The Broad goal of this ongoing research is to identify the molecular mechanisms which underlie the immunomodulatory effects of opioids and to determine their role in health and disease. Opioids have been suggested to accelerate HIV progression to AIDS. T cells are critical effectors and regulators of both humoral and cell mediated immune function and opioid modulation of T cell cytokine secretion is likely to be an important mechanism of opioid immunomodulation. The expression of """"""""neural"""""""" opioid receptors that may mediate opioid effects in immune cells has now been verified by many laboratories. Results from the current grant show that while none of the three pharmacologically defined opioid receptors, delta, mu and kappa are expressed in non-stimulated T cells, the delta opioid receptor (deltaOR) is induced in both Con A activated CD4+ and CD8+ T cells. Induction of deltaOR in T cells apparently requires co-stimulation by other immune cells.
In aim one of this proposal, deltaOR mRNA expression will be examined in murine splenic T cells activated with different stimuli to specifically elicit either helper or cytotoxic T cells, using both antigen presenting cell dependent and independent mechanisms in order to determine the types of T cell activation which result in deltaOR expression. Mu opioid receptor expression also will be examined in mouse strains sensitive to immunosuppression with the mu agonist morphine.
The second aim i s to identify the specific soluble mediators or cell surface receptors which induce deltaOR during Con A stimulation and other activation models identified in aim one. The ability of the specific activation signals identified to induce delta receptor expression in human cells will be investigated in aim four. The effect of opioid modulation on T cell polarization to T1 and T2 phenotypes and on T cell secretion of polarizing cytokines (e.g. IL-4 and IFN-gamma) will be examined in aim three. The half-life of deltaOR mRNA and protein in activated T cells will be determined in aim three. The results of these studies will identify conditions of in vivo immune activation likely to result in opioid sensitive T cell immunomodulation, and the type of T cell responses, i.e. humoral or cytotoxic, affected. Potential mechanisms for therapeutic intervention for either the induction or suppression of T cell opioid receptor expression will be identified.
