Effects of peripherally restricted κ opioid receptor agonists on pain-related stimulation and depression of behavior in rats

J Pharmacol Exp Ther. 2012 Mar;340(3):501-9. doi: 10.1124/jpet.111.186783. Epub 2011 Nov 29.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural

MeSH terms

  • 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


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