PT  - JOURNAL ARTICLE
AU  - Negus, S. Stevens
AU  - O'Connell, Robert
AU  - Morrissey, Ember
AU  - Cheng, Kejun
AU  - Rice, Kenner C.
TI  - Effects of Peripherally Restricted κ Opioid Receptor Agonists on Pain-Related Stimulation and Depression of Behavior in Rats
AID  - 10.1124/jpet.111.186783
DP  - 2012 Mar 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 501--509
VI  - 340
IP  - 3
4099  - http://jpet.aspetjournals.org/content/340/3/501.short
4100  - http://jpet.aspetjournals.org/content/340/3/501.full
SO  - J Pharmacol Exp Ther2012 Mar 01; 340
AB  - 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-NH2 (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.