title: Nalfurafine prevents 5'-guanidinonaltrindole- and compound 48/80-induced spinal c-fos expression and attenuates 5'-guanidinonaltrindole-elicited scratching behavior in mice.
abstract: The aims of the present study were to establish if nalfurafine, a kappa opioid agonist, inhibits compulsive scratching in mice elicited by the s.c. administration (behind the neck) of 5'-guanidinonaltrindole (GNTI), a kappa opioid antagonist; to assess if nalfurafine prevents c-fos expression provoked by GNTI or compound 48/80, two chemically diverse pruritogens; and to distinguish on the basis of neuroanatomy, those neurons in the brainstem activated by either GNTI-induced itch or formalin-induced pain (both compounds given s.c. to the right cheek). Pretreatment of mice with nalfurafine (0.001-0.03 mg/kg s.c.) attenuated GNTI (0.3 mg/kg)-evoked scratching dose-dependently. A standard antiscratch dose of nalfurafine (0.02 mg/kg) had no marked effect on the spontaneous locomotion of mice. Tolerance did not develop to the antiscratch activity of nalfurafine. Both GNTI and compound 48/80 provoked c-fos expression on the lateral side of the superficial layer of the dorsal horn of the cervical spinal cord and pretreating mice with nalfurafine inhibited c-fos expression induced by both pruritogens. In contrast to formalin, GNTI did not induce c-fos expression in the trigeminal nucleus suggesting that pain and itch sensations are projected differently along the sensory trigeminal pathway. Our data indicate that the kappa opioid system is involved, at least in part, in the pathogenesis of itch; and that nalfurafine attenuates excessive scratching and prevents scratch-induced neuronal activity at the spinal level. On the basis of our results, nalfurafine holds promise as a potentially useful antipruritic in human conditions involving itch.
authors.affiliation: Department of Pharmacology, Temple University School of Medicine, 3420 North Broad Street, Philadelphia, PA 19140, USA. sinan@temple.edu
authors.forename: S
authors.initials: S
authors.lastname: Inan
authors.forename: N J
authors.initials: NJ
authors.lastname: Dun
authors.forename: A
authors.initials: A
authors.lastname: Cowan
mesh_terms: D000344:Afferent Pathways / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D000701:Analgesics, Opioid / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000982:Antipruritics / Q000494:pharmacology* / Q000627:therapeutic use; D015415:Biomarkers / Q000032:analysis / Q000378:metabolism; D004195:Disease Models, Animal; D006146:Guanidines; D008297:Male; D051379:Mice; D009019:Morphinans / Q000494:pharmacology* / Q000627:therapeutic use; D009271:Naltrexone / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors; D009292:Narcotic Antagonists / Q000494:pharmacology; D009619:Nociceptors / Q000187:drug effects / Q000378:metabolism; D010147:Pain Measurement; D020671:Posterior Horn Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000187:drug effects / Q000378:metabolism; D011537:Pruritus / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D017473:Receptors, Opioid, kappa / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000378:metabolism; D011984:Sensory Receptor Cells / Q000187:drug effects / Q000378:metabolism; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D013141:Spiro Compounds / Q000494:pharmacology* / Q000627:therapeutic use; D016896:Treatment Outcome; D003189:p-Methoxy-N-methylphenethylamine / Q000037:antagonists & inhibitors*
chemical_list: C411465:17-cyclopropylmethyl-6,7-didehydro-4,5-epoxy-5'-guanidinyl-3,14-dihydroxyindolo(2',3'-6,7)morphinan; D000701:Analgesics, Opioid; D000982:Antipruritics; D015415:Biomarkers; D006146:Guanidines; D009019:Morphinans; D009292:Narcotic Antagonists; D016760:Proto-Oncogene Proteins c-fos; D017473:Receptors, Opioid, kappa; D013141:Spiro Compounds; C111212:TRK 820; D003189:p-Methoxy-N-methylphenethylamine; D009271:Naltrexone