Adaptations in nucleus accumbens circuitry during opioid withdrawal associated with persistence of noxious stimulus-induced antinociception in the rat

We studied adaptations in nucleus accumbens opioidergic circuitry mediating noxious stimulus-induced antinociception (NSIA) in rats withdraw ing from chronic morphine administration. Although the magnitude of NSIA in withdrawing rats was similar to that observed in naïve rats despite the tolerance of withdrawing rats to the antinociceptive effects of acutely administered morphine, the involvement of nucleus accumbens opioid receptors in NSIA in withdrawing rats was different from previous observations in both naïve and tolerant rats. In withdrawing rats intraaccumbens administration of the mu-opioid receptor antagonist Cys², Tyr₃, Orn₅, Pen⁷ amide (CTOP), but not the delta-receptor antagonist naltrindole, blocked NSIA. Both antagonists blocked NSIA in the naïve state, but neither was effective in tolerant rats. Also, intra-accumbens administration of the muagonist [D-Ala², N-Me-Phe^4, Gly⁵-ol]-enkephalin (DAMGO) alone was sufficient to induce antinociception in withdrawing rats, whereas a combination of both mu- and delta-receptor agonists (ie, DAMGO and D-Pen^2,5-enkephalin [DPDPE], respectively) is required to induce antinociception in naïve rats. The delta- agonist DPDPE was without effect in the withdrawing rat, alone or when combined with DAMGO. Thus, although the magnitude of NSIA does not differ significantly among the 3 states, it is mediated by both mu- and delta-receptors in the naive rat, mu- but not delta-receptors in the withdrawing rat, and neither receptor type in the morphine tolerant rat. These changes may result from different degrees of tolerance, with delta-receptors being the most sensitive; however, it is not known how these changes occur without affecting the magnitude of the resultant antinociception.