title: Involvement of kappa opioid receptors in formalin-induced inhibition of analgesic tolerance to morphine in mice.
abstract: This study examined the role of kappa opioid receptors (KOR) in the mechanism underlying tolerance to the analgesic effects of morphine induced by chronic pain. The analgesic effect of morphine (10 mg kg(-1)), estimated by the tail-flick test in mice, gradually decreased during repeated daily morphine treatment. A significant decrease in the analgesic effect of morphine was seen on the fifth day of repeated morphine treatment compared with the first day. Chronic pain was induced by subcutaneous administration of 2% formalin into the dorsal part of the left hind paw, which significantly inhibited development of tolerance to morphine analgesia. The effect of formalin-induced pain on inhibition of morphine tolerance was reversed by the KOR antagonist nor-binaltorphimine. Furthermore, an antisense oligodeoxynucleotide, but not a missense oligodeoxynucleotide, against KOR completely suppressed the inhibitory effect of formalin-induced pain on morphine tolerance. Naltrindole, an antagonist of delta opioid receptor, did not affect chronic-pain-induced tolerance to morphine. Our findings show that the inhibitory effect of chronic pain on analgesic tolerance to morphine is mediated by KOR rather than delta opioid receptors.
authors.affiliation: Department of Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Kobe Gakuin University, 1-1-3, Minatojima, Chuo-ku, Kobe, 650-8586, Japan. stoku@pharm.kobegakuin.ac.jp
authors.forename: Shogo
authors.initials: S
authors.lastname: Tokuyama
authors.forename: Ryuji
authors.initials: R
authors.lastname: Nagae
authors.forename: Emiko
authors.initials: E
authors.lastname: Mashida
authors.forename: Wakako
authors.initials: W
authors.lastname: Hamabe
mesh_terms: D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer / Q000494:pharmacology; D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D002908:Chronic Disease; D004361:Drug Tolerance; D005557:Formaldehyde / Q000494:pharmacology; D008297:Male; D051379:Mice; D009020:Morphine / Q000008:administration & dosage / Q000494:pharmacology*; D009271:Naltrexone / Q000031:analogs & derivatives / Q000494:pharmacology; D016376:Oligonucleotides, Antisense; D010146:Pain / Q000139:chemically induced / Q000188:drug therapy*; D010147:Pain Measurement; D017288:Pain Threshold; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa / Q000187:drug effects* / Q000378:metabolism; D013623:Tail
chemical_list: D000701:Analgesics, Opioid; D016376:Oligonucleotides, Antisense; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D005557:Formaldehyde; C051844:norbinaltorphimine; D009271:Naltrexone; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D009020:Morphine; C055382:naltrindole