S. Stevens Negus, Ph.D. Professor 410 North 12th Street Robert Blackwell Smith Building P.O. Box 980613 Richmond, Virginia 23298-0613 Phone: (804) 828-3158 Fax: (804) 828-2117 E-mail: ssnegus@vcu.edu Publications: selected | PubMed Lab: Video:

Education: University of North Carolina, Neurobiology, Ph.D. 1990

Research interests: My research as a behavioral pharmacologist and neurobiologist emphasizes the study of drug effects on the behavior of whole organisms and on the neural substrates implicated in the mediation of those behaviors. I collaborate with medicinal chemists and biologists to integrate my work with research conducted at molecular, cellular and systems levels of biological organization. I am also concerned with the translation of my preclinical research into the clinic. My ultimate goal is to identify fundamental principles of pharmacology, neurobiology and behavior that can be used both to guide the discovery of new drugs and to develop more effective strategies for the use of existing drugs.

One theme of my research is focused on opioids because of their clinical importance in the treatment of pain. Morphine-like opioids, which act at the mu subtype of the opioid receptor, are effective analgesics; however, their clinical utility is limited by undesirable effects such as tolerance and abuse liability. Accordingly, I became interested in the investigation of novel opioids that might produce clinically useful effects without these undesirable effects. Opioids that act at the delta opioid receptor subtype appear to offer some promise in this regard. A major finding from research in my laboratory has been that delta opioid agonists produce analgesic effects in a novel model of inflammatory pain, and they also enhance the analgesic effects of morphine-like opioids. The abuse liability and other undesirable effects of delta agonists appear to be minimal, and delta agonists also appear to attenuate some undesirable effects of mu agonists. One implication of this work is that delta agonists may be useful either alone or in combination with morphine-like analgesics for the treatment of pain. On the basis of this research, I am now collaborating with both academic and industrial chemists to study novel mixed-action mu/delta opioids. This research program has also yielded other dividends. First, these studies required the refinement and implementation of methods of data analysis for evaluating effects of drug combinations. These methods are now being applied to study other types of drug interactions in my laboratory. Second, these studies have encouraged us to develop new procedures for the preclinical evaluation of pain and analgesia, and I am especially interested in the overlap between pain and depression. Lastly, our work on the behavioral effects of opioid drugs has served as an invaluable foundation for ongoing pilot studies on opioid-induced brain activation as measured by functional magnetic resonance imaging (fMRI).

In addition to my work with opioids, I have also conducted research to examine the in vivo pharmacology of CNS stimulants such as cocaine and amphetamine. The abuse of stimulants either alone or in combination with opioids remains a major public health problem. My research with stimulants has focused on the identification and evaluation of pharmacological strategies that could reduce the abuse-related effects of stimulants. One major finding of this work has been that monoamine releasers with modest dopaminergic selectivity appear to function as very promising candidate medications for the treatment of cocaine abuse. In the course of this research, we have also developed a novel procedure that allows us to evaluate choice behavior involving drugs of abuse. This new procedure has allowed us to explore the impact of several environmental variables on choice of drug vs. non-drug reinforcers, and to also examine interactions between environmental and pharmacological treatments.
 

Selected publications:

Stevenson GW, Folk JE, Rice KC, Negus SS: Interactions between delta and mu opioid agonists in assays of schedule-controlled responding, antinociception, drug self-administration and drug vs. food choice in rhesus monkeys: Studies with SNC80 and heroin. J Pharmacol Exp Ther, 2005; 314:221-231.

Negus SS, Vanderah TW, Brandt MR, Bilsky EJ, Becerra L, Borsook D. Preclinical assessment of candidate analgesic drugs: recent advances and future challenges. Invited “Perspectives in Pharmacology” Article in J. Pharmacol. Exp. Ther., 2006; 319:507-514.

Negus SS, Mello NK, Blough BE, Baumann MH, Rothman RB: Monoamine releasers with varying selectivity for dopamine vs. serotonin release as candidate “agonist” medications for cocaine dependence: Studies in assays of cocaine discrimination and cocaine self-administration in rhesus monkeys. J Pharmacol Exp Ther, 2007; 320:627-636.

Negus SS. Rapid assessment of choice between cocaine and food in rhesus monkeys: effects of environmental manipulations and treatment with d-amphetamine and flupenthixol. Neurpsychopharmacology 2003; 28:919-931
 

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