americans suffer from chronic pain each year, including debilitating headaches, joint pain, cancer pain, and severe back pain. 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. Increasing the dose is often not sufficient to overcome tolerance, leading to increased risk of developing additional negative side effects, including drug withdrawal symptoms, addiction, and even difficulty breathing and risk of death (Trescot et al. 2006). Because over 90% of chronic pain sufferers are treated with opioids, including morphine, understanding tolerance development is of critical importance
 
Recent studies have demonstrated that glial cells, the immune cells of the central nervous system, are tightly linked to increased pain sensation and decreased ability of morphine to relieve pain (Watkins et al., 2009). Under normal conditions glial cells (i.e., microglia and astrocytes) survey the environment for bacteria, debris and, surprisingly, morphine. In the presence of foreign substances, glia become activated and release, among other things, cytokines and chemokines.  These substances alter the activity of neurons, and actively decrease the pain relieving effects of morphine.
 
The midbrain periaqueductal gray (PAG) is part of an essential brain circuit for morphine-based pain relief, and is known to be a key brain region for the development of morphine tolerance; however, the involvement of PAG glial cells has not been investigated. Lori’s dissertation research tests the hypothesis that PAG glia become activated in response to morphine, and that this response (i.e., glial activation) contributes to the development of tolerance. In her Journal of Pain paper, Lori shows that morphine administered in the absence of pain results in the rapid development of tolerance that is accompanied by a significant increase in PAG glial cell activation. Consistent with clinical observations, Lori also demonstrated that pain delays the development of morphine tolerance. Interestingly, pain also prevents the observed increase in PAG glial activation. These results support the hypothesis that activated PAG glial cells contribute to morphine tolerance development.
 
Lori’s more recent data demonstrate that blocking PAG glial cell activation completely eliminates the development of morphine tolerance. A paper describing these studies is under review at Journal of Neuroscience. Together, Lori’s data demonstrate that PAG glial cells play a significant role in the development of morphine tolerance. Collectively, this research could provide novel and crucial information that leads to an understanding of how central nervous system glial cells regulate morphine tolerance, and may provide a potential therapeutic target to enhance the effects of morphine in the clinical treatment of chronic pain.