Opioids have become the second most abused class of drugs in the United States and are prevalent among teens and young adults.(1) Given that opioid abuse is associated with high rates of drug-related mortality, morbidity and criminality, the ramifications of this trend are cause for public health concern.(2) The rewarding effects of heroin are mediated by the activation of the G-protein coupled μ-opioid receptor (MOR).(3, 4) MOR stimulation leads to modulation of multiple effectors, including the inhibition of adenylyl cyclase,(5) regulation of voltage-gated calcium (Ca2+) channels,(6, 7) and control of the canonical mitogen-activated protein kinases (MAPK) extracellular regulated kinase (ERK)-1 and -2.(8) Active ERK1/2 phosphorylates the transcription factors ELK1 and cyclic AMP responsive element binding protein (CREB), which translocate to the nucleus to regulate expression of target genes,(9) the physiological consequences of which result in synaptic plasticity and aberrant behaviors that maintain the cycle of drug abuse.(10) Experimental models have led to the postulation that long-term repeated exposure to opioid drugs results in receptor desensitization and/or down-regulation events linked to opioid tolerance and dependence.(11, 12) However, the signaling and transcriptional events that underlie adaptation within the human brain as a result of repeated MOR activation remain poorly understood.
