title: Genetic variance in nociception and its relationship to the potency of morphine-induced analgesia in thermal and chemical tests.
abstract: The perceived intensity of a painful stimulus is determined in part by the stimulus intensity and environmental conditions. The purpose of this study was to determine the influence of genetic factors in nociception and its contribution to the potency of morphine to produce antinociception. Eight inbred strains of mice were tested across a range of stimulus intensities in thermal (hot plate) and chemical irritant (acetic acid) nociceptive tests. Stimulus intensities in the thermal test included hot plate temperatures of 51, 53, 55, 57 and 59 degrees C. Stimulus 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 effective temperature resulting in a 10 s latency on the hot-plate (ET10") and the acetic acid concentration resulting in the same number of writhes as determined by the area under the curve (AUC50). There was no genetic correlation between sensitivity to thermal versus chemical stimuli. Morphine dose response curves were then determined at a fixed stimulus intensity in each test (55 degrees C and 0.6% acetic acid) to determine analgesic ED50 doses for each inbred strain. A significant effect of genotype on relative sensitivity to morphine-induced analgesia in both the thermal and chemical irritant tests was found, however there was no genetic correlation between the potency of morphine in each test. There was an inverse genetic correlation between sensitivity to thermal and chemical stimuli and morphine ED50 values in each respective 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 antinociceptive potency. In summary, this study demonstrated (i) a large degree of genetically-determined variability in sensitivity to painful stimuli, (ii) sensitivity to thermal stimuli (hot-plate) is genetically unrelated to sensitivity to chemical (acetic acid) stimuli, (iii) the mechanism by which morphine produces its antinociceptive effects against thermal stimuli is largely genetically independent of the mechanism by which morphine produces its antinociceptive effects against chemical stimuli, and (iv) inherent differences in sensitivity to painful stimuli may be responsible, in part, for individual differences in the potency of morphine's antinociceptive effects.
authors.affiliation: Behavioral Pharmacology and Genetics Section, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, P.O. Box 5180, Baltimore, MD 21224, USA Alcohol and Drug Addiction Research Center, McLean Hospital, 115 Mill Street, Belmont, MA 02178, USA Department of Pharmacology, University of Michigan, Medical Science Bldg 1, 6322 Medical Science, Ann Arbor, MI 48104, USA.
authors.forename: Gregory I
authors.initials: GI
authors.lastname: Elmer
authors.forename: Jeanne O
authors.initials: JO
authors.lastname: Pieper
authors.forename: Stevens S
authors.initials: SS
authors.lastname: Negus
authors.forename: James H
authors.initials: JH
authors.lastname: Woods
mesh_terms: D019342:Acetic Acid / Q000494:pharmacology; D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D005260:Female; D014644:Genetic Variation / Q000502:physiology*; D006358:Hot Temperature; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains / Q000235:genetics* / Q000502:physiology*; D009020:Morphine / Q000494:pharmacology*; D009619:Nociceptors / Q000187:drug effects / Q000502:physiology*; D009994:Osmolar Concentration; D017288:Pain Threshold / Q000502:physiology; D013268:Stimulation, Chemical
chemical_list: D000701:Analgesics, Opioid; D009020:Morphine; D019342:Acetic Acid