Abstract
Naloxone benzoylhydrazone (NalBzoH) is often used as a nociceptin opioid peptide (NOP) receptor antagonist. However, NalBzoH is also a mixed I¼ antagonist/Io and I´ opioid agonist and its actions at the NOP receptor range from an antagonist to partial agonist, depending on the effector response/system studied. We now report that NalBzoH activates endogenously expressed Io3 opioid, but not NOP, receptors to stimulate extracellular signal-regulated protein kinases 1/2 and, subsequently, to mediate changes in the expression of tyrosine hydroxylase and G protein-coupled receptor kinase 2 in SH-SY5Y human neuroblastoma cells. Furthermore, pretreatment with NalBzoH produces homologous desensitization of the Io3 opioid receptor as well as heterologous desensitization of the NOP receptor. In contrast, pretreatment with the NOP agonist, orphanin FQ/nociceptin (OFQ/N), desensitizes only NOP but not the NalBzoH response, suggesting the involvement of a receptor, distinct from NOP, in mediating the actions of NalBzoH in SH-SY5Y cells.
Highlights
The multiplicity of opioid receptors and their widespread distribution throughout the central and peripheral nervous systems enables opiates and endogenous opioid peptides to elicit a broad spectrum of pharmacological and physiological actions
Time- and concentration-dependent activation of ERK1/2 by Naloxone benzoylhydrazone (NalBzoH): SH-SY5Y cells were stimulated with NalBzoH (1 μM) for various time periods ranging from 1-60 min and cell lysates were subjected to SDSPAGE as described in Methods to determine ERK1/2 activation
We provide further evidence suggesting that NalBzoH activates the κ3 opioid receptor and that it upregulates tyrosine hydroxylase (TH) and GRK2 protein expression via stimulation of ERK1/2 through the κ3 opioid receptor
Summary
The multiplicity of opioid receptors and their widespread distribution throughout the central and peripheral nervous systems enables opiates and endogenous opioid peptides to elicit a broad spectrum of pharmacological and physiological actions. Besides demonstrating a potent antagonistic action of NalBzoH at μ opioid receptors, the initial in vivo studies revealed that NalBzoH was an agonist at a novel κ opioid receptor and produced analgesia when administered into the cerebral ventricles. NalBzoH inhibited forskolin-stimulated cAMP accumulation, and this was not reversed by selective antagonists[10,11] or by antisense μ-, δDNA or κ1-receptor targeting the NOP receptor[12]. It was, reversed by a less selective μ/κ antagonist, Mr2266[10,12]. NalBzoH-mediated analgesia was not reversed by selective μ-, exhibit any cδr-oossr-tκo1l-erreacnecpetowr aitnhtaμg-onoirstsκ,1-aangdofnaiisltesd[3,4to]
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