Delta opioid agonists attenuate TAT(1-72)-induced oxidative stress in SK-N-SH cells.
Previous reports have indicated that the use of delta agonists may prove to be a viable therapeutic tool as an analgesic agent without conventional opioid side effects. In addition, recent evidence suggests that delta ligands may exert neuroprotective effects under a variety of toxin insults. The aim of the present studies was to assess the ability of delta agonists (peptide: [D-Pen(2,5)] enkephalin (DPDPE), non-peptide: (+)-4-[(aR)-a-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide (SNC-80)) and antagonists (naltrindole) to modify dichlorofluorescein (DCFH) fluorescence in the presence of the peroxynitrite generator, 3-morpholinylsydnoneimine chloride (SIN-1) or HIV-protein, TAT(1-72) (TAT) in SK-N-SH cells. Both DPDPE (100 nM) and SNC-80 (250 nM) attenuated (30-50%) the increased oxidative stress in the presence of SIN-1. This effect was partially reversed by addition of naltrindole, suggesting involvement of delta receptors. Peroxynitrite radicals are involved in neurotoxicity associated with TAT. Incubation with TAT (10-250 nM) demonstrated a concentration-dependent increase in oxidative stress up to 200% over control values. Preincubation with delta agonists reduced 50 nM TAT-mediated oxidative stress 15-40%, which was partially reversed by naltrindole. Increasing log-concentrations of DPDPE or SNC-80 (0.01-100 microM) attenuated TAT-mediated oxidative stress up to 50% at 100 microM. In conclusion, these data demonstrate that both peptide and non-peptide delta agonists can partially attenuate intracellular oxidative stress, in part through a receptor-mediated mechanism. This suggests that delta ligands may have therapeutic usefulness in HIV patients beyond analgesia.
Wallace
David R
DR
Oklahoma State University, Center for Health Sciences, Departments of Pharmacology, Physiology and Forensic Sciences, 1111 West 17th Street, Tulsa, OK 74107-1898, USA. walladr@chs.okstate.edu
Dodson
Summer L
SL
Nath
Avindra
A
Booze
Rosemarie M
RM
D001549:Benzamides / Q000494:pharmacology; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D020881:Enkephalin, D-Penicillamine (2,5)- / Q000494:pharmacology; D005452:Fluoresceins; D005609:Free Radicals / Q000378:metabolism; D015696:Gene Products, tat / Q000037:antagonists & inhibitors*; D006801:Humans; D008981:Molsidomine / Q000031:analogs & derivatives; D009271:Naltrexone / Q000031:analogs & derivatives / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D018847:Opioid Peptides / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects*; D010879:Piperazines / Q000494:pharmacology; D017465:Receptors, Opioid, delta / Q000819:agonists* / Q000378:metabolism; D054322:tat Gene Products, Human Immunodeficiency Virus
D001549:Benzamides; D005452:Fluoresceins; D005609:Free Radicals; D015696:Gene Products, tat; D009292:Narcotic Antagonists; D018847:Opioid Peptides; D010879:Piperazines; D017465:Receptors, Opioid, delta; D054322:tat Gene Products, Human Immunodeficiency Virus; C470431:tat peptide (1-72), Human immunodeficiency virus 1; C088464:4-(alpha-(4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl)-N,N-diethylbenzamide; C029569:diacetyldichlorofluorescein; C002385:linsidomine; D009271:Naltrexone; D020881:Enkephalin, D-Penicillamine (2,5)-; D008981:Molsidomine; C055382:naltrindole