EXCEED THE SPACE PROVIDED. Recent research has produced a wealth of information on the immunomodulatory effects of opioids, but little is known about how the sex of the individual impacts opioid-induced immunomodulation. Given the widespread clinical use of opioids and their high abuse potential, an understanding of the interaction of sex with opioid- induced immune alterations is critical.
Specific Aim I provides a pharmacological analysis of the effects of morphine on the contact hypersensitivity (CHS) response in males and females, with an emphasis on clinical outcome measures (i.e., swelling), as well as the immunological and receptor mechanisms that mediate these effects. Our initial findings indicate that morphine enhances CHS in both males and females, but in females, morphine is more than twice as potent, has a greater maximal effect, and'the effects persist for a longer period of time. The proposed studies will determine the specific immune mechanisms that account for these dramatic sex differences by evaluating the role of immunologic mediators at the site of CHS, including IL- l [3,TNF-c_, IFN-7, IL-4, IL-6, IL-10, and nitric oxide expression. Studies will also test hypotheses that morphine activates different central and peripheral opioid receptor types in males and females.
Specific Aim II will determine if the gonadal (or sex) hormones mediate sex differences in morphine-induced alterations of contact hypersensitivity (CHS). Given the ample evidence that gonadal hormones contribute to observed sex differences in both immune function and opioid sensitivity, depleting these hormones represents a logical and critical first step in the analysis of the hormonal mechanisms underlying the profound sex differences in opioid- induced immunomodulation. The proposed studies test if gonadal hormone depletion in males and females impacts morphine-induced alterations of CHS and the specific immunologic mediators of this sexually differentiated response.
Specific Aim III determines the generality of sex differences across clinically relevant opioids, and whether the magnitude of the sex differences is related to the relative efficacy (i.e., ability to stimulate the # opioid receptor) of the opioid. Our plan is to evaluate sex differences in opioid- immunomodulation with a series of clinically important opioids that differ along a continuum of efficacy. Our hypothesis is that the sex differences will be apparent with opioids other than morphine, and that the magnitude of the sex-related differences will be inversely related to their ability to stimulate the/x opioid receptor. Given that virtually nothing is known about how the sex of the individual interacts with the immunomodulatory actions of opioids, the proposed studies are the first to advance our understanding of the regulatory role of sex in opioid- induced immunomodulation. These studies have clinical importance and will influence the selection of opioids for patient care, as well as enhance our understanding of potential sex differences in the adverse consequences of opioid use and abuse. PERFORMANCE SITE ========================================Section End===========================================

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA015709-03
Application #
6837601
Study Section
Special Emphasis Panel (ZRG1-IFCN-2 (01))
Program Officer
Purohit, Vishnudutt
Project Start
2003-02-01
Project End
2006-12-31
Budget Start
2005-01-01
Budget End
2005-12-31
Support Year
3
Fiscal Year
2005
Total Cost
$215,874
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Psychology
Type
Schools of Arts and Sciences
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
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Lomas, Lisa M; Barrett, Andrew C; Terner, Jolan M et al. (2007) Sex differences in the potency of kappa opioids and mixed-action opioids administered systemically and at the site of inflammation against capsaicin-induced hyperalgesia in rats. Psychopharmacology (Berl) 191:273-85
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Elliott, Jay C; Picker, Mitchell J; Nelson, Christina J et al. (2003) Sex differences in opioid-induced enhancement of contact hypersensitivity. J Invest Dermatol 121:1053-9