Dissociation of mu opioid tolerance from receptor down-regulation in rat spinal cord.
The effect of continuous intrathecal infusions of opioids was studied in rats. Chronic intrathecal infusion of the highly selective mu agonist, [NMPhe3, D-Pro4]morphiceptin produced a rapid onset of tolerance to the drug in the analgesic test. However, membrane prepared from the spinal cords of the rats chronically infused with a low dose of the drug showed no statistically significant change in the number of mu or delta receptor binding sites. In addition, membrane prepared from rats challenged with a single high-dose bolus injection of [NMPhe3, D-Pro4]morphiceptin did not produce alterations in the receptor binding number. If the chronically treated rats were challenged with an acute bolus dose of [NMPhe3, D-Pro4]morphiceptin, there was a significant decrease in the number of binding sites. The reduced binding site number was observed for the mu ligand but not for the delta ligand. A similar decrease of receptor binding can also be achieved by chronic infusion of the drug at high doses. Scatchard plot showed a decrease of maximum mu binding sites in the membranes prepared from the combined chronic infusion-acute injection treated rats. Brain tissue from the same rats showed no change in the number of mu and delta receptor binding sites, indicating that the down-regulation of mu receptors was confined to the spinal cord only. Morphine did not induce receptor down-regulation by acute, chronic or combined treatments. These results suggest that in the rat spinal cord, tolerance can be induced without apparent receptor down-regulation.(ABSTRACT TRUNCATED AT 250 WORDS)
Nishino
K
K
Department of Anesthesiology, Duke University Medical Center, Durham, North Carolina.
Su
Y F
YF
Wong
C S
CS
Watkins
W D
WD
Chang
K J
KJ
D000818:Animals; D015536:Down-Regulation; D004361:Drug Tolerance; D004723:Endorphins / Q000494:pharmacology*; D008297:Male; D009020:Morphine / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D011957:Receptors, Opioid / Q000187:drug effects*; D017450:Receptors, Opioid, mu; D013116:Spinal Cord / Q000187:drug effects*
D004723:Endorphins; D011957:Receptors, Opioid; D017450:Receptors, Opioid, mu; D009020:Morphine; C044708:morphiceptin, N-Me-Phe(3)-