Extensive study of opioids has generated much information regarding the mechanisms of their analgesic and reinforcing properties. Distinct anatomical pathways have been elucidated for the antinociceptive and reinforcing properties of opioids using antagonists and neurotoxin- induced lesions of specific neuronal populations. However, these two important aspects of opioid pharmacology have largely been studied in isolation. The analgesic effects of opioids are studied in the laboratory following passive administration, in which the animal does not control the dose or dosing interval. Similarly, the reinforcing effects of opiates are studied in the laboratory in the absence of pain, and little is known regarding the relevance of reinforcing mechanisms identified in this manner to the clinical use of opioids for pain relief. This project seeks to examine the pharmacology of opioids using a self-medication paradigm in rats with nerve injury. These studies will focus on the development of opioid tolerance in the presence of pain and exploration of the mechanisms of tolerance. Dosing will be accomplished through self-administration, in which the animal is allowed to determine the drug quantity necessary to achieve the desirable pharmacological effect. This technique has proven to be invaluable in the study of drug abuse, but is being applied in this project to the study of pain mechanisms and should provide equally invaluable information. Experiments are designed to determine receptor mechanisms related to the development of tolerance as well as to develop strategies for minimizing the development of tolerance and self-determined dose escalation through experiments using 24 hr self-administration. Preliminary data show that animals rapidly escalate opioid intake when given 24 hr access to self-administration, and that tolerance to the anti-allodynic effects of opioids results. Initial strategies include using drugs of differing efficacies and a dose-fading procedure to determine the optimum maintenance dose that minimized total dose escalation over time. Intrathecal agents will then be given as adjuvant analgesics as another strategy to inhibit or retard the development of tolerance to opioids and subsequent dose escalation. Parallel clinical studies are proposed to address these concerns in patients self-administering opioids. These studies will hopefully identify mechanisms of tolerance to opioids self- administered for pain relief and strategies to minimize such effects.
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