Biphasic modulation of mu-opoid receptor (MOR) transcription by nociceptin in neuroblastoma cells co-expressing MOR and NOP receptors

Nociceptin (NC), the endogenous NOP receptor (NOPr) ligand, counteracts several effects of opioids and is involved in the development of morphine tolerance and in the modulation of neuropathic pain in animal models. In this study we found that NOP receptor activation by nociceptin-amide [NCNH2 ], a NC derivative more resistant to peptidases, caused a biphasic, concentration-dependent modulation of MOR expression in SH-SY5Y cells: 10-100nM NC-NH2 determined an initial upregulation of MOR mRNA levels followed by a significant down-regulation after 18h-24h exposure. Ongoing transcription is required for NC-NH2- induced modulation of MOR expression, whereas the translational inhibitor cycloheximide prevented only the reduction of MOR mRNA levels. A series of MOR-luciferase promoter/reporter constructs showed that NC-NH2-induced down-regulation of MOR transcription requires a CRE element within the MOR promoter (-1599/-1579). These findings suggest that a de novo-synthesised transcriptional repressor is involved in NC-NH2-induced downregulation of MOR mRNA levels. Any involvement of the inducible cAMP early repressor (ICER) is under investigation.