title: Morphine withdrawal enhances constitutive μ-opioid receptor activity in the ventral tegmental area.
abstract: μ-Opioid receptors (MORs) in the ventral tegmental area (VTA) are pivotally involved in addictive behavior. While MORs are typically activated by opioids, they can also become constitutively active in the absence of any agonist. In the current study, we present evidence that MOR constitutive activity is highly relevant in the mouse VTA, as it regulates GABAergic input to dopamine neurons. Specifically, suppression of MOR constitutive activity with the inverse agonist KC-2-009 enhanced GABAergic neurotransmission onto VTA dopamine neurons. This inverse agonistic effect was fully blocked by the specific MOR neutral antagonist CTOP, which had no effect on GABAergic transmission itself. We next show that withdrawal from chronic morphine further increases the magnitude of inverse agonistic effects at the MOR, suggesting enhanced MOR constitutive activity. We demonstrate that this increase can be an adaptive response to the detrimental elevation in cAMP levels known to occur during morphine withdrawal. These findings offer important insights in the physiological occurrence and function of MOR constitutive activity, and have important implications for therapeutic strategies aimed at normalizing MOR signaling during addiction and opioid overdose.
authors.affiliation: Rudolf Magnus Institute, Department of Neuroscience and Pharmacology, University Medical Center Utrecht, 3584 CG Utrecht, The Netherlands.
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Meye
authors.forename: Ruud
authors.initials: R
authors.lastname: van Zessen
authors.forename: Marten P
authors.initials: MP
authors.lastname: Smidt
authors.forename: Roger A H
authors.initials: RA
authors.lastname: Adan
authors.forename: Geert M J
authors.initials: GM
authors.lastname: Ramakers
mesh_terms: D000262:Adenylyl Cyclases / Q000378:metabolism; D000701:Analgesics, Opioid / Q000009:adverse effects* / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000502:physiology; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000494:pharmacology; D020536:Enzyme Activators / Q000494:pharmacology; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009020:Morphine / Q000009:adverse effects* / Q000494:pharmacology; D011247:Pregnancy; D017450:Receptors, Opioid, mu / Q000187:drug effects / Q000378:metabolism*; D013375:Substance Withdrawal Syndrome / Q000378:metabolism*; D017557:Ventral Tegmental Area / Q000378:metabolism*; D005680:gamma-Aminobutyric Acid / Q000502:physiology
chemical_list: D000701:Analgesics, Opioid; D020536:Enzyme Activators; D017450:Receptors, Opioid, mu; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D005576:Colforsin; D005680:gamma-Aminobutyric Acid; D009020:Morphine; D000242:Cyclic AMP; D000262:Adenylyl Cyclases