title: Analgesic and mechanistic evaluation of spiradoline, a potent kappa opioid.
abstract: Spiradoline (a congener of the kappa opioid agonist, U-50488H) was evaluated for analgesic and related activities in rodents. In nine antinociceptive assays utilizing various thermal, pressure and chemical and physical irritants, the potency of spiradoline ranges from 4.7 to 23 (mean = 13) times that of U-50488H. Naloxone blocks the analgesic effect of spiradoline. The in vivo naloxone pA2 for this antagonism is much lower than that for the antagonism of morphine and approximates that of U-50488H. The analgesic potency of spiradoline is greatly reduced in mice made tolerant to U-50488H but not in those made tolerant to morphine. Repeated treatment with spiradoline does not induce physical dependence as evidenced by a lack of naloxone-precipitated jumping and withdrawal-induced hyperalgesia. In sum, these observations suggest that spiradoline is a potent kappa agonist analgesic. However, further evaluation of spiradoline revealed differences between this compound and U-50488H. We have previously shown that the analgesic effect of the latter compound, but not that of morphine, is profoundly antagonized by reserpine or p-chlorophenylalanine. In contrast, spiradoline is only marginally antagonized by these serotonin-depleting treatments. Evaluation of the enantiomers of spiradoline revealed that the (-)-enantiomer is more than 30 times as potent as the (+)-enantiomer in analgesic tests. The (-)-enantiomer is similar to U-50488H with regard to antagonism by p-chlorophenylalanine, lack of physical dependence-inducing properties and cross-tolerance. In contrast the (+)-enantiomer induces physical dependence and displays marked cross-tolerance in morphine-tolerant mice.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Upjohn Company, Central Nervous System Diseases Research, Kalamazoo, Michigan.
authors.forename: P F
authors.initials: PF
authors.lastname: Vonvoigtlander
authors.forename: R A
authors.initials: RA
authors.lastname: Lewis
mesh_terms: D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D004361:Drug Tolerance; D005260:Female; D010134:Fenclonine / Q000494:pharmacology; D008297:Male; D051379:Mice; D009020:Morphine / Q000494:pharmacology; D009270:Naloxone / Q000494:pharmacology; D011759:Pyrrolidines / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D011957:Receptors, Opioid / Q000378:metabolism*; D017473:Receptors, Opioid, kappa
chemical_list: D000700:Analgesics; D011759:Pyrrolidines; D011957:Receptors, Opioid; D017473:Receptors, Opioid, kappa; D009270:Naloxone; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D009020:Morphine; C051272:spiradoline; D010134:Fenclonine