Morphine currently represents the best option for the management of severe pain and chronic pain states. Prolonged use of opiates often produces the need for ever- increasing doses to maintain pain relief, also known as analgesic tolerance. The mechanisms associated with analgesic tolerance are thought to due to morphine- induced cellular adaptations that produce a state of heightened pain or hyperalgesia. Recent studies suggest that opiates acting via the mu-opioid receptor can induce expression of chemokines and their receptors. Previous works from our laboratory demonstrate that some of these same chemokines/receptors have been shown to play central roles in chronic pain states. To uncover evidence of possible links between chronic morophine treatment, chemokine signaling and analgesic tolerance, we propose the hypothesis that opiate-induced chemokine signaling is central to analgesic tolerance.
Our specific aims i nclude 1) a characterization of the chronology of cellular/signaling events associated with opiate-induced hyperalgesia 2) explore mechanisms by which morphine induces chemokine/receptor expression in the dorsal root ganglia and 3) examine the cellular/molecular mechanisms by which chronic morphine treatment enhances chemokine signaling. Better understanding of these chemokine/receptor- mediated events may provide the necessary framework for the design of agents that counteract deleterious opiate-induced cellular adaptations and effectively reduce analgesic tolerance.

Public Health Relevance

Morphine is a powerful pain reliever for cancer and non-cancer pain, but also a potent inducer of tolerance. Opiate tolerance refers to a phenomenon in which exposure to a opiate results in the diminution of an analgesic effect (pain relief). Tolerance to the analgesic effect of morphine is a poorly understood phenomenon and can clearly present major management difficulties in some patients. Better understanding of the events associated with the development of tolerance may provide the necessary framework for the design of agents effectively reduce analgesic tolerance.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Project (R01)
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Special Emphasis Panel (ZDA1-MXH-H (11))
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Purohit, Vishnudutt
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Loyola University Chicago
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