Nuclear Factor κB 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, Ca 2+ channels, K + channels, and phosphatidylinositol 3-kinase/Akt, have been identified to be critical in opioid functions. Nuclear factor-κB (NF-κB), 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-κB-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-κB signaling in opioid functions and receptor gene expression in cells.

Toll-like receptor 4-mediated nuclear factor-κB activation in spinal cord contributes to chronic morphine-induced analgesic tolerance and hyperalgesia in rats

“…Nuclear factor-κB (NF-κB) is one of the most diverse and critical transcription factors that may either directly or indirectly transmit opioid receptor-mediated signals to the nucleus, and it regulates NF-κB-dependent gene expression in immune and non-immune cells [4] . NF-κB is composed of homo-and heterodimers among five members of the Rel family: NF-κB1 (p50), NF-κB2 (p52), RelA (p65), RelB, and c-Rel.…”

“…The development and maintenance of morphine tolerance are effectively prevented by inhibition of the synthesis of these cytokines or by their neutralization with specific antibodies in the spinal cord [15,[17][18][19][20] . NF-κB activation plays an important role in regulating the expression of TNF-α, IL-1β, IL-6, and other cytokines in immune cells [4] . Previous studies have also provided evidence that morphine treatment leads to NF-κB activation in cultured human NT2-N neurons [21] .…”

Effects of Inhibitor of κB Kinase Activity in the Nucleus Accumbens on Emotional Behavior

“…The IkK signaling pathway is activated by extracellular cytokines (such as interleukin 1 beta (IL-1b) and IL-6), infectious agents, glutamate, and neurotrophins (Israel, 2010;O'Neill and Kaltschmidt, 1997;Schölzke et al, 2003). Downstream of IkK, many target genes of the NFkB transcriptional complex contribute significantly to synaptic plasticity, such as NCAM, BDNF, opioid receptors, glutamate receptors, and neuregulin (Bunting et al, 2007;Chen et al, 2006;Frensing et al, 2008;Richter et al, 2002;Saha et al, 2006). Indeed, c-Rel, a member of the NFkB transcriptional complex, is required for long-term potentiation in the hippocampus (Ahn et al, 2008).…”

Ammonium pyrrolidine dithiocarbamate and RS 102895 attenuate opioid withdrawal in vivo and in vitro

“…Nuclear factor kappa B (NF-κB) is a transcription factor which causes the activation of multiple downstream signals to the nucleus, resulting in the regulation of a number of NF-κB-dependent genes responsible for the transcription of various cytokines, which are in turn implicated in mediating various effects of opioid drugs on the central nervous system (Chen et al 2006). NF-κB is a crucial regulator of many physiological and pathophysiological processes based on neuronal excitability.…”