OPIOID EFFECTS ON MITOGEN-ACTIVATED PROTEIN-KINASE SIGNALING CASCADES

Background: The molecular mechanisms underlying both beneficial and un desirable opioid actions are poorly understood. Recently, the three cu rrently known mammalian mitogen-activated protein kinase (MAPK) signal ing cascades (extra-cellular signal-related kinase [ERK], stress-activ ated protein kinase, and p38 kinase) were shown to play important role s in transducing receptor-mediated signaling processes, Methods: To de termine whether any of these kinase cascades were activated by opioids , mu, delta, or kappa opioid receptors mere transiently introduced int o COS-7 cells together with MAPKs tagged to allow recognition by speci fic antibodies, and then exposed to opioids. Mitogen-activated protein kinase activation was determined by an in vitro MAPK activation assay , In addition, C6 glioma cells with either mu, delta, or kappa recepto rs stably introduced were exposed to opioids and MAPK activation deter mined by in vitro activation assay or antibody detection of activated forms, Results: Transient experiments in CDS cells revealed potent sti mulation of ERK by mu and delta receptor activation, weak stimulation of stress-activated protein kinase by all receptor types, and no activ ation of p38. In stably transfected C6 glioma cells, only ERK activati on was observed. Extracellular signal-related kinase induction was rap id, peaking 5 min after stimulation, and its activation was receptor-t ype specific. Mu and delta receptor stimulation activated ERK, but kap pa stimulation did not. Conclusions: These results show that acute opi oid signaling is not only inhibitory, but can strongly activate an imp ortant signaling cascade. Extracellular signal-related kinase activati on may contribute to desirable responses to opioids, such as analgesia and sedation, and also to undesirable adaptive responses, such as tol erance, physical dependence, and possibly addiction. Further study of this system could provide greater insight into the molecular mechanism s underlying these clinical problems.