Using a modified tail-flick procedure a highly significant hyperalgesic response was found in narcotic dependent mice peaking 12 h following the removal of chronically implanted morphine pellets. Withdrawal-induced hyperalgesia correlated well with other signs of opiate withdrawal behavior. Intracerebroventricular i.c.v. injections of CaCl2, MnCl2 and MgCl2 further enhanced the hyperalgesic response in morphine-dependent mice; morphine-dependent mice were more than twice as sensitive to Ca2+-induced hyperalgesia as placebo-treated controls. On the other hand, i.c.v. injections of the Ca2+-specific chelator EGTA [ethylene glycol-bis-[.beta.-aminoethyl ether]-N,N''-tetraacetic acid] produced highly significant, dose-dependent antinociceptive responses in both morphine-dependent and control mice, but morphine-dependent mice were only half as sensitive to EGTA-induced analgesia as controls. Withdrawal hyperalgesia and EGTA analgesia may be directly related to changes in brain localization of Ca2+ that have been reported previously. Morphine and EGTA-induced analgesia may be associated with a Ca depleted state within a relatively small Ca2+ pool of the nerve cell and opiate withdrawal hyperalgesia is apparently a sensitive measure of narcotic dependency that is associated with an increased Ca2+ content in the same region.