The kappa-opioid receptor agonist U50,488H induces acute physical dependence in guinea-pigs.
The present study was undertaken to determine whether acute physical dependence occurred in guinea-pigs in vivo and guinea-pig isolated ileum following a single dose of the kappa-opioid receptor agonist U50,488H. Administration of naloxone hydrochloride, 15 and 30 mg/kg s.c., to guinea-pigs treated 1 h before with U50,488H, 10 mg/kg s.c., induced increased locomotor activity accompanied by behavioural responses which differed from those previously found in this species with morphine withdrawal. Nor-binaltorphimine, 10 mg/kg s.c., given 1 h after administration of U50,488H, 10 mg/kg s.c., produced a small but significant increase in locomotor activity but no other withdrawal behaviours. The morphine withdrawal response was not significantly affected by U50,488H, 1 or 10 mg/kg s.c. On the guinea-pig isolated ileum, nor-binaltorphimine, 1 microM, produced a withdrawal contracture following 2 min contact of the ileum with U50,488H 1 microM. U50,488H, 1 microM, abolished the [Met5]enkephalin withdrawal response of the ileum. It is concluded that dependence occurs following activation of kappa-opioid receptors, which is largely non-morphine-like in the central nervous system, but which is morphine-like in the enteric nervous system.
Brent
P J
PJ
Neuropharmacology Laboratory, Faculty of Medicine, University of Newcastle, NSW, Australia.
Chahl
L A
LA
Cantarell
P A
PA
Kavanagh
C
C
D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D005260:Female; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D009021:Morphine Dependence / Q000503:physiopathology; D009043:Motor Activity / Q000187:drug effects; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D009270:Naloxone / Q000494:pharmacology; D009271:Naltrexone / Q000031:analogs & derivatives / Q000494:pharmacology; D011759:Pyrrolidines / Q000494:pharmacology*; D017473:Receptors, Opioid, kappa / Q000187:drug effects*; D013375:Substance Withdrawal Syndrome / Q000503:physiopathology; D019966:Substance-Related Disorders / Q000209:etiology*
D000701:Analgesics, Opioid; D011759:Pyrrolidines; D017473:Receptors, Opioid, kappa; C051843:binaltorphimine; D009270:Naloxone; D009271:Naltrexone; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer