Low doses of naloxone produce analgesia in the mouse brain by blocking presynaptic autoinhibition of enkephalin release.

The involvement of presynaptic autoinhibition of Met-enkephalin release in naloxone-induced analgesia was studied. In both acetic acid writhing and tail-flick tests in mice, naloxone produced biphasic effects, analgesia at very low doses (1 microgram/kg s.c. or 1 ng intracisternal) and hyperalgesia at higher doses (100 micrograms/kg s.c. or 100 ng intracisternal). Morphine at 10(-6) to 10(-5)M depressed the high K+-evoked release of Met-enkephalin from slices of the rat brainstem by 12.5-55.9% of control, while naloxone at 10(-6)M significantly enhanced the release by 80.6%. These findings strongly suggest that in the mouse brain a very low dose of naloxone produces analgesia by blocking autoinhibition of enkephalin release.