The Role of interleukin-1 receptor-associated kinase 4 in drug addiction

Drug addiction remains an unmanageable and costly disease. Apart from neuronal adaptation,growing recognition arises that glial proinflammatory activation importantly contributes to the rewarding effects of multiple drugs of abuse. Recent studies suggest the central importance of Toll-like receptor 4（TLR4）,a candidate neuroimmune therapeutic target for drug addiction. While Interleukin-1 receptor associated kinase 4（IRAK4） plays a crucial role in TLR4 mediated innate immunity,there is no further studies support its functioning in drug addiction. We hypothesized that drug-taking activates IRAK4 and induces reinforcing effects,and disruption of IRAK4 signaling attenuates the addictive behaviors. In the present study,IRAK4 and IRAK1 phosphorylation after morphine and cocaine self-administration was evaluated using western blotting. The role of IRAK4 in morphine self-administration and cue-induced reinstatement was examined with its inhibitor,PF06650833. Moreover,local pharmacological manipulation was conducted to determine the role of IRAK4 in the nucleus accumbens（NAc） core in the cue-induced reinstatement of morphine seeking. We found that morphine self-administration significantly increased the phosphorylation of IRAK4,but not IRAK1,both in NAc and VTA.However,neither cocaine short access nor long access self-administration had any effect on the phosphorylation of IRAK4. Systemic administration of PF06650833 significantly attenuated cue-induced reinstatement of morphine seeking without affecting the spontaneous locomotion in rats,and microinjection of PF06650833 into NAc core sufficiently decreased cue-induced morphine reinstatement. These results demonstrated that modulation of IRAK4 activity regulates the cue-induced morphine reinstatement,and suggested it as a novel candidate target in treating drug addiction.