title: Maturational alterations in constitutive activity of medial prefrontal cortex kappa-opioid receptors in Wistar rats.
abstract: Opioid receptors can display spontaneous agonist-independent G-protein signaling (basal signaling/constitutive activity). While constitutive κ-opioid receptor (KOR) activity has been documented in vitro, it remains unknown if KORs are constitutively active in native systems. Using [(35) S] guanosine 5'-O-[gamma-thio] triphosphate coupling assay that measures receptor functional state, we identified the presence of medial prefrontal cortex KOR constitutive activity in young rats that declined with age. Furthermore, basal signaling showed an age-related decline and was insensitive to neutral opioid antagonist challenge. Collectively, the present data are first to demonstrate age-dependent alterations in the medial prefrontal cortex KOR constitutive activity in rats and changes in the constitutive activity of KORs can differentially impact KOR ligand efficacy. These data provide novel insights into the functional properties of the KOR system and warrant further consideration of KOR constitutive activity in normal and pathophysiological behavior. Opioid receptors exhibit agonist-independent constitutive activity; however, kappa-opioid receptor (KOR) constitutive activity has not been demonstrated in native systems. Our results confirm KOR constitutive activity in the medial prefrontal cortex (mPFC) that declines with age. With the ability to presynaptically inhibit multiple neurotransmitter systems in the mPFC, maturational or patho-logical alterations in constitutive activity could disrupt corticofugal glutamatergic pyramidal projection neurons mediating executive function. Regulation of KOR constitutive activity could serve as a therapeutic target to treat compromised executive function.
authors.affiliation: Laboratory of Alcoholism and Addictions Neuroscience, Department of Psychology, Washington State University, Pullman, Washington, USA.|Department of Integrative Physiology & Neuroscience, College of Veterinary Medicine, Washington State University, Pullman, Washington, USA.
authors.forename: Sunil
authors.initials: S
authors.lastname: Sirohi
authors.affiliation: Laboratory of Alcoholism and Addictions Neuroscience, Department of Psychology, Washington State University, Pullman, Washington, USA.|Department of Integrative Physiology & Neuroscience, College of Veterinary Medicine, Washington State University, Pullman, Washington, USA.|Graduate Program in Neuroscience, Washington State University, Pullman, Washington, USA.|Translational Addiction Research Center, Washington State University, Pullman, Washington, USA.
authors.forename: Brendan M
authors.initials: BM
authors.lastname: Walker
mesh_terms: D000367:Age Factors; D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D004305:Dose-Response Relationship, Drug; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000494:pharmacology; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000493:pharmacokinetics; D008297:Male; D009271:Naltrexone / Q000031:analogs & derivatives / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D017397:Prefrontal Cortex / Q000000981:diagnostic imaging / Q000187:drug effects / Q000254:growth & development* / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D011877:Radionuclide Imaging; D051381:Rats; D017208:Rats, Wistar; D017473:Receptors, Opioid, kappa / Q000378:metabolism*; D013004:Somatostatin / Q000031:analogs & derivatives / Q000494:pharmacology; D013460:Sulfur Isotopes / Q000493:pharmacokinetics
chemical_list: D000701:Analgesics, Opioid; D009292:Narcotic Antagonists; D017473:Receptors, Opioid, kappa; D013460:Sulfur Isotopes; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; C049352:phenylalanyl-cyclo(cysteinyltyrosyl-tryptophyl-ornithyl-threonyl-penicillamine)threoninamide; C051844:norbinaltorphimine; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D013004:Somatostatin; D009271:Naltrexone
keywords: age; constitutive activity; dynorphin; negative efficacy antagonist; nor-binaltorphimine; κ-opioid receptors