Date of Award


Degree Type


Degree Name

Doctor of Philosophy (PhD)




Shepard Siegel


The Pavlovian conditioning analysis of drug tolerance emphasizes that cues present at the time of drug administration become associated with drug-induced disturbances. These disturbances elicit unconditional responses that compensate for the pharmacological perturbation. The drug-compensatory responses eventually come to be elicited by drug-paired cues. These conditional compensatory responses (CCRs) mediate tolerance by counteracting the drug effect when the drug is administered in the presence of cues previously paired with the drug. Although there are many findings consistent with the conditioning analysis of tolerance, there also are contrary findings. The results of experiments reported in Chapter 2 suggest that some of the apparently contradictory findings result because interoceptive pharmacological cues, as well as exteroceptive environmental cues, are paired with a drug effect. That is, within each administration, early drug-onset cues may become associated with the later, larger drug effect, and these pharmacological cues may overshadow simultaneously-present environmental cues. The results of these experiments demonstrate that such intra-administration associations contribute to tolerance to the analgesic effect of morphine and to the expression of conditional compensatory hyperalgesia. Although there is substantial evidence that conditioning contributes to tolerance, there has been little research concerning the physiological events that mediate this contribution. The experiments reported in Chapter 3 were designed to evaluate the role of a putative anti-opioid peptide--cholecystokinin-8 (CCK-8)--in the associative mechanisms of opiate tolerance. The results of these experiments demonstrate that endogenous CCK-8 activity is important to the expression of conditional compensatory responding and the expression of established morphine tolerance. In addition to the theoretical implications of the work presented in this thesis, the present findings may also be of clinical interest. The clinical report presented in Chapter 4, describes how a conditioning analysis of tolerance that includes intra-administration associations may be relevant to understanding a case report of enigmatic opiate overdose. Patients receiving drugs for pain relief may be at risk for opiate overdose when the route of administration is altered, thus effectively altering the pharmacological drug-onset cues. The results of these experiments and the clinical report demonstrate that intra-administration associations are important to a compound-conditioning analysis of tolerance.

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