The present study was undertaken to evaluate the effects of ultra low concentrations (10(-9) or 10(-14)M) of morphine on neurite elongation in cultured neurons dissociated from rat spinal cords and cerebral cortex. In fetal serum (FS) or fetal serum-free supplemented with cAMP media, the length of longest neurite was significantly increased by 10(-9) or 10(-14)M morphine. For example, 10(-14)M morphine increased neurite length by 24 +/- 0.5% and 27 +/- 0.3% in spinal cord neurons, and 18 +/- 0.2% and 17 +/- 0.6% in cortical neurons. Morphine (10(-6)M) had no significant effect on neurite length of spinal and cortical neurons. The relative frequency distribution of neurite length revealed 61 +/- 2.7% of spinal neurons and 48 +/- 2.6% of cortical neurons are responsive to ultra low concentrations of morphine. In the responsive populations, morphine (10(-14)M) enhanced the neurite outgrowth in spinal neurons by 58 +/- 0.9% and 48 +/- 1.2% and in cortical neurons by 31 +/- 0.6% and 28 +/- 0.9% in FS and cAMP-supplemented media, respectively. Pretreatment with naloxone did not prevent the morphine effect. The result shows that morphine at ultra low concentrations enhances neurite outgrowth of spinal and cortical neurons via a naloxone-independent mechanism.