The positive reinforcement provided by opiates have been considered as primary factors in promoting drug abuse and dependence. However, opiates also produce a host of "negative" effects which can manifest both during opiate administration and which are particularly expressed during withdrawal. Withdrawal from opiates is unpleasant and may provide negative reinforcement and contribute to drug dependence. Thus, both positive and negative reinforcement are likely to contribute to the compulsive use of opioids, a critical feature of "opioid addiction". The mechanisms by which opiates produce negative effects are unknown. Our preliminary data indicate that blockade of descending facilitation in the rostral ventromedial medulla (RVM) prevents expression of somatic and autonomic signs of opiate withdrawal indicating that facilitatory outflow from the RVM is critical in mediating both nociceptive (i.e., opiate-induced hyperalgesia) and many nonnociceptive features of the withdrawal syndrome. We hypothesize that opiate-induced descending facilitation from the RVM and subsequent upregulation of spinal dynorphin are essential for the expression of many of the negative symptoms which comprise withdrawal from opiates. Mechanisms which underlie the expression of the withdrawal syndrome thus also represent mechanisms likely promote negative reinforcement which may contribute to opiate dependence, the continued use and abuse of opiates and drug seeking behavior. This hypothesis will be explored with four Specific Aims: First, we will characterize pronociceptive transmitters in the RVM in which can mediate naloxone-precipitated withdrawal. Second, we will determine whether prevention of descending facilitation from the RVM prevents opiate-induced physical dependence (naloxone-induced or spontaneous withdrawal). Third, we will determine whether blockade of the pronociceptive actions of spinal dynorphin, or the bradykinin B2 receptor will prevent withdrawal. Fourth, we will determine if blockade of descending facilitation blocks withdrawal-induced aversion/negative reinforcement. These studies assess mechanisms which may contribute to negative reinforcement, drug dependence and abuse.

Public Health Relevance

This project explores the role of adapative changes elicited by opiates which may produce negative reinforcement and contribute to continued drug use and abuse. Understanding these mechanisms may lead to new strategies which may help to counter drug abuse.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Program Projects (P01)
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Human Development Research Subcommittee (NIDA)
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University of Arizona
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Lee, Yeon Sun; Muthu, Dhanasekaran; Hall, Sara M et al. (2014) Discovery of amphipathic dynorphin A analogues to inhibit the neuroexcitatory effects of dynorphin A through bradykinin receptors in the spinal cord. J Am Chem Soc 136:6608-16
Meske, Diana S; Xie, Jennifer Y; Oyarzo, Janice et al. (2014) Opioid and noradrenergic contributions of tapentadol in experimental neuropathic pain. Neurosci Lett 562:91-6
Lee, Yeon Sun; Rankin, David; Hall, Sara M et al. (2014) Structure-activity relationships of non-opioid [des-Arg(7)]-dynorphin A analogues for bradykinin receptors. Bioorg Med Chem Lett 24:4976-9
Vardanyan, Ruben S; Hruby, Victor J (2014) Fentanyl-related compounds and derivatives: current status and future prospects for pharmaceutical applications. Future Med Chem 6:385-412
Hruby, Victor J (2013) Adventures in peptides and science with students! the joys of research. Biopolymers 100:127-31
Nair, Padma; Yamamoto, Takashi; Largent-Milnes, Tally M et al. (2013) Truncation of the peptide sequence in bifunctional ligands with mu and delta opioid receptor agonist and neurokinin 1 receptor antagonist activities. Bioorg Med Chem Lett 23:4975-8
Largent-Milnes, T M; Brookshire, S W; Skinner Jr, D P et al. (2013) Building a better analgesic: multifunctional compounds that address injury-induced pathology to enhance analgesic efficacy while eliminating unwanted side effects. J Pharmacol Exp Ther 347:7-19
Cai, Minying; Stankova, Magda; Muthu, Dhanasekaran et al. (2013) An unusual conformation of ýý-melanocyte-stimulating hormone analogues leads to a selective human melanocortin 1 receptor antagonist for targeting melanoma cells. Biochemistry 52:752-64
Petrov, Ravil R; Lee, Yeon Sun; Vardanyan, Ruben S et al. (2013) Effect of anchoring 4-anilidopiperidines to opioid peptides. Bioorg Med Chem Lett 23:3434-7
Liu, Zhihua; Mehta, Sukeshi J; Lee, Kwang-Soo et al. (2012) Thio-Claisen rearrangement used in preparing anti-ýý-functionalized ýý,ýý-unsaturated amino acids: scope and limitations. J Org Chem 77:1289-300

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