Vol. 302, Issue 3, 1070-1079, September 2002

Chronic Agonist Treatment Converts Antagonists into Inverse Agonists at -Opioid Receptors

Jing-Gen Liu and Paul L. Prather

Department of Pharmacology and Toxicology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas

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 -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 -opioid ligands in GH₃ cells expressing -receptors. In opioid naive cells, -receptors were constitutively active, and a series of -ligands displayed a range of intrinsic activities for G protein activation. Chronic treatment with the full -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-[³⁵S]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 -antagonist (N,N-bisallyl)-Tyr-Gly-Gly--(CH₂S)-Phe-Leu-OH (ICI-154129). Finally, as is also characteristic of inverse agonists, naloxone and naltriben demonstrated higher affinities for uncoupled -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 µ- and -opioid receptors and therefore may serve as an important common mechanism involved the development of tolerance and/or dependence.