PT  - JOURNAL ARTICLE
AU  - Jing-Gen Liu
AU  - Paul L. Prather
TI  - Chronic Agonist Treatment Converts Antagonists into Inverse Agonists at δ-Opioid Receptors
AID  - 10.1124/jpet.102.035964
DP  - 2002 Sep 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 1070--1079
VI  - 302
IP  - 3
4099  - http://jpet.aspetjournals.org/content/302/3/1070.short
4100  - http://jpet.aspetjournals.org/content/302/3/1070.full
SO  - J Pharmacol Exp Ther2002 Sep 01; 302
AB  - In cellular models, chronic exposure to μ-opioid agonists converts antagonists into inverse agonists at μ-receptors. Such adaptations could contribute to the development of tolerance and/or dependence. To determine whether δ-receptors respond similarly, or whether this adaptation is unique for μ-receptors, this study examined the effects of prolonged agonist exposure on the intrinsic activity of several δ-opioid ligands in GH3 cells expressing δ-receptors. In opioid naive cells, δ-receptors were constitutively active, and a series of δ-ligands displayed a range of intrinsic activities for G protein activation. Chronic treatment with the full δ-agonist [d-Pen2,5]-enkephalin reduced the acute ability of [d-Pen2,5]-enkephalin to stimulate and the full inverse agonistN,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-[35S]thio)triphosphate binding after prolonged exposure to [d-Pen2,5]-enkephalin or to the partial agonist morphine. This effect was reversed by a neutral δ-antagonist (N,N-bisallyl)-Tyr-Gly-Gly-ψ-(CH2S)-Phe-Leu-OH (ICI-154129). Finally, as is also characteristic of inverse agonists, naloxone and naltriben demonstrated higher affinities for uncoupled δ-receptors in cells chronically treated with [d-Pen2,5]-enkephalin, relative to opioid naive cells. Therefore, this relatively novel adaptation is shared by both μ- and δ-opioid receptors and therefore may serve as an important common mechanism involved the development of tolerance and/or dependence. The American Society for Pharmacology and Experimental Therapeutics