Opioid abuse remains a significant public health problem despite continued research and the availability of new drugs for treatment. In addition to the ongoing problem of heroin abuse is a growing concern about the recreational use of potent, efficacious opioid analgesics such as oxycodone. This is a competing continuation of a grant that has developed novel drug discrimination procedures for studying opioid dependence and withdrawal; those procedures have been used in concert with other measures of opioid activity to examine a range of pharmacologic and behavioral parameters that contribute to the abuse and dependence liability of morphine and related opioids. Studies proposed in this renewal exploit these discrimination procedures to focus on the neuropharmacology of opioid dependence and withdrawal as well as the role of opioid withdrawal in drug taking.
AIM I characterizes the neuropharmacology of opioid withdrawal in rhesus monkeys by examining monoaminergic drugs for their ability to modulate discriminative stimulus and other effects (directly observable and HPA activation) of opioid withdrawal in monkeys. These studies build upon published data from this laboratory showing that dopamine uptake blockers attenuate discriminative stimulus and not other indices of withdrawal.
AIM II combines a well-established drug discrimination procedure with i.v. self administration in monkeys to examine the effects of withdrawal on self administration of cocaine and mu agonists that vary in efficacy.
AIM III provides a comprehensive set of descriptive data from rhesus monkeys on the behavioral pharmacology of several prescription opioids that are believed to be increasingly abused, including oxycodone, oxymorphone, hydrocodone and hydromorphone. While it is assumed that these opioids have exclusively morphine-like actions, there are limited data available to support that view. The four opioids will be compared to morphine using measures of drug discrimination, antinociception, and respiration. Finally, studies under AIM IV investigate the relationship between opioid tolerance and dependence, on the one hand, and constitutive activity and inverse agonism at opioid receptors, on the other hand, using drug discrimination procedures in pigeons with varying degrees of morphine tolerance and dependence. These studies should provide insight to the lasting neurobiological changes that can occur as a consequence of chronic drug treatment. Collectively these studies will apply drug discrimination and other procedures to important question regarding opioid dependence, withdrawal and abuse and will provide information that will facilitate the development of new therapeutics for opioid abuse.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Project (R01)
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Special Emphasis Panel (ZRG1-IFCN-4 (12))
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Thomas, David A
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University of Texas Health Science Center San Antonio
Other Domestic Higher Education
San Antonio
United States
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Collins, Gregory T; Gerak, Lisa R; France, Charles P (2018) The behavioral pharmacology and therapeutic potential of lorcaserin for substance use disorders. Neuropharmacology 142:63-71
Gerak, Lisa R; Collins, Gregory T; Maguire, David R et al. (2018) Effects of lorcaserin on reinstatement of responding previously maintained by cocaine or remifentanil in rhesus monkeys. Exp Clin Psychopharmacol :
Minervini, Vanessa; France, Charles P (2018) Effects of morphine/CP55940 mixtures on an impulsive choice task in rhesus monkeys. Behav Pharmacol 29:60-70
Gerak, Lisa R; Maguire, David R; Woods, James H et al. (2018) Reversal and prevention of the respiratory-depressant effects of heroin by the novel ยต opioid receptor antagonist methocinnamox in rhesus monkeys. J Pharmacol Exp Ther :
Weed, Peter F; Gerak, Lisa R; France, Charles P (2018) Ventilatory-depressant effects of opioids alone and in combination with cannabinoids in rhesus monkeys. Eur J Pharmacol 833:94-99
Maguire, David R; France, Charles P (2018) Reinforcing effects of opioid/cannabinoid mixtures in rhesus monkeys responding under a food/drug choice procedure. Psychopharmacology (Berl) 235:2357-2365
Weed, Peter F; France, Charles P; Gerak, Lisa R (2017) Preference for an Opioid/Benzodiazepine Mixture over an Opioid Alone Using a Concurrent Choice Procedure in Rhesus Monkeys. J Pharmacol Exp Ther 362:59-66
Maguire, David R; Gerak, Lisa R; France, Charles P (2016) Effect of daily morphine administration and its discontinuation on delay discounting of food in rhesus monkeys. Behav Pharmacol 27:155-64
Gerak, L R; France, C P (2016) Combined Treatment with Morphine and ?9-Tetrahydrocannabinol in Rhesus Monkeys: Antinociceptive Tolerance and Withdrawal. J Pharmacol Exp Ther 357:357-66
Maguire, David R; France, Charles P (2016) Effects of daily delta-9-tetrahydrocannabinol treatment on heroin self-administration in rhesus monkeys. Behav Pharmacol 27:249-57

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