Placebo neural systems: nitric oxide, morphine and the dopamine brain reward and motivation circuitries

Med Sci Monit. 2005 May;11(5):MS54-65. Epub 2005 Apr 28.


Evidence suggests that the placebo response is related to the tonic effects of constitutive nitric oxide in neural, vascular and immune tissues. Constitutive nitric oxide levels play a role in the modulation of dopamine outflow in the nigrostriatal movement and the mesolimbic and mesocortical reward and motivation circuitries. Endogenous morphine, which stimulates constitutive nitric oxide, may be an important signal molecule working at mu receptors on gamma aminobutyric acid B interneurons to disinhibit nigral and tegmental dopamine output. We surmise that placebo induced belief will activate the prefrontal cortex with downstream stimulatory effects on these dopamine systems as well as on periaqueductal grey opioid output neurons. Placebo responses in Parkinson's disease, depression and pain disorder may result. In addition, mesolimbic/mesocortical control of the stress response systems may provide a way for the placebo response to benefit other medical conditions.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, P.H.S.
  • Review

MeSH terms

  • Animals
  • Anxiety, Separation / physiopathology
  • Anxiety, Separation / psychology
  • Anxiety, Separation / therapy
  • Brain / physiology
  • Depression / physiopathology
  • Depression / psychology
  • Depression / therapy
  • Dopamine / physiology*
  • Humans
  • Models, Neurological
  • Models, Psychological
  • Morphine / metabolism*
  • Motivation
  • Nitric Oxide / physiology*
  • Pain / physiopathology
  • Pain / psychology
  • Pain Management
  • Parkinson Disease / physiopathology
  • Parkinson Disease / psychology
  • Parkinson Disease / therapy
  • Placebo Effect*
  • Relaxation / physiology
  • Relaxation / psychology
  • Reward
  • Stress, Physiological / physiopathology
  • Stress, Physiological / psychology


  • Nitric Oxide
  • Morphine
  • Dopamine