title: Effects of peripherally restricted κ opioid receptor agonists on pain-related stimulation and depression of behavior in rats.
abstract: κ opioid receptor agonists that do not readily cross the blood-brain barrier are peripherally restricted and distribute poorly to the central nervous system after systemic administration. Peripherally restricted κ agonists have promise as candidate analgesics, because they may produce antinociception mediated by peripheral κ receptors more potently than they produce undesirable sedative and psychotomimetic effects mediated by central κ receptors. The present study used assays of pain-related stimulation and depression of behavior in rats to compare effects of 1) two peripherally restricted κ agonists [the tetrapeptide D-Phe-D-Phe-D-Ile-D-Arg-NH(2) (ffir) and the nonpeptidic compound ((R,S)-N-[2-(N-methyl-3,4-dichlorophenylacetamido)-2-(3-carboxyphenyl)-ethyl]pyrrolidine hydrochloride (ICI204448)], 2) a centrally penetrating κ agonist (salvinorin A), and 3) several reference drugs, including a nonsteroidal anti-inflammatory drug (NSAID; ketoprofen). Intraperitoneal injection of dilute lactic acid served as a noxious stimulus to stimulate a stretching response and depress intracranial self-stimulation (ICSS) maintained by the delivery of electrical brain stimulation to the medial forebrain bundle. Acid-stimulated stretching was blocked by ketoprofen, the peripherally restricted κ agonists, and salvinorin A. However, acid-induced depression of ICSS was blocked only by ketoprofen. The peripherally restricted κ agonists had little effect, and salvinorin A exacerbated acid-induced depression of ICSS. These results suggest that peripherally restricted κ agonists may be safer than centrally penetrating κ agonists but less efficacious than NSAIDS or μ opioid receptor agonists to block pain-related depression of behavior; however, the peripheral selectivity of ffir and ICI204448 is limited, and future studies with κ agonists capable of greater peripheral selectivity are warranted.
authors: Department of Pharmacology and Toxicology, Virginia Commonwealth University, 410 N. 12th Street, Richmond, VA 23220, USA. ssnegus@vcu.edu
authors: S Stevens
authors: SS
authors: Negus
authors: Robert
authors: R
authors: O'Connell
authors: Ember
authors: E
authors: Morrissey
authors: Kejun
authors: K
authors: Cheng
authors: Kenner C
authors: KC
authors: Rice
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D003042:Cocaine / Q000494:pharmacology; D045785:Diterpenes, Clerodane / Q000494:pharmacology; D005475:Flupenthixol / Q000494:pharmacology; D007660:Ketoprofen / Q000494:pharmacology; D008297:Male; D009842:Oligopeptides / Q000494:pharmacology; D010146:Pain / Q000523:psychology*; D011759:Pyrrolidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017473:Receptors, Opioid, kappa / Q000819:agonists*; D012653:Self Stimulation
chemical_list: D045785:Diterpenes, Clerodane; D009842:Oligopeptides; D011759:Pyrrolidines; D017473:Receptors, Opioid, kappa; C489140:phenylalanyl-phenylalanyl-norleucyl-argininamide; C060223:ICI 204448; D007660:Ketoprofen; D005475:Flupenthixol; D003042:Cocaine; C090499:salvinorin A