Hypertolerance to morphine in G(z alpha)-deficient mice

Our laboratory has generated a mouse deficient in the alpha (alpha) subunit of the G protein, G(z), (G(z alpha)) gene and we have examined the involve ment of G(z alpha) in spinal and supraspinal analgesia and tolerance mechan isms. Spinal analgesia was tested by the response times to heat or cold tai l flick times in a water bath at 50 degrees C or -5 degrees C and supraspin al analgesia was tested by the times for paw licking and jumping from a pla te at 52 degrees C or 0.5 degrees C. Tolerance to morphine was induced in w ild type and G(z alpha)-deficient mice over a 5 day period and the behavior al tests were performed daily. The rail hick reaction times to both hot and cold stimuli did not differ between the wild type and G(z alpha)-deficient mice. Analysis of the reaction times from the hot and cold plate tests sho wed the G(z alpha)-deficient mice developed tolerance to morphine to a grea ter degree and at a faster rate than wild type mice. Opioid binding assays were performed on synaptic membranes prepared from naive and morphine toler ant wild type and G(z alpha)-deficient brains. No changes in the affinity o f morphine for its receptor or in the density of mu and delta opioid recept ors were found between the two groups of mice in the naive or morphine tole rant state. This indicates that the absence of G(z alpha) does not affect o pioid receptor affinity or receptor up or down regulation. Our results sugg est that the presence of G(z alpha) delays the development of morphine tole rance and represents a possible therapeutic target for improving the clinic al use of morphine. (C) 2000 Elsevier Science B.V. All rights reserved.