GENETIC VARIANCE IN NOCICEPTION AND ITS RELATIONSHIP TO THE POTENCY OF MORPHINE-INDUCED ANALGESIA IN THERMAL AND CHEMICAL-TESTS

The perceived intensity of a painful stimulus is determined in part by the stimulus intensity and environmental conditions. The purpose of t his study was to determine the influence of genetic factors in nocicep tion and its contribution to the potency of morphine to produce antino ciception. Eight inbred strains of mice were tested across a range of stimulus intensities in thermal (hot plate) and chemical irritant (ace tic acid) nociceptive tests. Stimulus intensities in the thermal test included hot plate temperatures of 51, 53, 55, 57 and 59 degrees C. St imulus intensities in the chemical irritant test included acetic acid concentrations of 0.1, 0.3 and 0.6%. Linear interpolation of stimulus- effect curves revealed large genotype-dependent differences in the eff ective temperature resulting in a 10 s latency on the hot-plate (ET10' ') and the acetic acid concentration resulting in the same number of w rithes as determined by the area under the curve (AUC(50)). There was no genetic correlation between sensitivity to thermal versus chemical stimuli. Morphine dose response curves were then determined al a fixed stimulus intensity in each test (55 degrees C and 0.6% acetic acid) t o determine analgesic ED50 doses for each inbred strain. A significant effect of genotype on relative sensitivity to morphine-induced analge sia in both the thermal and chemical irritant tests was found, however there was no genetic correlation between the potency of morphine in e ach test. There was an inverse genetic correlation between sensitivity to thermal and chemical stimuli and morphine ED50 values in each resp ective test. In both tests, strains less sensitive to the nociceptive stimuli were more sensitive to the antinociceptive effects of morphine . Confirmation studies in a separate genetic population confirmed the inverse relationship between hot-plate sensitivity and antinoceptive p otency. In summary, this study demonstrated (i) a large degree of gene tically determined variability in sensitivity to painful stimuli, (ii) sensitivity to thermal stimuli (hot-plate) is genetically unrelated t o sensitivity to chemical (acetic acid) stimuli, (iii) the mechanism b y which morphine produces its antinociceptive effects against thermal stimuli is largely genetically independent of the mechanism by which m orphine produces its antinociceptive effects against chemical stimuli, and (iv) inherent differences in sensitivity to painful stimuli may b e responsible, in part, for individual differences in the potency of m orphine's antinociceptive effects. (C) 1998 International Association for the Study of Pain. Published by Elsevier Science B.V.