Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2002 Aug 1;22(15):6773-80.
doi: 10.1523/JNEUROSCI.22-15-06773.2002.

Altered nucleus accumbens circuitry mediates pain-induced antinociception in morphine-tolerant rats

Brian L Schmidt  1 , Claudia H Tambeli, Justine Barletta, Lei Luo, Paul Green, Jon D Levine, Robert W Gear
Affiliations

Altered nucleus accumbens circuitry mediates pain-induced antinociception in morphine-tolerant rats

Brian L Schmidt et al. J Neurosci. .

Abstract

We investigated the effect of chronic administration of morphine on noxious stimulus-induced antinociception (NSIA) produced by intraplantar capsaicin injection. In the untreated (naive) rat, we previously found that NSIA depends on activation of dopamine, nicotinic acetylcholine, and mu- and delta-opioid receptors in nucleus accumbens. Rats chronically implanted with subcutaneous morphine pellets demonstrated tolerance to the antinociceptive effects of acute systemic morphine administration but did not show cross-tolerance to NSIA. Morphine pretreatment, however, significantly reduced NSIA dependence on intra-accumbens opioid receptors but not on dopamine or nicotinic acetylcholine receptors. As observed in naive rats, intra-accumbens microinjection of either the dopamine receptor antagonist flupentixol or the nicotinic receptor antagonist mecamylamine blocked NSIA in rats tolerant to the antinociceptive effects of morphine, but, in contrast to naive rats, intra-accumbens microinjection of either the mu-receptor antagonist Cys2,Tyr3,Orn5,Pen7 amide or the delta-receptor antagonist naltrindole failed to block NSIA. These findings suggest that although NSIA is dependent on nucleus accumbens opioid receptors in the naive state, this dependence disappears in rats tolerant to the antinociceptive effects of morphine, which may account for the lack of NSIA cross-tolerance. In separate experiments, intra-accumbens extracellular dopamine levels were measured using microdialysis. Dopamine levels increased after either capsaicin or systemic morphine administration in naive rats but only after capsaicin administration in morphine pretreated rats. Thus, intra-accumbens dopamine release paralleled antinociceptive responses in naive and morphine pretreated rats.

PubMed Disclaimer

Figures

Fig. 1.
Fig. 1.
Location of injections. Open circles are considered to be within the target area of nucleus accumbens; note that they mostly fall within the area of the core.Filled circles designate offsite injections.Filled diamonds designate microdialysis probe location. Because some injections were mapped to identical locations, there are fewer symbols shown than the total number of injections performed.
Fig. 2.
Fig. 2.
The antinociceptive effect of acute subcutaneous morphine administration in naïve rats and in rats pretreated with either morphine or vehicle pellets. The ability of pretreatment protocol using morphine pellets to induce tolerance is indicated by the virtually complete disappearance of antinociception after acute morphine administration. In this and subsequent figures, antinociception is plotted as percentage attenuation from baseline of the JOR EMG amplitude on the y-axis (i.e., greater antinociception is represented as higher positive numbers). Baseline JOR recordings were obtained before interventions. Time 0 on thex-axis represents the time at which the last (or only) treatment was given for each group. Data are plotted as mean ± SEM. The number of rats in each group is shown inparentheses. Group numbers, precedinggroup names, refer to the Tukey post hoc analyses in Table 1.
Fig. 3.
Fig. 3.
The antinociceptive effect of intraplantar capsaicin administration in morphine-tolerant and naïve rats. Absence of cross-tolerance is indicated by the ability of capsaicin to induce a similar degree of antinociception in naïve and morphine-tolerant rats.
Fig. 4.
Fig. 4.
Effect of selective opioid receptor antagonists administered into nucleus accumbens to block the NSIA in morphine pretreated rats. None of these antagonists significantly reduced capsaicin-induced antinociception, indicating lack of participation of opioid receptors in nucleus accumbens in NSIA during morphine tolerance.
Fig. 5.
Fig. 5.
Effect of intra-accumbens administration of non-opioid receptor antagonists on NSIA in morphine pre-treated and naïve rats. a, NSIA was blocked by either flupentixol (nonselective dopamine receptor antagonist) or SCH-23390 (selective D1-receptor antagonist) in morphine pretreated rats. b, NSIA was blocked by intra-accumbens administration, but not by offsite administration, of the nicotinic receptor antagonist mecamylamine in morphine pretreated rats. c, NSIA was blocked by SCH-23390 in naïve rats. SCH-23390 had no effect when administered alone. cap, Capsaicin. Group numbers, preceding group names, refer to the Tukeypost hoc analyses in Table 1.
Fig. 6.
Fig. 6.
Effect of noxious stimulation on nucleus accumbens dopamine levels in naïve and morphine-tolerant rats. Although there was a spike in dopamine release in naïve rats at the 20 min time point, the overall effect of capsaicin on dopamine release was not significantly different.
Fig. 7.
Fig. 7.
Effect of morphine administration on nucleus accumbens dopamine levels in naïve or morphine-tolerant rats. Morphine induced an increase in dopamine in naïve rats, but neither effect was observed in tolerant rats.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Ableitner A, Schulz R. Neuroanatomical sites mediating the central actions of beta-endorphin as mapped by changes in glucose utilization: involvement of mu opioid receptors. J Pharmacol Exp Ther. 1992;262:415–423. - PubMed
    1. Ahn DK, Kim YS, Park JS. Central NO is involved in the antinociceptive action of intracisternal antidepressants in freely moving rats. Neurosci Lett. 1998;243:105–108. - PubMed
    1. Altier N, Stewart J. Dopamine receptor antagonists in the nucleus accumbens attenuate analgesia induced by ventral tegmental area substance P or morphine and by nucleus accumbens amphetamine. J Pharmacol Exp Ther. 1998;285:208–215. - PubMed
    1. Altier N, Stewart J. The role of dopamine in the nucleus accumbens in analgesia. Life Sci. 1999;65:2269–2287. - PubMed
    1. Badiani A, Leone P, Stewart J. Intra-VTA injections of the mu-opioid antagonist CTOP enhance locomotor activity. Brain Res. 1995;690:112–116. - PubMed

Publication types

MeSH terms