Review article Interface of physical and emotional stress regulation through the endogenous opioid system and A-opioid receptors Saulo C. Ribeiro a , Susan E. Kennedy a , Yolanda R. Smith b , Christian S. Stohler c , Jon-Kar Zubieta a, * a University of Michigan, Department of Psychiatry and Molecular and Behavioral Neuroscience Institute (MBNI), 205 Zine Pitcher Place, Ann Arbor, MI 48109-0720, USA b University of Michigan, Department of Obstetrics and Gynecology, Ann Arbor, MI, USA c University of Maryland, School of Dentistry, Baltimore, MD, USA Accepted 26 August 2005 Available online 26 October 2005 Abstract Unraveling the pathways and neurobiological mechanisms that underlie the regulation of physical and emotional stress responses in humans is of critical importance to understand vulnerability and resiliency factors to the development of a number of complex physical and psychopathological states. Dysregulation of central stress response circuits have been implicated in the establishment of conditions as diverse as persistent pain, mood and personality disorders and substance abuse and dependence. The present review examines the contribution of the endogenous opioid system and A-opioid receptors to the modulation and adaptation of the organism to challenges, such as sustained pain and negative emotional states, which threaten its internal homeostasis. Data accumulated in animal models, and more recently in humans, point to this neurotransmitter system as a critical modulator of the transition from acute (warning signals) to sustained (stressor) environmental adversity. The existence of pathways and regulatory mechanisms common to the regulation of both physical and emotional states transcend classical categorical disease classifications, and point to the need to utilize dimensional, ‘‘symptom’’-related approximations to their study. Possible future areas of study at the interface of ‘‘mind’’ (cognitive–emotional) and ‘‘body’’ (physical) functions are delineated in this context. D 2005 Elsevier Inc. All rights reserved. Keywords: Affect; Amygdala; Emotion; Endogenous opioids; Mu-opioid receptors; Neurotransmitter release; Nucleus accumbens; Pain; Positron emission tomography; Sex differences; Stress; Substantia innominata; Ventral pallidum Contents 1. Introduction ............................................................ 1265 2. Pain as warning signal and homeostatic emotion ......................................... 1265 3. Emotion regulation ........................................................ 1266 4. Interfaces between pain and emotion regulation through stress circuitry ............................. 1266 5. Endogenous opioids and the regulation of physical and emotional stressors ........................... 1267 6. Endogenous opioid regulation of pain and emotion in humans as measured with positron emission tomography ........ 1268 7. Similarities and differences in the response of the human A-opioid system to physical and emotional challenges ........ 1270 8. Overview and possible research directions ............................................ 1272 Acknowledgements ........................................................... 1274 References ............................................................... 1274 0278-5846/$ - see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.pnpbp.2005.08.011 Abbreviations: ACTH, adrenocorticotropic hormone; BP, binding potential; COMT, catechol-o-methyl transferase; CRH, cortico-releasing hormone; GABA, gamma-aminobutyric acid; PANAS, Positive and Negative Affectivity Scale; PET, positron emission tomography. * Corresponding author. E-mail address: zubieta@umich.edu (J.-K. Zubieta). Progress in Neuro-Psychopharmacology & Biological Psychiatry 29 (2005) 1264 – 1280 www.elsevier.com/locate/pnpbp