Pain is a tremendous human health problem accounting for considerable morbidity and even contributing directly to mortality. Clinical pain conditions feature marked gender differences in their frequency and severity. One possible explanation for these differences is that the sexes may be differentially sensitive to pain. Indeed, when differences are found, females - of many species including rodents - appear to be more sensitive to and less tolerant of pain. The greater sensitivity to pain in females is accompanied by reduced sensitivity to analgesic drugs like morphine. Evidence exists suggesting that these quantitative sex differences in pain and analgesic may reflect the activation of qualitatively different pain modulatory systems in each sex. Pharmacological and genetic evidence support the contention that female mice possess a sex-specific, non-opioid analgesic mechanism. The neurochemical identification of this mechanism remains obscure, but a chromosomal region (chromosome 8; greater than 52 cM) has recently been identified that contains a gene which mediates endogenous analgesia in females, but not males. Another sex-specific gene effect, associated with basal sensitivity to acute, thermal nociception and/or opioid analgesia in males but not females, has been localized to chromosome 4 (40-80 cM). Preliminary data suggests that the relevant gene in this region may be Oprdl, which encodes the murine d-opioid receptor. Finally, two inbred mouse strains have been identified that show significant male greater than female (AKR) and female greater than male (CBA) analgesic sensitivity to morphine.
The aims of this project are to make forward progress on each of these three sex-specific gene effects: the techniques to be employed are unique to each situation. Quantitative trait locus (QTL) mapping techniques will be applied to morphine analgesia using AKR and CBA strains in a directed attempt to identify female-specific QTLs. Testing of additional genetic populations, including transgenic """"""""knock-out"""""""" mice lacking functional expression of the Oprdl gene, will reveal the generalizability of the male-specific chromosome 4 QTL already identified. Finally, initial steps will be taken towards the positional cloning of the female- specific chromosome 8 QTL, in order to characterize the female-specific analgesic mechanism. Clinical applications of this work may include the development of novel and sex-specific analgesic strategies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE012735-04
Application #
6379853
Study Section
Special Emphasis Panel (ZDE1-YS (16))
Program Officer
Kousvelari, Eleni
Project Start
1998-09-20
Project End
2003-06-30
Budget Start
2001-07-01
Budget End
2003-06-30
Support Year
4
Fiscal Year
2001
Total Cost
$149,849
Indirect Cost
Name
University of Illinois Urbana-Champaign
Department
Psychology
Type
Schools of Arts and Sciences
DUNS #
041544081
City
Champaign
State
IL
Country
United States
Zip Code
61820
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Sternberg, Wendy F; Ritchie, Jennifer; Mogil, Jeffrey S (2004) Qualitative sex differences in kappa-opioid analgesia in mice are dependent on age. Neurosci Lett 363:178-81
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Mogil, Jeffrey S; Wilson, Sonya G; Chesler, Elissa J et al. (2003) The melanocortin-1 receptor gene mediates female-specific mechanisms of analgesia in mice and humans. Proc Natl Acad Sci U S A 100:4867-72
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Nemmani, K V S; Mogil, J S (2003) Serotonin-GABA interactions in the modulation of mu- and kappa-opioid analgesia. Neuropharmacology 44:304-10
Wilson, Sonya G; Smith, Shad B; Chesler, Elissa J et al. (2003) The heritability of antinociception: common pharmacogenetic mediation of five neurochemically distinct analgesics. J Pharmacol Exp Ther 304:547-59

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