title: Subcutaneous, intrathecal and periaqueductal grey administration of asimadoline and ICI-204448 reduces tactile allodynia in the rat.
abstract: The purpose of this study was to assess the possible antiallodynic effect of asimadoline ([N-methyl-N-[1S)-1-phenyl)-2-(13S))-3-hydroxypyrrolidine-1-yl)-ethyl]-2,2-diphenylacetamide HCl]) and ICI-20448 ([2-[3-(1-(3,4-Dichlorophenyl-N-methylacetamido)-2-pyrrolidinoethyl)-phenoxy]acetic acid HCl]), two peripheral selective kappa opioid receptor agonists, after subcutaneous, spinal and periaqueductal grey administration to neuropathic rats. Twelve days after spinal nerve ligation tactile allodynia was observed, along with an increase in kappa opioid receptor mRNA expression in dorsal root ganglion and dorsal horn spinal cord. A non-significant increase in periaqueductal grey was also seen. Subcutaneous (s.c.) administration of asimadoline and ICI-204448 (1-30 mg/kg) dose-dependently reduced tactile allodynia. This effect was partially blocked by s.c., but not intrathecal, naloxone. Moreover, intrathecal administration of asimadoline or ICI-204448 (1-30 mug) reduced tactile allodynia in a dose-dependent manner and this effect was completely blocked by intrathecal naloxone. Microinjection of both kappa opioid receptor agonists (3-30 mug) into periaqueductal grey also produced a naloxone-sensitive antiallodynic effect in rats. Our results indicate that systemic, intrathecal and periaqueductal grey administration of asimadoline and ICI-204448 reduces tactile allodynia. This effect may be a consequence of an increase in kappa opioid receptor mRNA expression in dorsal root ganglion, dorsal horn spinal cord and, to some extent, in periaqueductal grey. Finally, our data suggest that these drugs could be useful to treat neuropathic pain in human beings.
authors.affiliation: Departamento de Farmacobiología, Centro de Investigación y de Estudios Avanzados, Sede Sur, México, D.F., Mexico.
authors.forename: Nadia L
authors.initials: NL
authors.lastname: Caram-Salas
authors.forename: Gerardo
authors.initials: G
authors.lastname: Reyes-García
authors.forename: Gerd D
authors.initials: GD
authors.lastname: Bartoszyk
authors.forename: Claudia I
authors.initials: CI
authors.lastname: Araiza-Saldaña
authors.forename: Mónica
authors.initials: M
authors.lastname: Ambriz-Tututi
authors.forename: Héctor I
authors.initials: HI
authors.lastname: Rocha-González
authors.forename: Rosaura
authors.initials: R
authors.lastname: Arreola-Espino
authors.forename: Silvia L
authors.initials: SL
authors.lastname: Cruz
authors.forename: Vinicio
authors.initials: V
authors.lastname: Granados-Soto
mesh_terms: D000081:Acetamides / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D005260:Female; D007278:Injections, Spinal; D007279:Injections, Subcutaneous; D008026:Ligation / Q000009:adverse effects / Q000379:methods; D008160:Lumbosacral Plexus / Q000293:injuries; D008297:Male; D009270:Naloxone / Q000008:administration & dosage / Q000494:pharmacology; D017288:Pain Threshold / Q000187:drug effects; D010487:Periaqueductal Gray / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D010523:Peripheral Nervous System Diseases / Q000235:genetics / Q000503:physiopathology / Q000517:prevention & control; D011759:Pyrrolidines / Q000008:administration & dosage / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D017473:Receptors, Opioid, kappa / Q000819:agonists / Q000235:genetics / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020886:Somatosensory Disorders / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D013997:Time Factors
chemical_list: D000081:Acetamides; D011759:Pyrrolidines; D012333:RNA, Messenger; D017473:Receptors, Opioid, kappa; C060223:ICI 204448; D009270:Naloxone; C092095:asimadoline