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: S Stevens Negus, Robert O'Connell, Ember Morrissey, Kejun Cheng, Kenner C Rice
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 340 Issue 3 Pg. 501-9 (Mar 2012) ISSN: 1521-0103 [Electronic] United States
• PMID: 22128346 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural)

Chemical References

• Diterpenes, Clerodane
• Oligopeptides
• Pyrrolidines
• Receptors, Opioid, kappa
• phenylalanyl-phenylalanyl-norleucyl-argininamide
• ICI 204448
• Ketoprofen
• Flupenthixol
• Cocaine
• salvinorin A

Topics

• Animals
• Behavior, Animal (drug effects)
• Cocaine (pharmacology)
• Diterpenes, Clerodane (pharmacology)
• Flupenthixol (pharmacology)
• Ketoprofen (pharmacology)
• Male
• Oligopeptides (pharmacology)
• Pain (psychology)
• Pyrrolidines (pharmacology)
• Rats
• Rats, Sprague-Dawley
• Receptors, Opioid, kappa (agonists)
• Self Stimulation