title: Spinal antinociceptive actions and naloxone reversibility of intravenous mu- and kappa-opioids in spinalized rats: potency mismatch with values reported for spinal administration.
abstract: 1. The relative spinal effectiveness of mu- and kappa-opioids has been assessed by their intravenous potencies on nociceptive responses (heat and/or pinch) of single motoneurones recorded in alpha-chloralose anaesthetized, spinalized rats. 2. The depressant actions of both mu- and kappa-opioids were reversed by low intravenous doses of naloxone (10 to 100 micrograms kg-1). When tested at a dose of 1 microgram kg-1 i.v., naloxone antagonized the effects of the mu-agonist morphine but had no effect on the kappa-opioid U-50,488. This provides further support for the theory that the actions of mu- and kappa-ligands were mediated at different subclasses of opioid receptor but highlights the difficulties in using antagonists with poor receptor selectivity to differentiate between mu- and kappa-receptor-mediated effects in vivo. 3. The molar potency rations of fentanyl: morphine:U-50,488: tifluadom for thermal and mechanical nociceptive responses were 620: 1.0:0.74:5.7 and 520:1.0:0.56:7.7 respectively. These potency ratios, as well as the absolute potencies, agree well with those reported in several behavioural studies in which systemic administration of agonists was used in non-thermal tests. 4. The agonist potency values obtained in this study contrast with those reported for local spinal administration. By this route, the potency of lipophilic opioids (e.g. fentanyl, U-50,488 and tifluadom) relative to hydrophilic opioids (e.g. morphine) is much reduced, implying that activity of intrathecally administered opioids is more dependent on the physico-chemical properties of the agonists used than on the relative abundance in the spinal cord of functional opioid receptors of the mu- and kappa-subtypes. This conclusion indicates that the results with locally applied opioids should not be used to assess spinal opioid receptor function.
authors.affiliation: Department of Physiology, School of Medical Sciences, University of Bristol.
authors.forename: C G
authors.initials: CG
authors.lastname: Parsons
authors.forename: D C
authors.initials: DC
authors.lastname: West
authors.forename: P M
authors.initials: PM
authors.lastname: Headley
mesh_terms: D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D000700:Analgesics; D000818:Animals; D001569:Benzodiazepines / Q000494:pharmacology; D003655:Decerebrate State; D004594:Electrophysiology; D006358:Hot Temperature; D007267:Injections; D009270:Naloxone / Q000494:pharmacology*; D009294:Narcotics / Q000008:administration & dosage / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects; D010146:Pain / Q000503:physiopathology; D011759:Pyrrolidines / Q000494:pharmacology; D051381:Rats; D011957:Receptors, Opioid / Q000502:physiology*; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D012018:Reflex / Q000187:drug effects; D013116:Spinal Cord / Q000187:drug effects*
chemical_list: D000700:Analgesics; D009294:Narcotics; D011759:Pyrrolidines; D011957:Receptors, Opioid; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D001569:Benzodiazepines; D009270:Naloxone; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; C035470:tifluadom