There is a great public health need in finding an efficacious therapy for pain management for HIV- infected individuals. We have shown that both opioid and chemokine receptors can influence each other's functions by heterologous desensitization. Particularly, we have demonstrated that the activation of CXCR4 in the PAG diminishes the analgesic efficacy of morphine (Adler et al., 2006). Based on the fact that gp120 (T- tropic) and a CXCR4 antagonist (e.g. AMD 3100, T40) share the same receptor for their mechanism of action [the gp120 effect (T-tropic) is mediated by its binding to and activation of CXCR4 receptor, and AMD 3100 is an antagonist for this receptor], and the activation of CXCR4 diminishes morphine-induced analgesia (Adler et al., 2006], we propose to investigate whether the blockade of gp120 action on CXCR4 by CXCR4 antagonists will impact the analgesic efficacy of opioid medication. Our hypothesis is that, in addition to its ability to decrease HIV entry into cells, CXCR4 antagonists, by blocking the gp120 utilization of the CXCR4 receptor, can prevent or diminish gp120-induced pain. This occurs via an interaction between CXCR4 and mu-opioid receptors, thus preventing the blocking action that results from the heterologous desensitization of the mu opioid receptor, thereby increasing the analgesic efficacy of opioid medications. In this proposal we will investigate the in vivo consequences of the combined effect CXCR4 antagonists and morphine on gp120-induced pain (AIM#1). Combinations of drugs are frequently used therapeutically to achieve an enhanced effect without using an excess quantity of either drug. Given the recent approval of small chemokine antagonists for treatment of HIV and their ability to prevent HIV from entering cells, the determination of whether the combinations of chemokine antagonists and opioid medication will achieve superior efficacy in managing HIV-related pain is crucial, timely and completely novel. The opportunities for effectively addressing the functional interaction between chemokine antagonists and opioid medications in the presence of HIV-gp120 in the brain is relevant for public health, particularly the field of HIV- related pain and opioids. Ultimately, these studies may provide a rational basis for a therapeutic strategy that targets simultaneously the HIV infection and related pain. ! !

Public Health Relevance

Finding an efficacious therapy that targets simultaneously the HIV-related pain and HIV infection is of great interest. Combinations of drugs are frequently used therapeutically to achieve an enhanced effect without using an excess quantity of either drug. The opportunities for effectively addressing the functional interaction between chemokine antagonists and opioid medications in the presence of HIV-gp120 in the brain is relevant for public health, particularly the field of HIV-related pain and opioids, and ultimately, these studies may provide a rational basis for a therapeutic strategy that targets simultaneously the HIV infection and related pain.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Small Research Grants (R03)
Project #
5R03DA031605-02
Application #
8266369
Study Section
Special Emphasis Panel (ZRG1-AARR-J (53))
Program Officer
Khalsa, Jagjitsingh H
Project Start
2011-06-01
Project End
2013-12-31
Budget Start
2012-06-01
Budget End
2013-12-31
Support Year
2
Fiscal Year
2012
Total Cost
$153,000
Indirect Cost
$53,000
Name
Temple University
Department
Miscellaneous
Type
Schools of Medicine
DUNS #
057123192
City
Philadelphia
State
PA
Country
United States
Zip Code
19122
Palma, Jonathan; Abood, Mary E; Barbe, Mary F et al. (2014) Functional interaction between HIV-gp120 and opioid system in the preoptic anterior hypothalamus. Drug Alcohol Depend 134:383-6