Long after their first use by humans, narcotics remain the most widely used and effective treatment for clinical pain despite their disadvantages: numerous side effects, the development of tolerance, and the opportunity for drug abuse. Genetic and molecular biological techniques are needed to make major advances in addressing the problems associated with narcotics but pain modulation has been almost exclusively studied in the rat. The goal of this proposal is to develop the mouse as a model for studying morphine analgesia and its side effects and thereby allow modern molecular and genetic methods to impact pain management. In the anesthetized rat, the discharge of cells in the medullary raphe magnus (RM) predicts the magnitude and speed of motor withdrawals from noxious stimulation both before and after systemic morphine. In contrast, our preliminary results in anesthetized mouse suggest that RM cell discharge predicts homeostatic adjustments but not withdrawals from noxious stimulation, either before or after morphine. The first aim of this proposal is to identify potential targets of RM cell modulation in the anesthetized mouse. The contribution of RM cells to opioid analgesia in awake animals, if any, has not been defined. The second aim of this proposal is to test whether murine RM cells mediate morphine analgesia in the awake mouse, even if, as our preliminary results suggest, they do not do so in the anesthetized mouse. In the rat, RM neurons protect important homeostatic functions, such as sleep and feeding, from interruption. To test whether this murine RM cells similarly defend homeostasis, the activity of RM neurons will be recorded while unanesthetized mice naturally cycle through sleep and wake states and drink water. A mechanistic model for opioid action in the genetically tractable mouse will allow development of therapeutic strategies that minimize side effects and maximize analgesia.

R21DA022429

2008-02-01

2011-01-31