The present proposal is aimed at using basic animal research to understand the relative contribution of behavioral and biological factors to analgesic tolerance in the clinical setting. We propose to characterize the mechanisms that underlie the development of tolerance to morphine analgesia by testing the hypothesis that """"""""stress-triggered"""""""" changes during pain influence the therapeutic actions of morphine. More specifically, we propose that the effects of pain on the development of tolerance to morphine analgesia depends on corticosterone activity during pain. We will test this hypothesis in a rat model that approximates the clinical use of opiates for pain control, in which we recently showed that repeated injections of morphine do not produce analgesic tolerance when administered in the presence of pain, but do in the absence of pain. To determine the role of corticosterone in the development of tolerance to morphine analgesia during pain we will establish a relationship between the pain, tolerance and corticosterone activity. Our hypothesis predicts that pharmacological blockade of pain-triggered corticosterone activity will prevent the blockade of tolerance by pain. In addition, we will establish a relationship between strain differences in pain-triggered corticosterone activity and the development of tolerance to morphine analgesia during pain. Our hypothesis predicts that a strain of rat identified to lack typical stress-induced endocrine responses (Lewis strain) will not show an increase in corticosterone following pain, and thus will not show a blockade of tolerance by pain. This proposal will also evaluate the biobehavioral factors that influence the development of tolerance during pain by examining the contribution of type of pain, corticosterone, and method of morphine administration. We will examine the conditions in which pain attenuates tolerance versus conditions in which pain fails to attenuate tolerance. Our hypothesis predicts that the effects of pain and corticosterone on tolerance development can be predicted based on the presence or absence of environmental cues associated with morphine administration. The identification of the biological and behavioral factors that influence tolerance to morphine analgesia during pain will provide insights into the mechanisms that determine the development of aped tolerance in the clinical setting.
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