The primary focus of our research is to understand the molecular mechanisms underlying the development of opioid tolerance and dependence and the interactions of pain and analgesic signaling.  We employ a multidisciplinary approach to understand these problems using cutting-edge techniques.  After demonstrating clinical and physiological relevance in animal behavioral studies, we dissect mechanisms underlying opioid tolerance, physical dependence, and pain.  Since these are very complex phenomena, involving the interaction of genetic, environmental, and social factors, we have turned to the emerging field of proteomics in an effort to determine in the broadest possible fashion which changes in cellular signaling are responsible for the adaptations causing opioid tolerance and chronic pain.  Combining the techniques of laser-capture microdissection to analyze neurons expressing specific markers, 2-dimensional gel electrophoresis to separate proteins, and high-throughput mass spectrometry for protein identification permits us to address this issue with a power never before imagined.

The overall goal of these projects is to develop more effective therapies for treating chronic pain without causing the devastating side effects of tolerance, dependence, and addiction. Trainees gain experience integrating molecular, genetic, neuroanatomic, biochemical, and behavioral techniques to explore important neurobiological questions from many perspectives. Close relations with clinical colleagues in the pain clinic provide opportunities to translate our basic findings into clinical practice and eventually see the direct application of our efforts.

A tutorial in our laboratory would introduce students to concepts in addiction, pain mechanisms and opioid pharmacology.  Students would employ a wide range of integrative techniques to explore these important neurobiological questions from many perspectives.  Experience can be gained with techniques such as in situ hybridization, immunocytochemistry, cell culture and transfection, 2-D gel electrophoresis, mass spectrometry, image analysis, and behavioral studies on rats and mice.

Selected publications

• Gutstein, HB and Akil, H:  “Opioid Analgesics”, in Goodman and Gilman’s The Pharmacological Basis of Therapeutics, eleventh edition, Brunton, L, Ed., McGraw-Hill, in press.
  
  
• Moulédous, L, and Gutstein, HB (2004) Modulation of extracellular-signal related kinase (ERK) activation by acute and chronic opioid treatment in neuronal and glial cell lines. Journal of Neurochemistry, 90:1371.
  
  
• Moulédous, L, and Gutstein, HB (2003) Gene Arrays and Proteomics: A Primer, in Opioid Research: Methods and Protocols, Pan, ZZ, Ed., series Methods in Molecular Medicine, Humana Press, pp. 141-154.
  
  
• Moulédous, L, Hunt, S., Hopwood, F, Harcourt, R, Harry, J, Williams, KL, and Gutstein, HB (2003) Proteomic analysis of immunostained, laser-capture microdissected samples. Electrophoresis, 24:296.
  
  
• Bishop, GB, Cullinan, WE, Curran, E, and Gutstein, HB (2002) Abused drugs differentially modulate RGS4 mRNA levels in rat brain: Comparison between acute drug treatment and a drug challenge after chronic treatment. Neurobiology of Disease, 10:334.
  
  
• Gutstein HB (1996) The effects of pain on opioid tolerance: How do we resolve the controversy? Pharmacol Rev 48: 403–407

Last updated 07/18/2007