Nuclear factor kappaB signaling in opioid functions and receptor gene expression

Abstract

Opiates are the most powerful of all known analgesics. The prototype opiate morphine has been used as a painkiller for several thousand years. Chronic usage of opiates not only causes drug tolerance, dependence, and addiction, but also suppresses immune functions and affects cell proliferation and cell survival. The diverse functions of opiates underscore the complexity of opioid receptor signaling. Several downstream signaling effector systems, including adenylyl cyclase, mitogen-activated protein kinase, Ca2+ channels, K+ channels, and phosphatidylinositol 3-kinase/Akt, have been identified to be critical in opioid functions. Nuclear factor-kappaB (NF-kappaB), one of the most diverse and critical transcription factors, is one of the downstream molecules that may either directly or indirectly transmit the receptor-mediated upstream signals to the nucleus, resulting in the regulation of the NF-kappaB-dependent genes, which are critical for the opioid-induced biological responses of neuronal and immune cells. In this minireview, we focus on current understanding of the involvement of NF-kappaB signaling in opioid functions and receptor gene expression in cells.

Fig. 1

Possible cellular responses and transcriptional regulation initiated by activation of opioid receptor signaling. Arrows indicate activation of the signaling pathway; the “⊣” signs indicate inhibition of the signaling pathway. AC, adenylyl cyclase; Akt, also called protein kinase B (PKB); cAMP, cyclic AMP; PI3K, phosphatidylinositol 3-kinase; PKC, protein kinase C; PLC, phospholipase C.

Fig. 2

Proposed model for the involvement of NF-κB signaling in opioid receptor-expressing immune and neuronal cells. Arrows indicate activation of the signaling pathway; the “⊣” signs indicate inhibition of the signaling pathway. Both immune and neuronal cells express opioid receptors. Modulation of NF-κB signaling leads to the regulation of a variety of genes, including the opioid receptor genes and proinflammatory genes. Nitration or nitrosylation of NF-κB may be one of the feedback mechanisms of controlling homeostasis of NF-κB signaling in vivo. Deregulation of NF-κB signaling could result in opioid-mediated immunosuppression, cell survival, morphine tolerance, and physical dependence. MEKK, mitogen-activated protein kinase kinase; IκB, inhibitor of κB protein; p65, NF-κB/p65 subunit; p50, NF-κB/p50 subunit; iNO, inducible NO.