Altered nucleus accumbens circuitry mediates pain-induced antinociception in morphine-tolerant rats.
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.
Schmidt
Brian L
BL
Graduate Program in Oral Biology, University of California, San Francisco, California 94143-0440, USA.
Tambeli
Claudia H
CH
Barletta
Justine
J
Luo
Lei
L
Green
Paul
P
Levine
Jon D
JD
Gear
Robert W
RW
D000818:Animals; D002211:Capsaicin / Q000494:pharmacology; D004298:Dopamine / Q000032:analysis / Q000378:metabolism; D018492:Dopamine Antagonists / Q000008:administration & dosage; D004333:Drug Administration Routes; D004343:Drug Implants; D004361:Drug Tolerance / Q000502:physiology*; D005110:Extracellular Space / Q000737:chemistry / Q000378:metabolism; D008297:Male; D017551:Microdialysis; D008845:Microinjections; D009020:Morphine / Q000008:administration & dosage / Q000494:pharmacology*; D018733:Nicotinic Antagonists / Q000008:administration & dosage; D009714:Nucleus Accumbens / Q000187:drug effects* / Q000378:metabolism*; D010146:Pain / Q000188:drug therapy / Q000503:physiopathology; D010147:Pain Measurement / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D017465:Receptors, Opioid, delta / Q000037:antagonists & inhibitors / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000037:antagonists & inhibitors / Q000378:metabolism; D012018:Reflex / Q000187:drug effects
D018492:Dopamine Antagonists; D004343:Drug Implants; D018733:Nicotinic Antagonists; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu; D009020:Morphine; D002211:Capsaicin; D004298:Dopamine