The interaction of the mu-opioid receptor and G protein is altered after chronic morphine treatment in rats.
The interaction of mu-opioid receptors and G proteins after chronic morphine treatment was investigated in rats. Male Sprague-Dawley rats (200-260 g) were rendered tolerant to morphine by i.p. injections of increasing doses of morphine twice daily for 4 or 6 days. During this period, there was a time-dependent increase in the AD50 values for morphine to inhibit the tail-flick response. In addition, in vitro mu-opioid receptor binding to midbrain P2 membranes from these animals revealed that the ability of 10 mumol/l Gpp(NH)p (guanyl-5'-yl imidodiphosphate) to decrease [3H]DAMGO (Tyr-D-Ala-Gly-MePhe-Gly-ol) binding affinity, i.e., the ratio Kd(+Gpp(NH)p)/Kd(-Gpp(NH)p), decreased significantly from the control value of 3.68 +/- 0.40 to 2.37 +/- 0.35 after 6 days of morphine treatment (P < 0.05). The ability of DAMGO to stimulate low Km GTPase activity was also investigated. The EC50 significantly increased from 2.7 +/- 1.1 x 10(-8) mol/l in the control group to 10.8 +/- 1.5 x 10(-8) mol/l after 4 days of morphine treatment and was further increased to 13.5 +/- 2.1 x 10(-8) mol/l after 6 days of morphine treatment. The maximal stimulation by DAMGO decreased significantly from 18.0 +/- 1.7% to 12.8 +/- 1.6% after 6 days of morphine treatment. These results indicate that the interaction between mu-opioid receptors and G proteins had been altered after chronic morphine treatment.
Tao
P L
PL
Department of Pharmacology, National Defense Medical Center, Taipei, Taiwan, R.O.C.
Lee
C R
CR
Law
P Y
PY
Loh
H H
HH
D000595:Amino Acid Sequence; D000700:Analgesics / Q000494:pharmacology; D000818:Animals; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D004361:Drug Tolerance; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D004745:Enkephalins / Q000493:pharmacokinetics / Q000494:pharmacology; D020558:GTP Phosphohydrolases / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000378:metabolism*; D006165:Guanylyl Imidodiphosphate / Q000494:pharmacology; D007700:Kinetics; D008297:Male; D008636:Mesencephalon / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D008969:Molecular Sequence Data; D009020:Morphine / Q000494:pharmacology*; D010147:Pain Measurement / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D017450:Receptors, Opioid, mu / Q000187:drug effects / Q000378:metabolism*; D013268:Stimulation, Chemical
D000700:Analgesics; D004745:Enkephalins; D017450:Receptors, Opioid, mu; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D006165:Guanylyl Imidodiphosphate; D009020:Morphine; D020558:GTP Phosphohydrolases; D019204:GTP-Binding Proteins