| Modulation of the Endogenous Cannabinoid System to Attenuate Inflammation in Central Nervous System Injury Zachary Wilmer Reichenbach Degree: Doctor of Medicine Doctor of Philosophy Temple University, 2013 Doctoral Advisory Committee Chair: Ronald F. Tuma, Ph.D. In non-pathological states the central nervous system maintains a degree of immunological privilege. When illness or injury occur, this privilege can be lost and the immune system drives pathology in the brain and spinal cord. More so, resident immune cells, the microglial, act as major effectors of this response. Cerebral ischemia, or stroke, is the fourth leading cause of death in developed nations. After the initial ischemia, the inflammatory response propagates further injury and cell death. Another affliction of the central nervous system, chronic pain and persistent use of the opioid analgesic, morphine, leads to tolerance and ineffectiveness of the drug. Currently, only one in three patients receive adequate pain relief from their pharmacological regiment. This loss of efficacy in morphine is also driven by an inflammatory response. Thus, a way to quell inflammation in both disease states could lead to better treatments for both disorders.;The endogenous cannabinoid system has two known receptors, CB1 and CB2. Both of these receptors have been intimately linked to inflammation and the activation or antagonism of the receptors can impart desired outcomes in modulating the immune response. Primarily the CB 1 receptor expression is on presynaptic terminals of neurons to modulate neuronal firing. The CB2 receptor's expression predominates on immunological cells including microglial. However, some degree of expression exists with reports of neuronal CB2 receptors and immunological CB1 receptors. This makes pharmacological therapies targeted at both receptors ideal candidates in treating not only stroke and but also preventing the induction of morphine tolerance.;In the studies described here, we sought to investigate the role of the endogenous cannabinoid system in both stroke and as a way to prevent the induction of morphine tolerance. The results showed that CB1 -/- CB 2 -/- receptor mice were able to maintain greater blood flow during cerebral ischemia. More so, CB1 antagonism in a permanent occlusion of cerebral vessels showed a protective effect independent of the serotonin receptor. Lastly, a CB2 agonist was able to limit the degree of tolerance that developed from chronic morphine therapy and also prevent hyperalgesia in addition to showing a reduction in pro-inflammatory cytokines. Acutely, this same agonist was found to antagonize the morphine receptor but this could be avoided if morphine was administered before the CB2 agonist. In brief, the studies at hand show that the endogenous cannabinoid system can attenuate inflammation in central nervous system injury and shows great promise as a future therapeutic for clinical use. |
