Chronic agonist treatment converts antagonists into inverse agonists at delta-opioid receptors.
In cellular models, chronic exposure to mu-opioid agonists converts antagonists into inverse agonists at mu-receptors. Such adaptations could contribute to the development of tolerance and/or dependence. To determine whether delta-receptors respond similarly, or whether this adaptation is unique for mu-receptors, this study examined the effects of prolonged agonist exposure on the intrinsic activity of several delta-opioid ligands in GH(3) cells expressing delta-receptors. In opioid naive cells, delta-receptors were constitutively active, and a series of delta-ligands displayed a range of intrinsic activities for G protein activation. Chronic treatment with the full delta-agonist [D-Pen(2,5)]-enkephalin reduced the acute ability of [D-Pen(2,5)]-enkephalin to stimulate and the full inverse agonist N,N-diallyl-Tyr-Aib-Aib-Phe-Leu-OH (ICI-174864) to inhibit G protein activation. In contrast, although naloxone and naltriben exhibited weak partial agonism in opioid naive cells, both ligands acted as full inverse agonists to produce concentration-dependent inhibition of guanosine 5'-O-(3-[(35)S]thio)triphosphate binding after prolonged exposure to [D-Pen(2,5)]-enkephalin or to the partial agonist morphine. This effect was reversed by a neutral delta-antagonist (N,N-bisallyl)-Tyr-Gly-Gly-psi-(CH(2)S)-Phe-Leu-OH (ICI-154129). Finally, as is also characteristic of inverse agonists, naloxone and naltriben demonstrated higher affinities for uncoupled delta-receptors in cells chronically treated with [D-Pen(2,5)]-enkephalin, relative to opioid naive cells. Therefore, this relatively novel adaptation is shared by both mu- and delta-opioid receptors and therefore may serve as an important common mechanism involved the development of tolerance and/or dependence.
Department of Pharmacology and Toxicology, College of Medicine, University of Arkansas for Medical Sciences, 4301 W. Markham Street, Little Rock, AR 72205, USA.
Jing-Gen
JG
Liu
Paul L
PL
Prather
D000262:Adenylyl Cyclases / Q000378:metabolism; D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D004361:Drug Tolerance; D020881:Enkephalin, D-Penicillamine (2,5)- / Q000494:pharmacology; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D009020:Morphine / Q000494:pharmacology; D009270:Naloxone / Q000494:pharmacology; D009271:Naltrexone / Q000031:analogs & derivatives* / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D009294:Narcotics / Q000494:pharmacology*; D009293:Opioid-Related Disorders / Q000503:physiopathology; D017465:Receptors, Opioid, delta / Q000819:agonists* / Q000037:antagonists & inhibitors*; D017450:Receptors, Opioid, mu / Q000819:agonists / Q000037:antagonists & inhibitors
D000701:Analgesics, Opioid; D009292:Narcotic Antagonists; D009294:Narcotics; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu; C068868:naltrindole benzofuran; D009270:Naloxone; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D009271:Naltrexone; D009020:Morphine; D020881:Enkephalin, D-Penicillamine (2,5)-; D000262:Adenylyl Cyclases