Endogenous morphine is present in the mammalian brain as determined by gas chromatography/mass spectrometry. The criteria essential for satisfying the definition of morphine as a neurotransmitter are examined. The detection of endogenous morphine-like compounds inside brain neurons by immunocytochemistry and the Ca(+) dependent release of endogenous morphine from rat brain slices provide evidence for its transmitter status. Indirect evidence that endogenous morphine modulates thermonociception and weakens memory through mu opioid receptors again supports a neurotransmitter role for this chemical messenger. Evidence has been found for its endogenous synthesis in animal tissues as well. These findings indicate that endogenous morphine might function as neuromodulator/neurotransmitter agent in the CNS.